[ CAS No. 35654-56-9 ] {[proInfo.proName]}

Name: 35654-56-9|4-Chloro-6,7-dimethoxyquinoline|98%
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SKU: A159010
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Quality Control of [ 35654-56-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 35654-56-9 ]

Product Details of [ 35654-56-9 ]

CAS No. :	35654-56-9	MDL No. :	MFCD07778437
Formula :	C₁₁H₁₀ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WRVHQEYBCDPZEU-UHFFFAOYSA-N
M.W :	223.66	Pubchem ID :	459610
Synonyms :

Calculated chemistry of [ 35654-56-9 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.18
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	59.74
TPSA :	31.35 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.48
Log Po/w (XLOGP3) :	2.76
Log Po/w (WLOGP) :	2.91
Log Po/w (MLOGP) :	1.72
Log Po/w (SILICOS-IT) :	3.05
Consensus Log Po/w :	2.58

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.33
Solubility :	0.105 mg/ml ; 0.000471 mol/l
Class :	Soluble
Log S (Ali) :	-3.07
Solubility :	0.189 mg/ml ; 0.000844 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.58
Solubility :	0.0059 mg/ml ; 0.0000264 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 35654-56-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 35654-56-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 35654-56-9 ]
Downstream synthetic route of [ 35654-56-9 ]

[ 35654-56-9 ] Synthesis Path-Upstream 1~21

1
[ 13425-93-9 ]
[ 35654-56-9 ]

Yield	Reaction Conditions	Operation in experiment
82.7%	With trichlorophosphate In toluene at 115℃; for 1 h;	To a suspension of 6,7-dimethoxyquinolin-4-ol (45 g, 0.22 mol) in toluene (100 mL) was added phosphoryl trichloride (60 mL, 0.66 mol, Tianjin FuChen Chem. Co. Ltd.). The reaction was heated to 115 °C for 1 hour and then cooled down to rt. The mixture was diluted with EtOAc (400 mL), and the pH of the solution was adjusted to 7-8 with 3 M NaOH aqueous solution. The resulted mixture was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na₂S0₄ and concentrated in vacuo to give the title compound as a pale yellow solid (40.5 g, 82.7percent). MS (ESI, pos. ion) m/z: 224.0 [M+H]⁺; *H NMR (400 MHz, CDC1₃): δ 4.05 (s, 3H), 4.06 (s, 3H), 7.27 (s, 1H), 7.35 (d, J= 4.8 Hz, 1H), 7.41 (s, 1H), 7.42 (s, 1H), 8.57 (d, J= 4.8 Hz, 1H)
78%	at 100℃; for 6 h;	A solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100°C for 6 h. Most of the solvent was recovered under vacuum. The residue was added slowly to cooled water 500 mL and adjusted with 10percent K2CO3 to pH ~ 9, and stirred for another 1 h. The resulting solid was filtrated, washed with H2O (50 mL × 2), and dried at 55°C for 4 h to give 7 (41.8 g, 78percent) as a light brown solid; mp 130.2-131.4° C (Lit.13 130−131 C). 1H NMR (400 MHz, DMSO-d6): δ 3.96 (s, 3H),3.97 (s, 3H), 7.35 (s, 1H), 7.44(s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H). MS (ESI): m/z =223.2 [M + H]+, 245.2 [M + Na]+.
55%	at 125℃; for 2 h;	6,7-Dimethoxyquinolin-4-ol (0.64g) was dissolved in net POCI3 (3 mL). The solution was heated to 125°C for 2 h. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with sat. NaHC03 (aq) and then extracted with EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using 10No.20percent methanol/EtOAc to give 4-chloro-6,7-dimethoxyquinoline (0.38 g, 55percent yield) ; ¹H NMR (400 MHz, CHCI3- d) 6 ppm 4.04 (s, 3 H) 4.06 (s, 3 H) 7.35 (d, J=5.1 Hz, 1 H) 7.40 (s, 1 H) 7.42 (s, 1 H) 8.57 (d, J=4.8 Hz, 1 H).

43.4%	With trichlorophosphate In N,N-dimethyl-formamide for 4 h; Heating / reflux	To a mixture 6,7-dimethoxyquinolin-4-ol (Intermediate A, Step 2, 245 mg, 1.2 mmol) in phosphorus oxychloride (10 ml_) was added DMF (0.1 ml_). The reaction was heated at reflux for 4 h, then cooled to rt and concentrated under reduced pressure. The residue was dissolved with ethyl acetate, and the organic solution was washed successively with NaHCψ₃ (saturated aqueous solution) and water, dried (Na₂SO₄), filtered and concentrated under reduced pressure to give 116 mg (43.4percent) of title compound, which was taken onto next step without further purification.
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 70℃; Large scale	Preparation of 4-Chloro-6,7-dimethoxy-quinoline[0059] A reactor was charged sequentially with 6,7-dhnethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl₃, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77°C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ??,?? (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
8.0 kg	With trichlorophosphate In acetonitrile at 80℃; for 9 h; Large scale	A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 °C and phosphorus oxychloride (POCb, 50.0 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 80 °C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 °C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30percent ΝΗ,ΟΗ (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 °C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 °C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 °C to afford the title compound (8.0 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	[00119] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl₃, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77°C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	Preparation of 4-Chloro-6,7-dimethoxy-quinoline [00114] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCl₃, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	A reactor was charged sequentially with 6,7-dimemoxy-quinoline-4— ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	A reactor was charged sequentially with 6,7—dimethoxy—quinoline—4—ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCi3, 130.6 kg) was added. After the addition of POCi3, the temperature of the reaction mixture was raised to approximatey 77 °C. The reaction was deemed compiete (approximatey 13 hours) when less than 3percent of the starting materia remained, as measured by in-process bigh-performance liquid cbromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a cbilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resultmg mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyfio super-cel NF (Celite; 5.4 kg), and the futer bed was washed with DCM (118.9 kg). The combined organic phase was washed with brnie (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by yacuum distillation with the remoyal of solyent (approximately 95 L residual yolume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by yacuum distiliation with the remoyal of soiyent (approximateiy 90 L residual yolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to —20 to —25 °C and heid for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a futer at approximately 25 °C under rtrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	[00264] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphonas oxychioride (POd3, 130.6 kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-2 5 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NP (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase wasconcentrated by vacuum distillation with the removal of solvent (approximateLy 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 77℃; for 13 h; Large scale	Fool 13] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POC13, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLCJ analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).
35.6 kg	Stage #1: at 60℃; Large scale Stage #2: at 77℃; for 13 h; Large scale	A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCl₃, 130.6 kg) was added. After the addition of POCl₃, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 - 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH₄OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 - 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-eel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	10096] A reactor was charged sequentially with 6,7- dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POC13, 130.6kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when <3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7° C. and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cd NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to —20 to —25° C. and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate In acetonitrile at 60 - 77℃; for 13 h; Large scale	The 6,7-dimethoxy-quinolin-4-ol (47.0 kg) and acetonitrile (318.8 kg) are sequentially added into the reactor. The resulting mixture is heated to about 60 °C, and add phosphorus acyl chlorine (POCl₃, 130.6 kg). Adding POCl₃the rear, the temperature of the reaction mixture the climbs to approximately 77 °C. When there is less than 3percent of the starting material (in the process for preparing the high performance liquid chromatography [HPLC] analysis), then the reaction as complete (about 13 hours). Cooling the reaction mixture to about 2-7°C, then the dichloromethane (DCM, 482.8 kg), 26percent NH₄OH (251.3 kg) and water (900 L) quenching of the frozen solution. The resulting mixture is heated to about 20-25°C, and separation phase. Silicon, organic AW is passes through NF (Celite^TM; 5.4 kg) bed filter, and the filter bed in a DCM (118.9 kg) washing. Combined organic phase with the saline (282.9 kg) washing with water (120 L) mixing. Separation-phase, and the vacuum distilling to concentrate the organic phase in order to remove the solvent (about 95 L of the residual volume). The DCM (686.5 kg) is added in the reactor containing organic phase and carry out vacuum distillation and condensation in order to remove the solvent (about 90 L of the residual volume). Furthermore, by adding methyl 3rd-butyl ether (MTBE, 226.0 kg), and the mixture temperature is adjusted to -20 to -25 ° C and keep 2.5 hours, form a solid precipitate, then filtered and with n-heptane (92.0 kg) washing and about 25 °C lower, in the nitrogen, is dried in the filter in order to obtain the title compound (35.6 kg).
8.0 kg	With trichlorophosphate In acetonitrile at 65 - 80℃; for 0.9 h; Large scale	Preparation of 4-Chloro-6,7-dimethoxy-quinoline A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 °C and phosphorus oxychloride (POCl₃, 50.0 kg) was added. After the addition of POCl₃, the temperature of the reaction mixture was raised to approximately 80 °C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 °C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30percent NH₄OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 °C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 °C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 °C to afford the title compound (8.0 kg).
1775.9 g	With thionyl chloride In N,N-dimethyl acetamide at 100 - 120℃; Large scale	1.65 kg (13.9 mol) of thionyl chloride was added dropwise to a solution containing 2.2 kg (10.72 mol)4-hydroxy-6,7-dimethoxyquinoline in 5.3 L (57 mol) solution of N, N-dimethylacetamide was added and heated to 100 to 120 ° C for 4 to 7 hours (when HPLC Indicating that the feed is less than 3percent unreacted as the reaction is complete). After the reaction was cooled to room temperature, was added 2.2L of ice water, with 30percent sodium hydroxide solution to PH = 7 ~ 8, and a temperature controlled at 25 . And after completion, stirring was continued for 1 hour, sufficiently precipitate solid particles, was filtered; the cake was washed twice with 1L of water, and dried at 60 ~ 70 , to give a yellowish white powder of 4-chloro-6,7-dimethoxy-quinoline 1775.9 g, molar yield 74.2percent
35.6 kg	With trichlorophosphate In acetonitrile at 77℃; for 13 h; Large scale	A reactor was charged sequentially with 6,7-dimethoxyquinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by [00841 A reactor was charged sequentially with 6,7—dimethoxy—quinoline—4—oI (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by
35.6 kg	With trichlorophosphate In acetonitrile at 0.6 - 0.77℃; for 13 h; Large scale	[00166] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxy chloride (POCb, 130.6 kg) was added. After the addition of POCb, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH₄OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).

Reference： [1] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0170
[2] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887
[3] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 41-42
[4] Patent: WO2008/48375, 2008, A1, . Location in patent: Page/Page column 49
[5] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[6] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
[8] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 172
[9] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2892 - 2901
[10] Patent: WO2010/83414, 2010, A1, . Location in patent: Page/Page column 24 - 25
[11] Patent: WO2012/109510, 2012, A1, . Location in patent: Page/Page column 27-28
[12] Patent: WO2013/59788, 2013, A1, . Location in patent: Paragraph 0059
[13] Patent: WO2013/43840, 2013, A1, . Location in patent: Paragraph 00111-00112
[14] Patent: WO2013/70890, 2013, A1, . Location in patent: Paragraph 00118-00119
[15] Patent: WO2013/166296, 2013, A1, . Location in patent: Paragraph 00114
[16] Patent: WO2014/165786, 2014, A1, . Location in patent: Paragraph 00196
[17] Patent: WO2014/165779, 2014, A1, . Location in patent: Paragraph 0077; 0078; 0079
[18] Patent: WO2015/164869, 2015, A1, . Location in patent: Paragraph 00263; 00264
[19] Patent: WO2016/22697, 2016, A1, . Location in patent: Paragraph 00111; 00112; 00113
[20] Patent: WO2016/19285, 2016, A1, . Location in patent: Paragraph 0095; 0096
[21] Patent: US2016/772, 2016, A1, . Location in patent: Paragraph 0095; 0096
[22] Patent: TWI516477, 2016, B, . Location in patent: Page/Page column 31; 32
[23] Patent: EP2758057, 2017, B1, . Location in patent: Paragraph 0107
[24] Patent: CN103664778, 2017, B, . Location in patent: Paragraph 0054-0058
[25] Patent: WO2018/136796, 2018, A1, . Location in patent: Paragraph 0081; 0082; 0083; 0084
[26] Patent: WO2018/227119, 2018, A1, . Location in patent: Paragraph 00163; 00164; 00165-00166

2
[ 127285-54-5 ]
[ 35654-56-9 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	With trichlorophosphate In toluene for 1 h; Heating / reflux	(4) Step of chlorination: Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6,7-dimethoxy-4-quinolone (1056 g), and the mixture was heated under reflux with stirring for one hr. The reaction solution was neutralized with an aqueous sodium hydroxide solution at 0°C. The resultant precipitate was collected by filtration and was slurried in water (10 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 4-chloro-6,7-dimethoxyquinoline (928 g, yield 87.6percent). ¹H-NMR (400 MHz, DMSO-d₆/ppm); δ 3.95 (s, 3H), 3.96 (s, 3H), 7.35 (s, 1H), 7.43 (s, 1H), 7.54 (d, 1H), 8.59 (d, 1H)
60%	at 130℃; for 1 h;	A mixture of 1 (1.0 g, 4.9 mmol) and POCl3 (0.68 mL, 7.3mmol) was heated at 130 °C (bath) for 1 h. The resulting liquid was allowed to cool and was stirred with CH2Cl2 (10 mL) and aqueous NH3 (25percent; 10 mL). The organic layer was washed with H2O (10 mL), dried over MgSO4 and the solvent removed. The residue was dissolved in a mixture of t-BuOMe (5 mL) and CH2Cl2 (2 mL) at 50 °C (bath), and the solution was kept at –30 °C overnight. The resulting crystals were collected and dried (0.65 g, 60percent); mp. 132–133 °C (lit.15,19 130–131 °C); IR (neat): 1470, 1221, 1139,1006, 853 cm–1; 1H NMR (300 MHz, CDCl3) δ 4.02 (s, 3H), 4.03 (s, 3H), 7.33 (d, J = 4.9 Hz, 1H), 7.36 (s,1H), 7.42 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 56.4, 56.5, 101.9, 108.1, 119.8,122.3, 140.9, 146.1, 147.4, 151.0, 153.4; HRMS (FAB) m/z 224.0434 (calcd 224.0473 for C11H11NO2Cl,[M+H]+).
35%	Stage #1: for 1 h; Heating / reflux Stage #2: With ammonium hydroxide In water	Step 2: 4-Chloro-6,7-dimethoxyquinoline (4) A suspension of the quinolone 3 (6.54 g, 31.9 mmol) in SOCl₂ (70 ml) and DMF (cat) was heated to reflux for 1 hr. The reaction mixture was cooled to room temperature and concentrated. The residue was basified with NH₄OH solution and then extracted with DCM. The extract was dried over anhydrous Na₂SO₄, filtered then concentrated. The residue was purified by column chromatography (eluent a gradient of 20percent EtOAc/hexane to 100percent EtOAc) to afford title compound 4 (2.5 g, 35percent yield) as a brown solid. LRMS (M+1): 224.1 (75percent)/226.1 (25percent).

Reference： [1] Patent: EP1559715, 2005, A1, . Location in patent: Page/Page column 19
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[3] Heterocycles, 2016, vol. 93, # 1, p. 323 - 332
[4] Patent: US2008/4273, 2008, A1, . Location in patent: Page/Page column 61
[5] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[6] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 23, p. 2935 - 2940
[7] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 3, p. 755 - 758
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[9] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4242 - 4251
[10] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0213-0216

3
[ 67000-01-5 ]
[ 35654-56-9 ]

Reference： [1] Patent: US2012/70368, 2012, A1,

4
[ 6315-89-5 ]
[ 35654-56-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[4] Patent: WO2013/180949, 2013, A1,
[5] Patent: WO2005/121125, 2005, A1,

5
[ 13425-93-9 ]
[ 67000-01-5 ]
[ 35654-56-9 ]

Reference： [1] Patent: US2012/252840, 2012, A1,

6
[ 13425-93-9 ]
[ 1634-04-4 ]
[ 96042-30-7 ]
[ 35654-56-9 ]

Reference： [1] Patent: US2012/252840, 2012, A1,

7
[ 13436-14-1 ]
[ 35654-56-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[3] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 3, p. 755 - 758
[4] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 23, p. 2935 - 2940

8
[ 26893-22-1 ]
[ 35654-56-9 ]

9
[ 26717-39-5 ]
[ 35654-56-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[2] Patent: WO2005/121125, 2005, A1,

10
[ 4101-30-8 ]
[ 35654-56-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[2] Patent: CN103739550, 2016, B,

11
[ 13436-14-1 ]
[ 35654-56-9 ]

Reference： [1] Journal of the American Chemical Society, 1946, vol. 68, p. 1264
[2] Patent: WO2005/121125, 2005, A1,

12
[ 26893-22-1 ]
[ 35654-56-9 ]

Reference： [1] Journal of the American Chemical Society, 1946, vol. 68, p. 1264

13
[ 213699-53-7 ]
[ 35654-56-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
[2] Patent: WO2013/180949, 2013, A1,

14
[ 1131-62-0 ]
[ 35654-56-9 ]

Reference： [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887

15
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[ 35654-56-9 ]

Reference： [1] Heterocycles, 2016, vol. 92, # 10, p. 1882 - 1887

16
[ 35654-56-9 ]
[ 666734-51-6 ]

Reference： [1] Patent: CN104788372, 2018, B, . Location in patent: Paragraph 0136; 0137

17
[ 35654-56-9 ]
[ 123-30-8 ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
83.6%	With sodium methylate In dimethyl sulfoxide at 90℃; for 9 h;	4-Chloro-6,7-dimethoxyquinoline (35.3 g, 157.8 mmol) andSodium methoxide (12.1 g, 224 mmol) was addedDimethyl sulfoxide (200 ml). 4-Aminophenol (20.67 g, 189.4 mmol)In dimethylsulfoxide (150 ml) was addedIn the reaction solution, the reaction solution was reacted at 90 ° C for 9 hours, cooled to room temperature, poured into 1600 ml of ice water, and added with 100 mlEthyl acetate, filtered and dried under reduced pressure to give 4 - [(6,7-dimethoxyquinolin-4-yl) oxy] aniline (39.1 g, yield:83.6percent).
74.6%	Stage #1: With sodium hydride In dimethyl sulfoxide at 20℃; for 0.166667 h; Stage #2: at 100℃; for 3 h;	For 100 ml is added to a round bottom flask NaH (3.3g, 82 . 5mmol) and anhydrous DMSO, after fully stirring, add the aminophenol (6g, 55mmol), stirring the mixture at room temperature for 10 min, then add 4-chloro-6,7-dimethoxy quinoline (12.3g, 55 . 1mmol) in the 100 degrees stirring 3h, TLC monitoring, after the reaction, water, chloroform extraction, the extraction liquid to be grey solid 12.2g, yield 74.6percent.
74.8%	at 100℃; for 9 h;	To a 1L three-necked flask was added 4-chloro-6,7-dimethoxy-quinoline 35. 3g (157. 8mmol), sodium tert-butoxide21.4g (224. Lmmol) and N,N-dimethylacetamide 200ml, stirred for standby.The N, N- dimethylacetamide 200ml 4-aminophenol with 24. 5g (224. Lmmol) mixed, added to the aboveAlternate reaction solution was added dropwise to control the temperature less than 25 ° C, the dropwise addition, temperature was raised to 100 ° C, the reaction nine hours, the reaction was stopped,Cooling to 15~20 ° C, the reaction mixture was poured into 1600ml ice water, controlling the temperature 15~30 ° C, was added 100ml ethyl Esters, solid separated stirring, suction filtered, the solid washed with ethyl acetate lml, blast drying at 40 ° C for 12 hours to give a brown solid 35g (74. 8percent)

61%	With caesium carbonate In dimethyl sulfoxide at 100℃; for 18 h;	A suspension of 4-chloro-6, 7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol) and cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) <n="221"/>was stirred at 100⁰C for 18 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran (=1/1) . ^.bul. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methyl acetate/methanol=60/40) . Ethyl acetate was added to the obtained residue and the mixture was filtrated to give the title compound (1267 mg, 61percent) as a white powder.¹H-NMR (DMSO-d₆, 300 MHz) δ 3.93 (6H, s) , 5.16 (2H, s) , 6.37 (IH, d, J = 5.4 Hz), 6.67 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J= 8.7 Hz), 7.36 (IH, s) , 7.50 (IH, s), 8.43 (IH, d, J = 5.4Hz) .
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 100 - 105℃; for 13 h; Large scale	4-Aminophenol (24.4 kg) dissolved in Ν,Ν-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately Ihour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF ( 147.6 kg) and dried on a filter under vacuum at approximately 25 "C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h; Large scale	[00120] 4-Aminophenol (24.4 kg) dissolved in Ν,Ν-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 °C. This mixture was then heated to 100 - 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2percent starting material remaining), the reactor contents were cooled at 15 to 20 °C and water (pre-cooled, 2 to 7 °C, 587 L) charged at a rate to maintain 15 to 30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7 -dimethoxy-quinoline- 4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour and then cooled to 0 to 5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 100 - 105℃; for 13 h; Large scale	Preparation of 4—(6, 7 —Dimethoxy_quinoline_4_yloxy)....phenylamjne [00115] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0—5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylam me (34.0 kg).
34 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h; Large scale	4-Aminophenol (24.4 kg) dissolved in Ν,Ν-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 °C. This mixture was then heated to 100 - 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2percent starting material remaining), the reactor contents were cooled at 15 to 20 °C, and water (pre-cooled, 2 to 7 °C, 587 L) was charged at a rate to maintain 15 to 30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 ^imethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 °C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 °C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).
34 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 100 - 105℃; for 13 h; Large scale	4-Aminophenol (24.4 kg) dissolyed in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg), and DMA (167.2 kg) at 20—25 °c. This mixture was then heated to 100— 105 °c for approximately 13 hours. After the reaction was deemed complete as determmed using in-process HPLC analysis (less than 2percent starting materia remaining), the reactor contents were cooled at 15 to 20 °c, and water (pre-cooled, 2 to 7 °c, 587 L) was charged at a rate to maintain 15 to 30 °c temperature. The resulting solid precipitate was fultered, washed with a mixture of water (47 L) and DMA (89.1 kg), and fmally washed with water (214 L). The futer cake was then dried at approximately 25 °C on futer to yield crude 4—(6, 7— dimethoxy—quinoline--1---yloxy)—phenylamine (59.4 kg wet, 41.6 kg di3” calculated based on limit of detection, hereinafter LOD”). Crude 4—(6, 7 —dimethoxy—quinoline—4—yloxy)— phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 2 11.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to O to 5 °C, and aged for approximately 1 hour, after which time the solid was fultered, washed with THF (147.6 kg), and dried on a futer under yacuum at approximatey 25 °c to yield 4—(6, 7 —dimethoxy— quinoline—4—yloxy)—phenylamine (3 4.0 kg).
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h;	Preparation of 4—(6, 7 —Dimethoxy--quinoline-4—yloxy)—phenylamiue[002651 4-Antinophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100-105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 DC temperature . The resulting solid precipitate was ifitered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0—5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4- yloxy)-phenylamine (34.0 kg).
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h; Large scale	[00114] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg), and DMA (167.2 kg) at 20 to 25 °C. This mixture was then heated to 100 to 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process 1-IPLC analysis (less than 2percent starting material remaining), the reactor contents were cooled at 15 to 20 °C, and water (pre-cooled, 2 to 7 °C, 587 L) was charged at a rate to maintain 15 to 30 °C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on limit of detection, hereinafter “LOU’). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (TI-IF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 DC, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 °C to yield 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34 kg	for 13 h; Large scale	4-Aminophenol (24.4 kg) dissolved in Ν,Ν-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- (0225) 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis ( (0226) 15 to 30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 h after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxyquinolin-3-yloxy)aniline (34.0 kg).
35 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 100 - 105℃; for 13 h; Large scale	10097] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25° C. This mixture was then heated to 100-105° C. for approximately 13 hours. Afier the reaction was deemed complete as determined using in-process HPLC analysis (<2percent starting material remaining), the reactor contents were cooled at 15 to 20° C. and water (pre-cooled, 2 to 7° C., 587 L) charged at a rate to maintain 15 to 30° C. temperature. The resulting solid precipitate was filtered, washed with a mixture ofwater (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25° C. on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 h and then cooled to 0-5° C. and aged for approximately 1 h afier which time the solid was filtered, washed with THF (147.6kg) and dried on a filter undervacuum at approximately 25° C. to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).
442 mg	With sodium hydride In dimethyl sulfoxide at 20 - 100℃; for 3 h;	At room temperature, will be 4-aminophenol (500 mg) is dissolved in dimethyl sulfoxide (DMSO) (5 ml), added and to 55percent sodium hydride (98 mg). Later, by adding 4-chloro -6,7-dimethoxy-quinoline (244 mg), and the mixture in 100 °C stirring 3 hours. The reaction solution is diluted with ethyl acetate, adding saturated aqueous solution of sodium bicarbonate, and stirring the mixture. Furthermore, by adding ethyl acetate and water, and extracting the organic layer. The organic layer with saturated aqueous salt solution washing, then drying with anhydrous sodium sulfate. The solvent is distilled under reduced pressure. The obtained residue is washed with methanol, to obtain the title compound (442 mg), which has the following physical property value.
34 kg	at 100 - 105℃; for 13 h; Large scale	In 20-25 °C lower, will be soluble in N, N-dimethyl acetic acid amine (DMA, 184.3 kg) in 4-amino phenol (24.4 kg) injected into the 4-chloro -6,7-dimethoxy-quinoline (35.3 kg), sodium butanol 3rd (21.4 kg), and DMA (167.2 kg) in the reactor. The mixture is then heated to 100-105 °C and heating for about 13 hours. HPLC analysis using in the process (less than 2percent residual starting material) determining after the reaction is complete, the contents of the reactor 15-20 °C lower cooling, and the water (pre-cool, 2 to 7 °C, 587 L) to a certain rate in order to maintain the temperature of injected 15-30°C. Filtering the resulting solid precipitate and water (47 L) and DMA (89.1 kg) washing and again a mixture of water (214 L) washing. Then on the filter and the filtration cake at about 25 °C lower drying, get the crude product 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine (to LOD computing, 59.4 kg of welded, 41.6 kg drymatter). The crude product 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine in tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) in the mixture (about 75 °C) about 1 hour, then cooling to 0-5°C, and aging about 1 hours, thereafter, filtering solid, to THF (147.6 kg) washing, on and in the filter, at a temperature of from about 25 °C the lower vacuum drying, to obtain 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine (34.0 kg).
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h; Large scale	Preparation of 4-(6, 7 -Dimethoxy-quinoline-4-yloxy)-phenylamine 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100-105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1hour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
208.3 g	With sodium t-butanolate In N,N-dimethyl acetamide at 100 - 120℃; for 2 h;	The 4-aminophenol 120g (1.1mol) was dissolved in 150ml (1.61mol) N, N- dimethyl acetamide at 20 ~ 25 , was slowly added to a solution of sodium tert-butoxide 171g (0.9mol) and 4- chloro-6,7-dimethoxy-quinolin-200g (0.9mol) in 400ml (4.30mol) N, N-dimethylacetamide was added dropwise after the reaction was heated to 100 ~ 120 , after two hours the remaining amount of starting material is detected by HPLC, and stopped when 2percent unreacted stop reaction, cooling to room temperature, poured into a 1L the ice water stirring 1 - 2 hours after the filtering, cake 200 ml water washing 2 times, and for 35 °C vacuum drying, yellowish-white powder from 4-(6,7dimethoxyquinolin-4-oxy)phenylamine 208.3g, molar yield 78.1percent
34.0 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 13 h; Large scale	4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg), and DMA (167.2 kg) at 20—25 °C. This mixture was then heated to 100 — 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process 1-IPEC analysis (less than 2percent starting material remaining), the reactor contents were cooled at 15 to 20 °C, and water (pre-cooled, 2 to 7 °C, 587 L) was charged at a rate to maintain 15 to 30 °C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4—(6, 7 —dimethoxy—quinoline—4—yloxy)—phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4—(6, 7 —dimethoxy—quinoline—4—yloxy)— phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 °C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 °C to yield 4—(6, 7— dimethoxy—quinoline—4—yloxy)—phenylamine (34.0 kg).
34 kg	With sodium t-butanolate In N,N-dimethyl acetamide at 20 - 105℃; for 0.13 h; Large scale	[00168] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 °C. This mixture was then heated to 100 - 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2percent starting material remaining), the reactor contents were cooled at 15 to 20 °C, and water (pre-cooled, 2 to 7 °C, 587 L) was charged at a rate to maintain 15 to 30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed(approximately 75 °C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 °C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 °C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).

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[8] Patent: US2012/252840, 2012, A1,
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[ 190728-25-7 ]

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[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 875 - 879
[4] Patent: WO2013/43840, 2013, A1,
[5] Patent: WO2013/166296, 2013, A1,
[6] Patent: WO2013/180949, 2013, A1,
[7] Patent: WO2015/164869, 2015, A1,
[8] Patent: US2016/772, 2016, A1,
[9] Patent: EP2758057, 2017, B1,
[10] Patent: CN103664778, 2017, B,
[11] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292

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[ 123-30-8 ]
[ 14593-46-5 ]
[ 190728-25-7 ]

Reference： [1] Patent: US2012/252840, 2012, A1,

20
[ 35654-56-9 ]
[ 394-41-2 ]
[ 228559-87-3 ]

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[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292
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[4] Patent: US2008/4273, 2008, A1, . Location in patent: Page/Page column 72

21
[ 35654-56-9 ]
[ 1140909-48-3 ]

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[2] Patent: WO2013/59788, 2013, A1,
[3] Patent: WO2013/43840, 2013, A1,
[4] Patent: WO2013/43840, 2013, A1,
[5] Patent: WO2013/166296, 2013, A1,
[6] Patent: US2016/772, 2016, A1,
[7] Patent: WO2013/166296, 2013, A1,
[8] Patent: WO2014/165786, 2014, A1,
[9] Patent: WO2015/164869, 2015, A1,
[10] Patent: WO2015/164869, 2015, A1,
[11] Patent: WO2016/22697, 2016, A1,
[12] Patent: US2016/772, 2016, A1,
[13] Patent: TWI516477, 2016, B,

[ 35654-56-9 ] Synthesis Path-Downstream 1~88

1
[ 13425-93-9 ]
[ 35654-56-9 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With trichlorophosphate; In acetonitrile; at 85℃; for 2h;	Phosphorus oxychloride (200 mL, 4 v/w) was slowly added into a stirred solution of the intermediate3(50.0 g, 0.24 mol) in acetonitrile (500 mL, 10 v/w), and then was heated at 85oCfor 2 h. After cooling to r.t., the phosphorus oxychloride was removed under reduced pressure. The residue was poured into ice water and adjusted to pH 12 with 10NNaOH. The precipitates were collected by filtration and the filter cake was washed with water until the filtrate was nearly neutral to give compound4as a pale yellow solid in 91.4% yield. MS (ESI) m/z: 224.13[M+H]+.
83.3%	With trichlorophosphate; for 5h;Reflux;	Weigh 2.0 g (9.76 mmol) of <strong>[13425-93-9]6,7-dimethoxy-4-hydroxyquinoline</strong> in 20 mL of phosphorus oxychloride.After refluxing for 5 hours, the mixture was distilled under reduced pressure to a solution volume of about 5 mL.Pour into 30 mL of ice water in an external ice water bath condition while vigorously stirring, and adjust the pH of the solution to 8-9 by 3M NaOH solution.There are large amount of solid precipitated was filtered, 10mL * 2 cake was washed with water,After drying, 1.8 g of a pale yellow solid was obtained, yield 83.3%.
82.7%	With trichlorophosphate; In toluene; at 115℃; for 1h;	To a suspension of 6,7-dimethoxyquinolin-4-ol (45 g, 0.22 mol) in toluene (100 mL) was added phosphoryl trichloride (60 mL, 0.66 mol, Tianjin FuChen Chem. Co. Ltd.). The reaction was heated to 115 C for 1 hour and then cooled down to rt. The mixture was diluted with EtOAc (400 mL), and the pH of the solution was adjusted to 7-8 with 3 M NaOH aqueous solution. The resulted mixture was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a pale yellow solid (40.5 g, 82.7%). MS (ESI, pos. ion) m/z: 224.0 [M+H]+; *H NMR (400 MHz, CDC13): delta 4.05 (s, 3H), 4.06 (s, 3H), 7.27 (s, 1H), 7.35 (d, J= 4.8 Hz, 1H), 7.41 (s, 1H), 7.42 (s, 1H), 8.57 (d, J= 4.8 Hz, 1H)

82.4%	With N,N-dimethyl-formamide; trichlorophosphate; at 110℃; for 1h;	General procedure: A stirred solution of 6,7-disubstituted-4-quiolin-ol 4a-c (6.5 mmol)in POCl3 (10 mL) with a few drops DMF (?20) were heated to 110 Cfor 1 h. After cooling to rt, the solution was concentrated and azetroped with toluene. The residue was poured over ice/H2O and neutralized with saturated NaHCO3 solution. The precipitate was collected via vacuum filtration, washed with excess H2O and EtOAc. The combined organic layer were washed with brine, dried over Na2SO4, and concentratedin vacuo to yield crude product. The crude product was purified by silica gel chromatography eluted with PE/EA=10:1-3:1 togive compounds 5a-c, respectively.
78%	With trichlorophosphate; at 100℃; for 6h;	A solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100C for 6 h. Most of the solvent was recovered under vacuum. The residue was added slowly to cooled water 500 mL and adjusted with 10% K2CO3 to pH ~ 9, and stirred for another 1 h. The resulting solid was filtrated, washed with H2O (50 mL × 2), and dried at 55C for 4 h to give 7 (41.8 g, 78%) as a light brown solid; mp 130.2-131.4 C (Lit.13 130-131 C). 1H NMR (400 MHz, DMSO-d6): delta 3.96 (s, 3H),3.97 (s, 3H), 7.35 (s, 1H), 7.44(s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H). MS (ESI): m/z =223.2 [M + H]+, 245.2 [M + Na]+.
78%	With trichlorophosphate; at 100℃; for 6h;	A solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100 C for 6 h. Most of the solvent was recovered under vacuum. The residue was added slowly to cooled water (500 mL) and adjusted with 10% K2CO3 to pH 9, and stirred for another 1 h.The resulting solid was filtered, washed with H2O (50mL 2), and dried at 55 C for 4 h to give 7 (41.8 g, 78%) as a light brown solid, mp 130.2-131.4 C (lit mp24130-131 C). 1H NMR (DMSO-d6): d 3.96 (s, 3H), 3.97 (s, 3H), 7.35 (s, 1H), 7.44(s,1H), 7.54 (d, J5.2 Hz, 1H), 8.61 (d, J5.2 Hz, 1H). ESI-MS (m/z): 223.2 (MH),245.2 (MNa).Anal: Calcd for C11H10ClNO2 : C; 59:07; H; 4:51: Found : C; 59:20; H; 4:46:
55%	With trichlorophosphate; at 125℃; for 2h;	6,7-Dimethoxyquinolin-4-ol (0.64g) was dissolved in net POCI3 (3 mL). The solution was heated to 125C for 2 h. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with sat. NaHC03 (aq) and then extracted with EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using 10No.20% methanol/EtOAc to give 4-chloro-6,7-dimethoxyquinoline (0.38 g, 55% yield) ; ¹H NMR (400 MHz, CHCI3- d) 6 ppm 4.04 (s, 3 H) 4.06 (s, 3 H) 7.35 (d, J=5.1 Hz, 1 H) 7.40 (s, 1 H) 7.42 (s, 1 H) 8.57 (d, J=4.8 Hz, 1 H).
43.4%	With trichlorophosphate; In N,N-dimethyl-formamide; for 4h;Heating / reflux;	To a mixture 6,7-dimethoxyquinolin-4-ol (Intermediate A, Step 2, 245 mg, 1.2 mmol) in phosphorus oxychloride (10 ml_) was added DMF (0.1 ml_). The reaction was heated at reflux for 4 h, then cooled to rt and concentrated under reduced pressure. The residue was dissolved with ethyl acetate, and the organic solution was washed successively with NaHCtheta3 (saturated aqueous solution) and water, dried (Na2SO4), filtered and concentrated under reduced pressure to give 116 mg (43.4%) of title compound, which was taken onto next step without further purification.
	With trichlorophosphate; at 85℃; for 3h;	6,7-Dimethoxy-4-hydroxyquinoline (Step A, 7.8 g) was dissolved in POC13 (45 mL) and heated at 85 C for 3 h. The mixture was cooled down to RT, POC13 was evaporated and the resulting oil was quenched by adding ice at 0 C. The aqueous phase was basified to pH 8 and a solid precipitated. The solid was filtered and dried under vacuum to give 4- chloro-6,7-dimethoxyquinoline.
	With trichlorophosphate; In acetonitrile; at 65 - 80℃;	A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (1 L, 10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65C and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition Of POCl3, the temperature of the reaction mixture was raised to approximately 8O0C. The reaction was deemed complete (approximately 9.0 hours) when <;2% of the starting material remained (in process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 100C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30% NH4OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 140C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation with the removal of solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 1O0C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n-heptane (20.0 kg), and dried at approximately 4O0C to afford the title compound (8.0 kg).
	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;	A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 - 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L).The resulting mixture was warmed to approximately 20 - 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 70℃;Large scale;	Preparation of 4-Chloro-6,7-dimethoxy-quinoline[0059] A reactor was charged sequentially with 6,7-dhnethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % ??,?? (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound (35.6 kg).
8.0 kg	With trichlorophosphate; In acetonitrile; at 80℃; for 9h;Large scale;	A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 C and phosphorus oxychloride (POCb, 50.0 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 80 C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30% NuEta,OmicronEta (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 C to afford the title compound (8.0 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	[00119] A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NuOmicronEta (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to - 20 to - 25 C and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	Preparation of 4-Chloro-6,7-dimethoxy-quinoline [00114] A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NuOmicronEta (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	A reactor was charged sequentially with 6,7-dimemoxy-quinoline-4- ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NuOmicronEta (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POCi3, 130.6 kg) was added. After the addition of POCi3, the temperature of the reaction mixture was raised to approximatey 77 C. The reaction was deemed compiete (approximatey 13 hours) when less than 3% of the starting materia remained, as measured by in-process bigh-performance liquid cbromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a cbilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resultmg mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyfio super-cel NF (Celite; 5.4 kg), and the futer bed was washed with DCM (118.9 kg). The combined organic phase was washed with brnie (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by yacuum distillation with the remoyal of solyent (approximately 95 L residual yolume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by yacuum distiliation with the remoyal of soiyent (approximateiy 90 L residual yolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to -20 to -25 C and heid for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a futer at approximately 25 C under rtrogen to afford the title compound (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	[00264] A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C and phosphonas oxychioride (POd3, 130.6 kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-2 5 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NP (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase wasconcentrated by vacuum distillation with the removal of solvent (approximateLy 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 77℃; for 13h;Large scale;	Fool 13] A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POC13, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLCJ analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to -20 to -25 C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound (35.6 kg).
35.6 kg		A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 - 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 - 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-eel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	10096] A reactor was charged sequentially with 6,7- dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C. and phosphorus oxychloride (POC13, 130.6kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when <3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 C. and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cd NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 C. and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C. under nitrogen to afford the title compound. (35.6 kg).
35.6 kg	With trichlorophosphate; In acetonitrile; at 60 - 77℃; for 13h;Large scale;	The <strong>[13425-93-9]6,7-dimethoxy-quinolin-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg) are sequentially added into the reactor. The resulting mixture is heated to about 60 C, and add phosphorus acyl chlorine (POCl3, 130.6 kg). Adding POCl3the rear, the temperature of the reaction mixture the climbs to approximately 77 C. When there is less than 3% of the starting material (in the process for preparing the high performance liquid chromatography [HPLC] analysis), then the reaction as complete (about 13 hours). Cooling the reaction mixture to about 2-7C, then the dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg) and water (900 L) quenching of the frozen solution. The resulting mixture is heated to about 20-25C, and separation phase. Silicon, organic AW is passes through NF (CeliteTM; 5.4 kg) bed filter, and the filter bed in a DCM (118.9 kg) washing. Combined organic phase with the saline (282.9 kg) washing with water (120 L) mixing. Separation-phase, and the vacuum distilling to concentrate the organic phase in order to remove the solvent (about 95 L of the residual volume). The DCM (686.5 kg) is added in the reactor containing organic phase and carry out vacuum distillation and condensation in order to remove the solvent (about 90 L of the residual volume). Furthermore, by adding methyl 3rd-butyl ether (MTBE, 226.0 kg), and the mixture temperature is adjusted to -20 to -25 C and keep 2.5 hours, form a solid precipitate, then filtered and with n-heptane (92.0 kg) washing and about 25 C lower, in the nitrogen, is dried in the filter in order to obtain the title compound (35.6 kg).
8.0 kg	With trichlorophosphate; In acetonitrile; at 65 - 80℃; for 0.9h;Large scale;	Preparation of 4-Chloro-6,7-dimethoxy-quinoline A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 C and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 80 C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30% NH4OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 C to afford the title compound (8.0 kg).
1775.9 g	With thionyl chloride; In N,N-dimethyl acetamide; at 100 - 120℃;Large scale;	1.65 kg (13.9 mol) of thionyl chloride was added dropwise to a solution containing 2.2 kg (10.72 mol)<strong>[13425-93-9]4-hydroxy-6,7-dimethoxyquinoline</strong> in 5.3 L (57 mol) solution of N, N-dimethylacetamide was added and heated to 100 to 120 C for 4 to 7 hours (when HPLC Indicating that the feed is less than 3% unreacted as the reaction is complete). After the reaction was cooled to room temperature, was added 2.2L of ice water, with 30% sodium hydroxide solution to PH = 7 ~ 8, and a temperature controlled at 25 . And after completion, stirring was continued for 1 hour, sufficiently precipitate solid particles, was filtered; the cake was washed twice with 1L of water, and dried at 60 ~ 70 , to give a yellowish white powder of 4-chloro-6,7-dimethoxy-quinoline 1775.9 g, molar yield 74.2%
35.6 kg	With trichlorophosphate; In acetonitrile; at 77℃; for 13h;Large scale;	A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxyquinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by [00841 A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-oI (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by
35.6 kg	With trichlorophosphate; In acetonitrile; at 0.6 - 0.77℃; for 13h;Large scale;	[00166] A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C, and phosphorus oxy chloride (POCb, 130.6 kg) was added. After the addition of POCb, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C under nitrogen to afford the title compound (35.6 kg).

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2
[ 35654-56-9 ]
[ 28994-41-4 ]
4-(2-Benzylphenoxy)-6,7-dimethoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	In 1,2-dichloro-benzene at 180℃;	Compound 1: 4-(2-Benzylphenoxy)-6,7-dimethoxyquinoline Compound 1: 4-(2-Benzylphenoxy)-6,7-dimethoxyquinoline; 4-Chloro-6,7-dimethoxyquinoline (230 mg) and 2-benzylphenol (254 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 180°C overnight. The reaction solution was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give the title compound (40 mg, yield 10%). 1H-NMR (CDCl3, 400 MHz): δ 3.90 (s, 2H), 3.96 (s, 3H), 4.05 (s, 3H), 6.31 (d, J = 5.4 Hz, 1H), 7.07 - 7.37 (m, 9H), 7.40 (s, 1H), 7.44 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 372 (M+1)+
	Heating / reflux;	r2 wherein Z represents -O-, -NH-, -S-, or -C(=O)-, and R20 to R24, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-10 alkyl, C1-8 alkoxy, C2-6 alkenyl, phenylcarbonyl, amino, nitro, or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group. R20 and R21, or R23 and R24 together may combine with the carbon atoms to which they are attached represent a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group. The other substituents are as defined in other production schemes in other Reference Examples. The aimed compounds, i.e., 4-phenoxyquinoline derivatives, 4-anilinoquinoline derivatives, or corresponding quinazoline derivatives can be synthesized by reacting a phenol derivative or a corresponding aniline derivative with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in a suitable solvent, for example, o-dichlorobenzene, or in the absence of a solvent, for example, at 120 to 180°C. In scheme r1, phosphoryl chloride may be mentioned as the chlorinating agent. 1H-NMR (CDCl3, 400 MHz): δ 3.90 (s, 2H), 3.96 (s, 3H), 4.05 (s, 3H), 6.31 (d, J = 5.4 Hz, 1H), 7.07 - 7.37 (m, 9H), 7.40 (s, 1H), 7.44 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 372 (M+1)+

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 60
[2]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1724268, 2006, A1 Location in patent: Page/Page column 128

3
[ 35654-56-9 ]
[ 98446-49-2 ]
(2,4-dichloro-5-methoxy-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3965 - 3977

4
[ 35654-56-9 ]
[ 394-41-2 ]
[ 228559-87-3 ]

Yield	Reaction Conditions	Operation in experiment
37.6%	In chlorobenzene; at 131.0℃; for 12h;	A mixture of B9 (500 mg, 2.24 mmol, 1 eq) and 3-fluoro-4-nitro-phenol (703 mg, 4.47 mmol, 2 eq) in chlorobenzene (10 mL) was stirred at 131 C for 12 hours to give an off-white suspension. LCMS (Rt = 1.045-1.107 min) showed -25% of 545-1 and -75% of desired MS value. The reaction mixture were filtered, filtrate cake was washed with toluene (10 mL) and dried under vacuum to give a crude compound. The crude compound was basified with 10% aq.NaOH, and the suspension was stirred for 1 hour at room temperature. The mixture was filtered, filtrate cake was dried in high vacuum to give B10 (300 mg, 37.6% yield, 96.5% purity) as a yellow solid.
	In diphenylether; at 140.0℃; for 24h;	Step 1. 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (52) A stirred suspension of 4 (500 mg, 2.24 mmol) and 3-fluoro-4-nitrophenol (862 mg, 5.49 mmol) in diphenylether (10 mL) was heated at 140 C. for one day. The reaction mixture was allowed to cool to room temperature, then purified by flash column chromatography on silica gel (eluents MeOH/DCM: 0/100-05/95) and triturated with Et2O to afford the title compound 52 (857 mg, contaminated with the phenol starting material) as a pale yellow solid. MS (m/z): 345.2 (M+H).

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1359 - 1366
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 6083 - 6101
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 6277 - 6292
[4]Patent: WO2019/229251,2019,A1 .Location in patent: Page/Page column 76
[5]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 875 - 879
[6]Patent: US2008/4273,2008,A1 .Location in patent: Page/Page column 72

5
[ 35654-56-9 ]
[ 88-30-2 ]
6,7-dimethoxy-4-(4-nitro-3-trifluoromethyl-phenoxy)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In chlorobenzene at 120℃;

Reference： [1]Shimizu, Toshiyuki; Fujiwara, Yasunari; Osawa, Tatsushi; Sakai, Teruyuki; Kubo, Kinya; Kubo, Kazuo; Nishitoba, Tsuyoshi; Kimura, Kaname; Senga, Terufumi; Murooka, Hideko; Iwai, Akemi; Fukushima, Kayoko; Yoshino, Tetsuya; Miwa, Atsushi [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 875 - 879]

6
[ 35654-56-9 ]
[ 19499-93-5 ]
4-(2,3-dimethyl-4-nitro-phenoxy)-6,7-dimethoxy-quinoline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 875 - 879

7
[ 35654-56-9 ]
[ 117-99-7 ]
{2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap In 1,2-dichloro-benzene at 160℃; for 4h;
5%	at 170℃; for 0.333333h;
	Stage #1: 6,7-dimethoxy-4-chloroquinoline; 2-Hydroxybenzophenone With dmap In 1,2-dichloro-benzene at 160℃; for 4h; Stage #2: With potassium hydroxide In chloroform; water	Compound 62: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone Compound 62: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone; 4-Chloro-6,7-dimethoxyquinoline (58 mg), 2-hydroxybenzophenone (271 mg), and 4-dimethylaminopyridine (166 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160°C for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 110.4 mg of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 3.82 (s, 3H), 3.99 (s, 3H), 6.43 (d, J = 5.1 Hz, 1H), 6.93 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.28 - 7.34 (m, 3H), 7.39 - 7.48 (m, 2H), 7.59 - 7.72 (m, 4H), 8.44 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 386 (M+1)+

Reference： [1]Location in patent: experimental part Shimizu, Toshiyuki; Kimura, Kaname; Sakai, Teruyuki; Kawakami, Kazuki; Miyazaki, Tetsuko; Nakouji, Masayoshi; Ogawa, Akira; Ohuchi, Hitomi; Shimizu, Kiyoshi [Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3326 - 3329]
[2]Kubo, Kazuo; Ohyama, Shin-Ichi; Shimizu, Toshiyuki; Takami, Atsuya; Murooka, Hideko; Nishitoba, Tsuyoshi; Kato, Shinichiro; Yagi, Mikio; Kobayashi, Yoshiko; Iinuma, Noriko; Isoe, Toshiyuki; Nakamura, Kazuhide; Iijima, Hiroshi; Osawa, Tatsushi; Izawa, Toshio [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133]
[3]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 77

8
[ 35654-56-9 ]
[ 13020-57-0 ]
{3-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	at 170℃; for 0.166667h;	Compound 77: {3-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)-methanone; 4-Chloro-6,7-dimethoxyquinoline (112 mg) and <strong>[13020-57-0]3-hydroxybenzophenone</strong> (297 mg) were mixed together, and the mixture was heated at 170C for 10 min. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-acetone as a solvent to give the title compound (126 mg, yield 65%). 1H-NMR (CDCl3, 400 MHz): delta 4.05 (s, 3H), 4.07 (s, 3H), 6.53 (d, J = 5.4 Hz, 1H), 7.42 - 7.65 (m, 8H), 7.72 (dd, J = 1.5 Hz, 6.3 Hz, 1H), 7.83 (dd, J = 1.2 Hz, 8.3 Hz, 2H), 8.53 (d, J = 5.1 Hz, 1H) Mass spectrometric value (FD-MS, m/z): 385 (M+)
65%		Example 128 {3-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}phenylmethanone [181] A mixture of 4-chloro-6,7-dimethoxyquinoline (112 mg) and commercially available <strong>[13020-57-0]3-hydroxybenzophenone</strong> (297 mg) was stirred at 170 C. for 10 minutes, the reaction mixture was then purified by thin layer chromatography on silica gel eluding with hexane/acetone (2/1) to obtain 126 mg of the title compound (yield: 65%). 1 H-NMR (CDCl3, 90 MHz): delta 4.4 (s, 3H), 4.05 (s, 3H), 6.53 (d, J=5.3 Hz, 1H), 7.34~7.88 (m, 11H), 8.53 (d, J=5.3 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 385 (M+)

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 5117 - 5133
[2]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 81
[3]Patent: US6143764,2000,A

9
[ 35654-56-9 ]
[ 25913-05-7 ]
(4-fluorophenyl){4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	at 170℃; for 0.333333h;

Reference： [1]Kubo, Kazuo; Ohyama, Shin-Ichi; Shimizu, Toshiyuki; Takami, Atsuya; Murooka, Hideko; Nishitoba, Tsuyoshi; Kato, Shinichiro; Yagi, Mikio; Kobayashi, Yoshiko; Iinuma, Noriko; Isoe, Toshiyuki; Nakamura, Kazuhide; Iijima, Hiroshi; Osawa, Tatsushi; Izawa, Toshio [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133]

10
[ 35654-56-9 ]
[ 42019-78-3 ]
(4-Chlorophenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		Example 41 (4-Chlorophenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}methanone [37] 4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-chlorophenyl 4-hydroxyphenyl ketone (349 mg) were mixed and stirred at 180° C. for 20 minutes. The reaction mixture was purified by thin layer chromatography on silica gel eluding with chloroform/ethyl acetate (5/1) to obtain 26 mg of the title compound (yield: 12percent). 1 H-NMR (CDCl3, 90 MHz): delta 4.03 (s, 3H), 4.07 (s, 3H), 6.66 (d, J=5.3 Hz, 1H), 7.19~7.34 (m, 2H), 7.44~7.56 (m, 4H), 7.71~7.99 (m, 4H), 8.58 (d, J=5.3 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 419 (M+)

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 5117 - 5133
[2]Patent: US6143764,2000,A

11
[ 35654-56-9 ]
[ 3964-52-1 ]
[ 347161-75-5 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1359 - 1366

12
[ 35654-56-9 ]
[ 52671-64-4 ]
[ 286371-44-6 ]

Yield	Reaction Conditions	Operation in experiment
77%		A solution of <strong>[52671-64-4]4-amino-3-chlorophenol hydrochloride</strong> 8 (10.0 g, 0.06 mol) and dimethylacetamide (40 mL) was stirred in an ice-water bath. t-BuOK (15.5 g, 0.14 mol) was added and the reaction mixture was stirred at the temperature for 1.5 h. Then 4-chloro-6,7-dimethoxyquinoline 7 (9.4 g, 0.04 mol) was added to the resulting solution, and heated to 115°C for another 5 h. After cooled to room temperature, the reaction mixture was then added to water(100 mL) and MeOH (100 mL), and stirred for 3 h. The resulting solid was collected by suction filtration, washed with H2O (50 mL × 3), and dried at 50°C for 5 h to give 9 (10.2 g, 77percent) as a faint yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 3.93 (s, 3H), 3.94 (s, 3H), 5.43 (s, 2H), 6.43 (d, J = 5.2 Hz, 1H), 6.91(d, J = 8.8 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.49 (s, 1H),8.45 (d, J = 5.2 Hz, 1H). MS (ESI): m/z = 331.1 [M + H]+.
69.9%		4-Amino-3-chlorophenol-HCl (990 g) was added to N,N-dimethylacetamide (6.6 L). Potassium t-butoxide (1452 g) was added thereto at 0°C, and the mixture was stirred at 20°C for 30 min. 4-Chloro-6,7-dimethoxyquinoline (825 g) was added to the reaction solution, and the mixture was then stirred at 115°C for 5 hr. The reaction solution was cooled to room temperature, water (8.3 L) and methanol (8.3 L) were then added thereto, and the mixture was stirred for 2 hr. The resultant precipitate was collected by filtration, and the filtered product was slurried in water (8.3 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline (852 g, yield 69.9percent). 1H-NMR (400 MHz, DMSO-d6/ppm); delta 3.92 (s, 3H), 3.93 (s, 3H), 5.41 (s, 2H), 6.41 (d, 1H), 6.89 (d, 1H), 6.98 (dd, 1H), 7.19 (d, 1H), 7.36 (s, 1H), 7.48 (s, 1H), 8.43 (d, 1H)
60%	With dimethyl sulfoxide; In methanol; water;	Production Example 1: 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline Sodium hydride (60 wtpercent, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50°C for 30 min and was then cooled to room temperature. <strong>[52671-64-4]4-Amino-3-chlorophenol hydrochloride</strong> (1.61 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and themixture was stirred at 100°C overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.89 g (yield 60percent) of the title compound. 1H-NMR (CDCl3, 400 MHz): delta 4.05 (s, 3H), 4.05 (s, 3H), 4.08 (s, 2H), 6.44 (d, J = 5.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.93 - 6.96 (m, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H)

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1359 - 1366
[2]Heterocycles,2016,vol. 92,p. 1882 - 1887
[3]Patent: EP1559715,2005,A1 .Location in patent: Page/Page column 19
[4]Patent: EP1153920,2001,A1

13
[ 35654-56-9 ]
[ 123-30-8 ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium t-butanolate; In N,N-dimethyl acetamide; at -5 - 110℃;	The compound (I) (500 g, 2.23 muM), 4-aminophenol (345 g, 3.16 muM) are added to a reaction in the bottle, adding DMA (3 L), lowering the temperature to 0 C -5 C, drop which is in butanol sodium (430 g) of DMA (2 L) suspension, then completing, heating up to 100 C -110 C, thermal insulation reaction 4 - 5 hours. (TLC monitoring the reaction is complete, Rf value 0.4 (dichloromethane: methanol=20:1)). Lowering the temperature to -5 C -0 C, adding ice water (10 L), stirring crystallization 15 - 16 hours. Filtering, cake a little water to wash, for 50 C drying by blowing 15 - 16 hours to obtain light yellow solid 595 g, yield 90%, HPLC purity 99.7%
89.1%	With sodium t-butanolate; In N,N-dimethyl acetamide; at 0 - 110℃; for 4h;	4-Chloro-6,7-dimethoxyquinoline (10 g, 0.045 mol, 1.0 eq.),4-Aminophenol (6.9 g, 0.063 mol, 1.4 eq.) was added to 50 mL of N,N-dimethylacetamide and cooled to 0 C.A suspension of sodium tert-butoxide (6.1 g, 0.063 mol, 1.4 eq.) and 50 mL of N,N-dimethylacetamide was slowly added.After the addition, the temperature is raised to 110 C, and the reaction is carried out for 4 hours.The reaction solution was cooled to 0 C, 400 mL of purified water was added, and the mixture was stirred for 15 to 16 hours.Stop stirring, filter, filter cake purified water 20 mL wash,4-((6,7-Dimethoxy-4-yl)oxy)aniline is obtained11.8g,The yield was 89.1%, and the purity was 99.1%.
89%	With sodium t-butanolate; In N,N-dimethyl acetamide; at 0 - 110℃;Large scale;	Compound (I) (1000 g, 4.47 mol),4-aminophenol (690 g, 6.32 mol) was added to the reaction flask.Add N,N-dimethylacetamide (6L), cool down to 0 ~ 5 C,A suspension of sodium, tert-butoxide (860 g) in N,N-dimethylacetamide (4 L) was added dropwise.The temperature is raised to 100 to 110 C, and the reaction is kept for 4 to 5 hours.Cool down to -5 to 0 C, add ice water (20 L), and stir and crystallize for 15 to 16 hours.Filter, filter cake washed with a small amount of water,Drying at 50 C for 15 to 16 hours gave a pale yellow solid 1180 g,The yield was 89.0%, and the HPLC purity was 99.7%.

87%	With potassium tert-butylate; In N,N-dimethyl acetamide; at 100℃; for 4h;	Compound 7 (16.0 g, 0.071 mol) and 4-aminophenol 8 (11.0 g, 0.10 mol) were added to dimethylacetamide (200 mL), and stirred for 10 min at room temperature; then a solutionof t-BuOK (9.68 g, 0.09 mol) in dimethylacetamide (20 mL) was added slowly such that the reaction temperature kept at or below 25 C; the reaction mixture was then stirred at 100 C for another 4 h, then cooled to room temperature, and poured slowly into water (400 mL) while stirring constantly. The solid formed was filtered off and washed with cold water (50mL 2), dried at 60 C for 4 h to afford 9 (18.4 g, 87%) as a light tan solid, mp 140 C (dec.). 1H NMR (DMSO-d6): d3 .93 (s, 3H), 3.94 (s, 3H),5.16 (s, 2H), 6.37 (d, J5.2 Hz, 1H), 6.67 (d, J8.8 Hz, 2H), 6.93 (d, J8.8 Hz, 2H),7.37 (s, 1H), 7.51 (s, 1H), 8.43 (d, J5.2 Hz, 1H). ESI-MS (m/z): 297.8 (MNa).Anal: Calcd for C17H16N2O3 : C; 68:91; H; 5:44: Found : C; 68:79; H; 5:49:
86.8%	With sodium t-butanolate; In N,N-dimethyl-formamide; at 0 - 110℃;	4 - Chloro -6, 7 -dimethoxyquinoline (10g, unitunitunit, 1.0 eq. 0.045 muM), 4 - aminophenol (6.9g, unitunitunit, 0.063 muM eq.) were added to unitunitunit. 50 ml N N - dimethylacetamide, 1.4 eq) were 0 C added to Kunit, N - dimethylacetamide, and the reaction solution was 50 ml N stirred until 0.063 muM unit. , and the 15~16h 1.4 HPLC was added, stirred and devitrified 110 C 6.1g. and 0 C HPLC was carried, alone or 4 hours in combination of N-dimethylacetamide, and N-dimethylacetamide 400 ml . unit. , N-dimethylacetamide was added to the unitz , N-dimethylacetamide. Stirring, filtration, and filter cake purification were 20 ml stopped and washed, yielding 4 - ((6, 7 -dimethoxy -4 -) oxy) aniline 11.5g, yield transformunitunitin, 86.8% and unitunit_ purity. 99.2%. Pat.
83.6%	With sodium methylate; In dimethyl sulfoxide; at 90℃; for 9h;	4-Chloro-6,7-dimethoxyquinoline (35.3 g, 157.8 mmol) andSodium methoxide (12.1 g, 224 mmol) was addedDimethyl sulfoxide (200 ml). 4-Aminophenol (20.67 g, 189.4 mmol)In dimethylsulfoxide (150 ml) was addedIn the reaction solution, the reaction solution was reacted at 90 C for 9 hours, cooled to room temperature, poured into 1600 ml of ice water, and added with 100 mlEthyl acetate, filtered and dried under reduced pressure to give 4 - [(6,7-dimethoxyquinolin-4-yl) oxy] aniline (39.1 g, yield:83.6%).
74.6%		For 100 ml is added to a round bottom flask NaH (3.3g, 82 . 5mmol) and anhydrous DMSO, after fully stirring, add the aminophenol (6g, 55mmol), stirring the mixture at room temperature for 10 min, then add 4-chloro-6,7-dimethoxy quinoline (12.3g, 55 . 1mmol) in the 100 degrees stirring 3h, TLC monitoring, after the reaction, water, chloroform extraction, the extraction liquid to be grey solid 12.2g, yield 74.6%.
74.8%	In N,N-dimethyl acetamide; at 100℃; for 9h;	To a 1L three-necked flask was added 4-chloro-6,7-dimethoxy-quinoline 35. 3g (157. 8mmol), sodium tert-butoxide21.4g (224. Lmmol) and N,N-dimethylacetamide 200ml, stirred for standby.The N, N- dimethylacetamide 200ml 4-aminophenol with 24. 5g (224. Lmmol) mixed, added to the aboveAlternate reaction solution was added dropwise to control the temperature less than 25 C, the dropwise addition, temperature was raised to 100 C, the reaction nine hours, the reaction was stopped,Cooling to 15~20 C, the reaction mixture was poured into 1600ml ice water, controlling the temperature 15~30 C, was added 100ml ethyl Esters, solid separated stirring, suction filtered, the solid washed with ethyl acetate lml, blast drying at 40 C for 12 hours to give a brown solid 35g (74. 8%)
61%	With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 18h;	A suspension of 4-chloro-6, 7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol) and cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) <n="221"/>was stirred at 1000C for 18 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran (=1/1) . ? The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methyl acetate/methanol=60/40) . Ethyl acetate was added to the obtained residue and the mixture was filtrated to give the title compound (1267 mg, 61%) as a white powder.1H-NMR (DMSO-d6, 300 MHz) delta 3.93 (6H, s) , 5.16 (2H, s) , 6.37 (IH, d, J = 5.4 Hz), 6.67 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J= 8.7 Hz), 7.36 (IH, s) , 7.50 (IH, s), 8.43 (IH, d, J = 5.4Hz) .
	With sodium t-butanolate; In ISOPROPYLAMIDE; at 20 - 105℃; for 13h;Product distribution / selectivity;	4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100- 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (<2% starting material remaining), the reactor contents were cooled at 15 to 20 C and water (pre-cooled, 2 to 7 C, 587 L) charged at a rate to maintain 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6,7-dimemoxy-quinoline-4-yloxy)- phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 C and aged for approximately 1 h after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6,7-dimemoxy-qumoline-4-yloxy)-phenylamine (34.0 kg).
	With 2,4-dichlorophenoxyacetic acid dimethylamine; In N,N-dimethyl acetamide; water;	Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide, (21.4 kg) and DMA (167.2 kg) at 20 to 25 C. This mixture was then heated to 100 to 105 C. for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15 to 20 C. and water (pre-cooled, 2 to 7 C., 587 L) charged at a rate to maintain 15 to 30 C. temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C. on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD).
	With sodium tert-pentoxide; In tetrahydrofuran; N,N-dimethyl acetamide; at 105 - 115℃; for 9h;Large scale;	Alternative Preparation of 4-(6, 7 -Dimethoxy-quinoline-4-yIoxy)-phenylamine[0061] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-Aminophenol (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105 to 115C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 25 C and water (315 kg) was added over a two hour period while maintaining the temperature between 20 and 30 C. The reaction mixture was then agitated for an additional hour at 20 to 25 C. The crude product was collected by filtration and washed with a mixture of 88 kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1% w/w.
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 100 - 105℃; for 13h;Large scale;	4-Aminophenol (24.4 kg) dissolved in Nu,Nu-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100- 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 C and water (pre-cooled, 2-7 C, 587 L) charged at a rate to maintain 15-30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately Ihour and then cooled to 0-5 C and aged for approximately 1 hour after which time the solid was filtered, washed with THF ( 147.6 kg) and dried on a filter under vacuum at approximately 25 "C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;Large scale;	[00120] 4-Aminophenol (24.4 kg) dissolved in Nu,Nu-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 C. This mixture was then heated to 100 - 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20 C and water (pre-cooled, 2 to 7 C, 587 L) charged at a rate to maintain 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7 -dimethoxy-quinoline- 4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour and then cooled to 0 to 5 C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 100 - 105℃; for 13h;Large scale;	Preparation of 4-(6, 7 -Dimethoxy_quinoline_4_yloxy)....phenylamjne [00115] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100- 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 C and water (pre-cooled, 2-7 C, 587 L) charged at a rate to maintain 15-30 C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylam me (34.0 kg).
34 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;Large scale;	4-Aminophenol (24.4 kg) dissolved in Nu,Nu-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 C. This mixture was then heated to 100 - 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20 C, and water (pre-cooled, 2 to 7 C, 587 L) was charged at a rate to maintain 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 ^imethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).
34 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 100 - 105℃; for 13h;Large scale;	4-Aminophenol (24.4 kg) dissolyed in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg), and DMA (167.2 kg) at 20-25 c. This mixture was then heated to 100- 105 c for approximately 13 hours. After the reaction was deemed complete as determmed using in-process HPLC analysis (less than 2% starting materia remaining), the reactor contents were cooled at 15 to 20 c, and water (pre-cooled, 2 to 7 c, 587 L) was charged at a rate to maintain 15 to 30 c temperature. The resulting solid precipitate was fultered, washed with a mixture of water (47 L) and DMA (89.1 kg), and fmally washed with water (214 L). The futer cake was then dried at approximately 25 C on futer to yield crude 4-(6, 7- dimethoxy-quinoline--1---yloxy)-phenylamine (59.4 kg wet, 41.6 kg di3? calculated based on limit of detection, hereinafter LOD?). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 2 11.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to O to 5 C, and aged for approximately 1 hour, after which time the solid was fultered, washed with THF (147.6 kg), and dried on a futer under yacuum at approximatey 25 c to yield 4-(6, 7 -dimethoxy- quinoline-4-yloxy)-phenylamine (3 4.0 kg).
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;	Preparation of 4-(6, 7 -Dimethoxy--quinoline-4-yloxy)-phenylamiue[002651 4-Antinophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100-105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 C and water (pre-cooled, 2-7 C, 587 L) charged at a rate to maintain 15-30 DC temperature . The resulting solid precipitate was ifitered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6,7-dimethoxy-quinoline-4- yloxy)-phenylamine (34.0 kg).
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;Large scale;	[00114] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium tbutoxide (21.4 kg), and DMA (167.2 kg) at 20 to 25 C. This mixture was then heated to 100 to 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process 1-IPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20 C, and water (pre-cooled, 2 to 7 C, 587 L) was charged at a rate to maintain 15 to 30 C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on limit of detection, hereinafter ?LOU?). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (TI-IF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 DC, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 C to yield 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
34 kg	With N,N-dimethyl acetamide; sodium t-butanolate; for 13h;Large scale;	4-Aminophenol (24.4 kg) dissolved in Nu,Nu-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100- (0225) 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis ( (0226) 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 C and aged for approximately 1 h after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6,7-dimethoxyquinolin-3-yloxy)aniline (34.0 kg).
35 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 100 - 105℃; for 13h;Large scale;	10097] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100-105 C. for approximately 13 hours. Afier the reaction was deemed complete as determined using in-process HPLC analysis (<2% starting material remaining), the reactor contents were cooled at 15 to 20 C. and water (pre-cooled, 2 to 7 C., 587 L) charged at a rate to maintain 15 to 30 C. temperature. The resulting solid precipitate was filtered, washed with a mixture ofwater (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C. on filter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C.) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 h and then cooled to 0-5 C. and aged for approximately 1 h afier which time the solid was filtered, washed with THF (147.6kg) and dried on a filter undervacuum at approximately 25 C. to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).
442 mg	With sodium hydride; In dimethyl sulfoxide; at 20 - 100℃; for 3h;	At room temperature, will be 4-aminophenol (500 mg) is dissolved in dimethyl sulfoxide (DMSO) (5 ml), added and to 55% sodium hydride (98 mg). Later, by adding 4-chloro -6,7-dimethoxy-quinoline (244 mg), and the mixture in 100 C stirring 3 hours. The reaction solution is diluted with ethyl acetate, adding saturated aqueous solution of sodium bicarbonate, and stirring the mixture. Furthermore, by adding ethyl acetate and water, and extracting the organic layer. The organic layer with saturated aqueous salt solution washing, then drying with anhydrous sodium sulfate. The solvent is distilled under reduced pressure. The obtained residue is washed with methanol, to obtain the title compound (442 mg), which has the following physical property value.
	With potassium tert-butylate;	2-acetyl-4,5-dimethoxy-ethyl aniline and cyclization occurs too quinolinone, phosphine oxychloride chlorinated 4-chloro-6,7-dimethoxy-quinoline, and then under alkaline conditions with p-aminophenol reaction.
34 kg	With sodium t-butanolate; at 100 - 105℃; for 13h;Large scale;	In 20-25 C lower, will be soluble in N, N-dimethyl acetic acid amine (DMA, 184.3 kg) in 4-amino phenol (24.4 kg) injected into the 4-chloro -6,7-dimethoxy-quinoline (35.3 kg), sodium butanol 3rd (21.4 kg), and DMA (167.2 kg) in the reactor. The mixture is then heated to 100-105 C and heating for about 13 hours. HPLC analysis using in the process (less than 2% residual starting material) determining after the reaction is complete, the contents of the reactor 15-20 C lower cooling, and the water (pre-cool, 2 to 7 C, 587 L) to a certain rate in order to maintain the temperature of injected 15-30C. Filtering the resulting solid precipitate and water (47 L) and DMA (89.1 kg) washing and again a mixture of water (214 L) washing. Then on the filter and the filtration cake at about 25 C lower drying, get the crude product 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine (to LOD computing, 59.4 kg of welded, 41.6 kg drymatter). The crude product 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine in tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) in the mixture (about 75 C) about 1 hour, then cooling to 0-5C, and aging about 1 hours, thereafter, filtering solid, to THF (147.6 kg) washing, on and in the filter, at a temperature of from about 25 C the lower vacuum drying, to obtain 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine (34.0 kg).
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;Large scale;	Preparation of 4-(6, 7 -Dimethoxy-quinoline-4-yloxy)-phenylamine 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100-105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 C and water (pre-cooled, 2-7 C, 587 L) charged at a rate to maintain 15-30 C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1hour and then cooled to 0-5 C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
208.3 g	With sodium t-butanolate; In N,N-dimethyl acetamide; at 100 - 120℃; for 2h;	The 4-aminophenol 120g (1.1mol) was dissolved in 150ml (1.61mol) N, N- dimethyl acetamide at 20 ~ 25 , was slowly added to a solution of sodium tert-butoxide 171g (0.9mol) and 4- chloro-6,7-dimethoxy-quinolin-200g (0.9mol) in 400ml (4.30mol) N, N-dimethylacetamide was added dropwise after the reaction was heated to 100 ~ 120 , after two hours the remaining amount of starting material is detected by HPLC, and stopped when 2% unreacted stop reaction, cooling to room temperature, poured into a 1L the ice water stirring 1 - 2 hours after the filtering, cake 200 ml water washing 2 times, and for 35 C vacuum drying, yellowish-white powder from 4-(6,7dimethoxyquinolin-4-oxy)phenylamine 208.3g, molar yield 78.1%
34.0 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 13h;Large scale;	4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg), and DMA (167.2 kg) at 20-25 C. This mixture was then heated to 100 - 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process 1-IPEC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20 C, and water (pre-cooled, 2 to 7 C, 587 L) was charged at a rate to maintain 15 to 30 C temperature. The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine was refluxed (approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 C to yield 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
	With Zr-doped Mg/Al composite metal oxide solid base; In chlorobenzene; at 120℃; for 0.5h;	10 mmol of 4-chloro-6,7-dimethoxyquinoline, 13 mmol of 4-aminophenol, 10 ml of DMSO and 0.5 g of LDO-X were added to the parallel synthesizer. The reaction was kept at 120 C, and the reaction solution was taken for HPLC every 0.5 h. Detection, when 4-chloro-6,7-dimethoxyquinoline is no longer converted, the conversion of each catalytic system (based on 4-chloro-6,7-dimethoxyquinoline) and selectivity.to obtained 4-(4-aminophenoxy)-6,7-dimethoxyquinoline.
34 kg	With sodium t-butanolate; In N,N-dimethyl acetamide; at 20 - 105℃; for 0.13h;Large scale;	[00168] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg), and DMA (167.2 kg) at 20 - 25 C. This mixture was then heated to 100 - 105 C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2% starting material remaining), the reactor contents were cooled at 15 to 20 C, and water (pre-cooled, 2 to 7 C, 587 L) was charged at a rate to maintain 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with water (214 L). The filter cake was then dried at approximately 25 C on filter to yield crude 4-(6, 7 - dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7 -dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed(approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour, then cooled to 0 to 5 C, and aged for approximately 1 hour, after which time the solid was filtered, washed with THF (147.6 kg), and dried on a filter under vacuum at approximately 25 C to yield 4-(6, 7 -dimethoxy-quinoline-4-yloxy)- phenylamine (34.0 kg).
2.05 g	With sodium t-butanolate; In N,N-dimethyl acetamide; at 105℃; for 12h;	Take a 100ml three-necked flask, add 2.23g 4-chloro-6,7-dimethoxyquinoline, 1.63g p-aminophenol, 1.44g sodium tert-butoxide, 10ml DMAC, and react at 105 C for 12.0h. The basic reaction of the raw materials was complete, poured into 100 ml of water, and filtered with suction to obtain a brown-black solid. Column chromatography gave 2.05 g of compound I-1-1.
261.8 g		N,N-dimethylacetamide (2000 mL) and potassium tertiary butoxide (180.61 g) were charged into 4N RB flask under nitrogen atmosphere, and stirred for 10 min at 25-30C. 4-aminophenol (175.65 g) was added lot wise to the reaction mixture and stirred for 30 min. 4-chloro-6,7-dimethoxy-quinoline compound of formula-4 (200 g) was added to the reaction mixture and heated to 90-95 C and stirred for 7h. Cooled the reaction mixture to 25-35C. Water (2000 mL) was added to the reaction mixture and stirred for 2h at the same temperature. Filtered and washed the compound with N,N- dimethylacetamide and water to get the freebase compound of formula-5. Methanol (1000 mL) was added to the obtained wet freebase compound of formula-5. Heated the reaction mixture to reflux temperature and stirred for 30 min and then cooled to 25- 30C. Filtered and washed the obtained compound with methanol to get the freebase compound of formula-5. Wet wt: 261.8 g

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[14]Patent: US2012/252840,2012,A1
[15]Patent: WO2013/59788,2013,A1 .Location in patent: Paragraph 0061
[16]Patent: WO2013/43840,2013,A1 .Location in patent: Paragraph 00119; 00121
[17]Patent: WO2013/70890,2013,A1 .Location in patent: Paragraph 00119-00120
[18]Patent: WO2013/166296,2013,A1 .Location in patent: Paragraph 00115
[19]Patent: WO2014/165786,2014,A1 .Location in patent: Paragraph 00197
[20]Patent: WO2014/165779,2014,A1 .Location in patent: Paragraph 0077; 0078; 0080; 0081; 0082
[21]Patent: WO2015/164869,2015,A1 .Location in patent: Paragraph 00263; 00265
[22]Patent: WO2016/22697,2016,A1 .Location in patent: Paragraph 00111; 00112; 00114
[23]Patent: WO2016/19285,2016,A1 .Location in patent: Paragraph 0096; 0097
[24]Patent: US2016/772,2016,A1 .Location in patent: Paragraph 0095; 0097
[25]Patent: CN105408312,2016,A .Location in patent: Paragraph 0820; 0821; 0822; 0823; 0824
[26]Patent: CN103739550,2016,B .Location in patent: Paragraph 0213-0216
[27]Patent: TWI516477,2016,B .Location in patent: Page/Page column 31; 32
[28]Heterocycles,2016,vol. 93,p. 323 - 332
[29]Patent: EP2758057,2017,B1 .Location in patent: Paragraph 0116
[30]Patent: CN103664778,2017,B .Location in patent: Paragraph 0040-0042; 0045; 0046
[31]Patent: WO2018/136796,2018,A1 .Location in patent: Paragraph 0081; 0082; 0085; 0086; 0087; 0089
[32]Patent: CN108658856,2018,A .Location in patent: Page/Page column 8-11
[33]Patent: WO2018/227119,2018,A1 .Location in patent: Paragraph 00163; 00164; 00167-00168; 00169-00171
[34]Patent: CN110330479,2019,A .Location in patent: Paragraph 0083-0085
[35]Patent: WO2019/234761,2019,A1 .Location in patent: Page/Page column 11

14
[ 35654-56-9 ]
[ 369-35-7 ]
[ 1000850-81-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate; CyJohnPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; at 20 - 100℃; for 17.25h;	Step 1. N-(2-fluoro-4-nitrophenyl)-6,7-dimethoxyquinolin-4-amine (54) To a degassed mixture of Pd2(dba)3 (102 mg, 0.11 mmol), (2-biphenyl)dicyclohexylphosphine (78 mg, 0.22 mmol) and K3PO4 (807 mg, 3.80 mmol) in a under nitrogen were added DME (20 mL), 4-chloro-6,7-dimethoxyquinoline (4) (500 mg, 2.24 mmol) and <strong>[369-35-7]2-fluoro-4-nitroaniline</strong> (523 mg, 3.35 mmol), respectively. The reaction mixture was degassed again, stirred for 15 min at room temperature and heated at 100 C. in a sealed flask for 17 h. The reaction mixture was allowed to cool to room temperature then diluted with AcOEt and successively washed with water, a saturated solution of NaHCO3 and a saturated solutionof NH4Cl. The combined aqueous layers were extracted with AcOEt. The extract and the original AcOEt phase were combined, concentrated, adsorbed on silica gel, purified by flash column chromatography (eluents MeOH/DCM: 5/95-10/90, then 2% of ammonium hydroxide in MeOH/DCM: 10/90?15/85) and triturated with AcOEt with traces of DCM/hexanes, to afford the title compound 54 (748 mg, 97% yield) as a dark red-brown solid. MS (m/z): 344.2 (M+H).

Reference： [1]Patent: US2008/4273,2008,A1 .Location in patent: Page/Page column 72; 73

15
[ 35654-56-9 ]
[ 84478-72-8 ]
[ 205447-28-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	In pentanol, 2-; at 120℃; for 6h;	EXAMPLE 2 A suspension of 4-chloro-6,7-dimethoxyquinoline (0.2 g, 0.89 mmol) and <strong>[84478-72-8]4-chloro-2-fluoro-5-hydroxyaniline</strong> (173 mg, 1 mmol), (as described in EP 61741 A2), in 2-pentanol (2.5 ml) was heated at 120 C. for 6 hours.. The resulting solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline hydrochloride (231 mg, 67%) as a white solid.

Reference： [1]Patent: US6809097,2004,B1 .Location in patent: Page column 37-38

16
[ 35654-56-9 ]
[ 15125-84-5 ]
Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	With dmap; In 1,2-dichloro-benzene; at 120℃;	Compound 86: Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodobenzoate; 5-Iodosalicylic acid (528 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give <strong>[15125-84-5]ethyl 5-iodosalicylate</strong> (457 mg, yield 78%). Ethyl 5-iodosalicylate (457 mg), 4-chloro-6,7-dimethoxyquinoline (348 mg), and 4-dimethylaminopyridine (573 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (31 mg, yield 4%). 1H-NMR (CDCl3, 400 MHz): delta 0.90 (t, J = 7.1 Hz, 3H), 4.07 (m, 8H), 6.29 (d, J = 5.3 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 7.56 (s, 1H), 7.91 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 5.3 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 480 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 83-84

17
[ 23003-30-7 ]
[ 35654-56-9 ]
4-[(6-methyl-pyridin-3-yl)oxy]-6,7-dimethoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; In 1,2-dichloro-benzene; at 140℃;	Compound 115: 4-[(6-Methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline; 4-Chloro-6,7-dimethoxyquinoline (229 mg), <strong>[23003-30-7]3-hydroxy-2-iodo-6-methylpyridine</strong> (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140C overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (186 mg, yield 61%). 1H-NMR (CDCl3, 400 MHz): delta 2.63 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H), 6.44 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 2.7 Hz, 8.6 Hz, 1H), 7.44 (s, 1H), 7.54 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 297 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 91

18
[ 23003-30-7 ]
[ 35654-56-9 ]
[ 666730-32-1 ]

Yield	Reaction Conditions	Operation in experiment
11%	With dmap; In 1,2-dichloro-benzene; at 140℃;	Compound 116: 4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline; 4-Chloro-6,7-dimethoxyquinoline (229 mg), <strong>[23003-30-7]3-hydroxy-2-iodo-6-methylpyridine</strong> (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140C overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (47 mg, yield 11%). 1H-NMR (CDCl3, 400 MHz): delta 2.62 (s, 3H), 4.06 (s, 3H), 4.07 (s, 3H), 6.35 (d, J = 5.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.58 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 423 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 91

19
[ 35654-56-9 ]
[ 24985-85-1 ]
5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With dmap; In o-xylene;Heating / reflux;	Compound 22: Ethyl 5-[(6,7-dimethoxy-4-quinolyl)oxy]-1H-2-indolecarboxylate; 5-Hydroxy-1H-2-indolecarboxylic acid (328 mg) was dissolved in ethanol (10 ml) to prepare a solution. Concentrated sulfuric acid was added to the solution, and the mixture was heated under reflux for 3 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydrogencarbonate solution was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane to give ethyl 5-hydroxy-1H-2-indolecarboxylate (336 mg, yield 88%). 4-Chloro-6,7-dimethoxyquinoline (362 mg), ethyl 5-hydroxy-1H-2-indolecarboxylate (277 mg), and 4-dimethylaminopyridine (195 mg) were suspended in o-xylene, and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane on silica gel to give the title compound (161 mg, yield 30%). 1H-NMR (CDCl3, 400 MHz): delta 1.43 (t, J = 7.1 Hz, 3H), 4.07 (s, 3H), 4.07 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H), 6.43 (d, J = 5.4 Hz, 1H), 7.18 (dd, J = 2.2 Hz, 9.0 Hz, 1H), 7.24 (m, 1H), 7.47 (s, 1H), 7.50 - 7.52 (m, 2H), 7.64 (s, 1H), 8.46 (d, J = 5.4 Hz, 1H), 9.05 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 393 (M+1)+
	With dmap; In toluene; at 180℃; for 2h;Microwave irradiation;	Example 105; 5- (6, 7-Dimethoxy-quinolin-4-yloxy)- 1H-indole-2-carboxylic acid (3- methoxy-phenyl)-amide; (a) 5- (6, 7-Dimethoxy-quinolin-4-yloxy)-lH-indole-2-carboxylic acid ethyl ester.; A mixture of 4-chloro-6, 7-dimethoxy-quinoline (0.4 g, 1.8 mmol), 5-hydroxy-lH-indole-2- carboxylic acid ethyl ester (0.37 g, 1.8 mmol, Biosynth AG) and DMAP (0.22 g, 1.8 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180 C for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide a white foam as the desired compound. MS (ESI pos. ion) m/z: 393 (M+H). Calc'd Exact Mass for C22H2oN20s : 392.40.

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 65-66
[2]Patent: WO2005/73224,2005,A2 .Location in patent: Page/Page column 74

20
[ 35654-56-9 ]
[ 16239-18-2 ]
4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; In 1,2-dichloro-benzene; at 150℃; for 4.0h;	Compound 18: 4-[(6-Bromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline; 4-Chloro-6,7-dimethoxyquinoline (223 mg), <strong>[16239-18-2]1,6-dibromo-2-naphthol</strong> (910 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150C for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (326 mg, yield 67%). 4-[(1,6-Dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (65 mg) was dissolved in tetrahydrofuran (3 ml) to prepare a solution which was then cooled to -78C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added thereto, and the mixture was stirred at -78C for 20 min. Acetyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (28 mg, yield 51%). 1H-NMR (CDCl3, 400 MHz): delta 4.05 (s, 3H), 4.06 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H), 7.27 (s, 1H), 7.50 - 7.97 (m, 6H), 8.06 (m, 1H), 8.53 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 410 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 64

21
[ 35654-56-9 ]
[ 131-57-7 ]
{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		Compound 64: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-(phenyl)methanone; 4-Chloro-6,7-dimethoxyquinoline (56.5 mg), 2-hydroxy-4-methoxybenzophenone (286 mg), and 4-dimethylaminopyridine (163 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160C for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (14.5 mg, yield 14%). 1H-NMR (CDCl3, 400 MHz): delta 3.87 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H), 6.42 (d, J = 5.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.92 (s, 1H), 6.96 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.24 - 7.33 (m, 3H), 7.41 (m, 1H), 7.61 - 7.66 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 416 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 77
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3326 - 3329

22
[ 35654-56-9 ]
[ 1843-05-6 ]
{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-octoxyphenyl}-(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With dmap; In 1,2-dichloro-benzene; at 120℃; for 6h;	Compound 66: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-octoxyphenyl}-(phenyl)methanone; 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[1843-05-6]2-hydroxy-4-n-octoxybenzophenone</strong> (652 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C for 6 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (85 mg, yield 33%). 1H-NMR (CDCl3, 400 MHz): delta 0.89 (t, J = 6.8 Hz, 3H), 1.23 - 1.50 (m, 10H), 1.82 (m, 2H), 3.87 (s, 3H), 3.99 - 4.06 (m, 5H), 6.42 (d, J = 5.3 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.92 (s, 1H), 6.94 (dd, J = 2.2 Hz, 8.6 Hz, 1H), 7.27 (m, 2H), 7.30 (s, 1H), 7.39 (m, 1H), 7.63 (m, 2H), 7.67 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 5.3 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 514 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 78

23
[ 35654-56-9 ]
[ 15128-90-2 ]
6,7-Dimethoxy-4-(6-methyl-2-nitro-pyridin-3-yloxy)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		Compound 210: 6,7-Dimethoxy-4-(6-methyl-2-nitro-pyridin-3-yloxy)-quinoline; 2-Nitro-6-methylpyridin-3-ol (4.1 g), 4-chloro-6,7-dimethoxyquinoline (2 g), and 4-(N,N-dimethylamino)-pyridine (3.3 g) were dissolved in 1,2-dichlorobenzene (90 ml) to prepare a solution which was then stirred at 130C overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (732 mg, yield 24%). 1H-NMR (CDCl3, 400 MHz): delta 2.67 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H), 7.43 (s, 1H), 7.44 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 364 (M+Na)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 117-118

24
[ 35654-56-9 ]
[ 7120-43-6 ]
5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; In 1,2-dichloro-benzene; at 120℃;	Compound 106: 5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide; 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[7120-43-6]5-chloro-2-hydroxybenzamide</strong> (343 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (265 mg, yield 100%). 1H-NMR (CDCl3, 400 MHz): delta 3.68 (s, 3H), 3.86 (s, 3H), 6.22 - 6.61 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 7.31 (s, 1H), 7.44 (s, 1H), 8.10 (m, 1H), 8.20 (d, J = 2.7 Hz, 1H), 8.58 - 8.62 (m, 2H) Mass spectrometric value (ESI-MS, m/z): 359 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 89

25
[ 35654-56-9 ]
[ 118-58-1 ]
Benzyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With dmap; In 1,2-dichloro-benzene; at 120℃;	Compound 103: Benzyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[118-58-1]benzylsalicylate</strong> (456 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (68 mg, yield 33%). 1H-NMR (CDCl3, 400 MHz): delta 3.93 (s, 3H), 4.09 (s, 3H), 5.02 (s, 2H), 6.28 (d, J = 5.5 Hz, 1H), 6.92 (m, 2H), 7.06 - 7.24 (m, 4H), 7.35 - 7.45 (m, 2H), 7.57 (s, 1H), 7.65 (td, J = 7.6, 1.7 Hz, 1H), 8.14 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 416 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 88

26
[ 35654-56-9 ]
[ 394-32-1 ]
1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-fluorophenyl}-1-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		Compound 33: 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-fluorophenyl}-1-ethanone; 4-Chloro-6,7-dimethoxyquinoline (58.2 mg), <strong>[394-32-1]5-fluoro-2-hydroxyacetophenone</strong> (409 mg), and 4-dimethylaminopyridine (317 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160C for 8 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (63.5 mg, yield 72%). 1H-NMR (CDCl3, 400 MHz): delta 2.53 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H), 6.41 (d, J = 5.1 Hz, 1H), 7.17 (dd, J = 4.4 Hz, 9.0 Hz, 1H), 7.30 (m, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 7.64 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 342 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 68
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3326 - 3329

27
[ 35654-56-9 ]
[ 52873-25-3 ]
Ethyl 4-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With dmap; In 1,2-dichloro-benzene; at 120.0℃;	Compound 81: Ethyl 4-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate; 4-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give <strong>[52873-25-3]ethyl 4-chlorosalicylate</strong> (174 mg, yield 43%). Ethyl 4-chlorosalicylate (174 mg), 4-chloro-6,7-dimethoxyquinoline (195 mg), and 4-dimethylaminopyridine (320 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (26 mg, yield 8%). 1H-NMR (CDCl3, 400 MHz): delta 0.88 (t, J = 7.1 Hz, 3H), 4.06 (m, 8H), 6.31 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.43 (s, 1H), 7.56 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 388 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 82

28
[ 35654-56-9 ]
[ 703-98-0 ]
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyphenyl}-1-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With dmap; In 1,2-dichloro-benzene; at 150℃; for 2h;	Compound 30: 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyphenyl}-1-ethanone; 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[703-98-0]2-hydroxy-3-methoxyacetophenone</strong> (223 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150C for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (46 mg, yield 28%). 1H-NMR (CDCl3, 400 MHz): delta 2.41 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.52 (d, J = 5.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.43 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 354 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 67

29
[ 53233-89-9 ]
[ 35654-56-9 ]
4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With dmap; In 1,2-dichloro-benzene; at 160℃; for 3.0h;	Compound 222: 4-(5-Chloro-2-cyclopentyloxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline; 4-Chloro-6,7-dimethoxyquinoline (226 mg), <strong>[53233-89-9]3-chloro-5,6-dihydroxypyridine</strong> (290 mg), and 4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160C for 3 hr. The reaction solution was cooled to room temperature, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (83 mg, yield 25%). 4-(5-Chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (39 mg) was suspended in N,N-dimethylformamide (7 ml). Cyclopentyl bromide (0.3 ml) and potassium carbonate (300 mg) were added to the suspension, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (29 mg, yield 62%). 1H-NMR (CDCl3, 400 MHz): delta 1.24 - 1.78 (m, 8H), 4.05 (s, 3H), 4.06 (s, 3H), 5.38 (m, 1H), 6.35 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.51 (m, 2H), 8.05 (m, 1H), 8.50 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 401 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 121

30
[ 35654-56-9 ]
[ 55758-32-2 ]
4-(6-Fluoro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dmap; In 1,2-dichloro-benzene; at 140℃; for 3.5h;	Compound 205: 4-(6-Fluoro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline; 6-Fluoro-3-hydroxypyridine (10 mg), 4-chloro-6,7-dimethoxyquinoline (59 mg), and 4-dimethylaminopyridine (32 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140C for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 76%). 1H-NMR (CDCl3, 400 MHz): delta 3.98 (s, 6H), 6.35 (d, J = 5.2 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 3.6 Hz, 1H), 7.36 (s, 1H), 7.44 (s, 1H), 7.56 (m, 1H), 8.09 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 301 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 116

31
[ 35654-56-9 ]
[ 117-99-7 ]
{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	Stage #1: 6,7-dimethoxy-4-chloroquinoline; 2-Hydroxybenzophenone at 180℃; for 1h; Stage #2: With sodium hydroxide In chloroform; water Stage #3: With hydrogenchloride In methanol	Compound 63: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone hydrochloride Compound 63: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-phenyl}(phenyl)-methanone hydrochloride; 4-Chloro-6,7-dimethoxyquinoline (0.92 g) and 2-hydroxybenzophenone (1.64 g) were stirred at 180°C for one hr, and the reaction solution was cooled to room temperature. Chloroform was then added to the reaction solution, and separation was carried out with a 10% aqueous sodium hydroxide solution. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using hexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) was added to the product, followed by concentration. The concentrate was suspended in ether. The suspension was filtered to give the title compound (174 mg, yield 10%). 1H-NMR (CDCl3, 400 MHz): δ 3.92 (s, 3H), 4.13 (s, 3H), 6.66 (d, J = 6.4 Hz, 1H), 7.15 (s, 1H), 7.35 - 7.41 (m, 3H), 7.52 - 7.61 (m, 2H), 7.67 - 7.79 (m, 4H), 8.08 (s, 1H), 8.44 (dd, J = 6.6 Hz, 6.6 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 386 (M-HCl+1)+

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 77

32
[ 35654-56-9 ]
[ 30992-63-3 ]
1-[5-Benzyloxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%	With dmap; In 1,2-dichloro-benzene; at 130℃; for 10h;	Compound 175: 1-[5-Benzyloxy-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone; 2,5-Dihydroxyacetophenone (3.00 g), benzyl bromide (2.48 g), and potassium carbonate (8.16 g) were suspended in acetonitrile (30 ml) to prepare a suspension which was heated under reflux overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give 3-benzyloxy-6-hydroxyacetophenone (1.88 g, yield 39%). 3-Benzyloxy-6-hydroxyacetophenone (1.88 g), 4-chloro-6,7-dimethoxyquinoline (3.43 g), and 4-dimethylaminopyridine (1.41 g) were suspended in o-dichlorobenzene (20 ml) to prepare a suspension which was then stirred at 130C for 10 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (188 mg, yield 6%). 1H-NMR (CDCl3, 400 MHz): delta 2.41 (s, 3H), 3.97 (s, 6H), 5.06 (s, 2H), 6.31 (d, J = 5.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H), 7.25 - 7.41 (m, 6H), 7.45 (d, J = 3.2 Hz, 1H), 7.49 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 430 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 107
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3326 - 3329

33
[ 35654-56-9 ]
[ 87-20-7 ]
Isoamyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; In 1,2-dichloro-benzene; at 120 - 140℃;	Compound 99: Isoamyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate; 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[87-20-7]isoamyl salicylate</strong> (416 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight and at 140C for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (110 mg, yield 56%). 1H-NMR (CDCl3, 400 MHz): delta 0.67 (m, 6H), 1.13 (m, 2H), 1.34 (m, 1H), 4.06 (m, 8H), 6.29 (d, J = 5.2 Hz, 1H), 7.23 (m, 1H), 7.40 (m, 2H), 7.62 (m, 2H), 8.07 (m, 1H), 8.46 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 396 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 87

34
[ 35654-56-9 ]
[ 6949-73-1 ]
2-[(6,7-Dimethoxy-4-quinolyl)oxy]fluoren-9-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With dmap; In 1,2-dichloro-benzene; at 160℃; for 7h;	Compound 19: 2-[(6,7-Dimethoxy-4-quinolyl)oxy]fluoren-9-one; 4-Chloro-6,7-dimethoxyquinoline (100 mg), <strong>[6949-73-1]2-hydroxy-9-fluorenone</strong> (269 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160C for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (58 mg, yield 34%). 1H-NMR (CDCl3, 400 MHz): delta 4.03 (s, 3H), 4.04 (s, 3H), 6.56 (d, J = 5.2 Hz, 1H), 7.27 - 7.29 (m, 2H), 7.44 - 7.67 (m, 7H), 8.51 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 384 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 64-65

35
[ 35654-56-9 ]
[ 3679-64-9 ]
N-(4-Chlorophenyl)-5-bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With dmap In 1,2-dichloro-benzene at 120℃;	Compound 108: N-(4-Chlorophenyl)-5-bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide Compound 108: N-(4-Chlorophenyl)-5-bromo-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide; 4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-bromo-4'-chlorosalicylanilide (653 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120°C overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (59 mg, yield 23%). 1H-NMR (CDCl3, 400 MHz): δ 3.85 (s, 3H), 4.02 (s, 3H), 6.83 (d, J = 5.1 Hz, 1H), 6.99 - 7.47 (m, 9H), 8.68 (d, J = 4.9 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 513 (M-1)-

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1548008, 2005, A1 Location in patent: Page/Page column 89

36
[ 35654-56-9 ]
[ 613-84-3 ]
[ 666734-37-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap In chloroform; 1,2-dichloro-benzene at 160℃; for 2h;	Compound 188: [2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-(4-hydroxy-phenyl)-methanone; 4-Bromophenol (1.00 g) was dissolved in N,N-dimethylformamide (20 ml) to prepare a solution. Imidazole (0.95 g) and tert-butylchlorodimethylsilane (1.05 g) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (1.586 g, yield 96%). 2-Hydroxy-5-methyl-benzaldehyde (344 mg), 4-chloro-6,7-dimethoxyquinoline (113 mg), and 4-dimethylaminopyridine (313 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160°C for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-benzaldehyde (157 mg, yield 96%). (4-Bromo-phenoxy)-tert-butyl-dimethyl-silane (175 mg) was dissolved in tetrahydrofuran (3 ml) to prepare a solution which was cooled to -78°C. A 1.41 M n-pentane solution (0.86 ml) of tert-butyllithium was added dropwise to the cooled solution, and the mixture was stirred at -78°C for 20 min. A solution of 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-benzaldehyde(164 mg) in tetrahydrofuran was added dropwise thereto, and the mixture was stirred at -78°C for one hr and then at 0°C for 30 min. A saturated ammonium chloride solution was added thereto to stop the reaction, and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue as such was used for the next reaction. The residue (252 mg) of the reaction was dissolved in methylene chloride (5 ml) to prepare a solution. A solution of 1,8-diazabicyclo[5.4.0]undeca-7-ene (154 mg) in methylene chloride was added to the solution, and the mixture was cooled to -78°C. A solution of N-tert-butylbenzenesulfineimidoyl (164 mg) in methylene chloride was added thereto, and the mixture was stirred at -78°C for one hr. Further, a solution of N-tert-butylbenzenesulfineimidoyl (55 mg) in methylene chloride was added thereto, and the mixture was stirred at -78°C for 30 min and then at 0°C for 20 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue as such was used for the next reaction. A part (384 mg) of the residue of the reaction was dissolved in tetrahydrofuran (5 ml) to prepare a solution which was cooled to 0°C. A solution (1 ml) of tetrabutylammonium fluoride in tetrahydrofuran was then added thereto, and the mixture was stirred for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (128 mg, yield 61%) (3 steps). 1H-NMR (CDCl3, 400 MHz): δ 2.45 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.44 (d, J = 5.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.38 - 7.41 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 8.33 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 416 (M+1)+
96%	With dmap In 1,2-dichloro-benzene at 160℃;
96%	With dmap In 1,2-dichloro-benzene at 160℃; for 2h;	1 4-Chloro-6,7-dimethoxyquinoline (113 mg), 2-hydroxy-5-methylbenzaldehyde (344 mg), and 4-dimethylaminopyridine (313 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160°C for 2 hr. The reaction mixture was cooled to room temperature, and the solvent was then removed from the reaction mixture by distillation under the reduced pressure. Chloroform was added to the residue. The organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed from the reaction mixture by distillation under the reduced pressure. The residue was purified by column chromatography with a chloroform system to give the title compound (157 mg, yield 96%). 1H-NMR (CDCl3, 400 MHz): δ 2.46 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H), 6.44 (d, J = 5.1 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.49 (m, 1H), 7.57 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 1.5 Hz, 1H), 10.28 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 324 (M+1)+

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1548008, 2005, A1 Location in patent: Page/Page column 111-112
[2]Shimizu, Toshiyuki; Kimura, Kaname; Sakai, Teruyuki; Kawakami, Kazuki; Miyazaki, Tetsuko; Nakouji, Masayoshi; Ogawa, Akira; Ohuchi, Hitomi; Shimizu, Kiyoshi [Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3326 - 3329]
[3]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1724268, 2006, A1 Location in patent: Page/Page column 99

37
[ 35654-56-9 ]
[ 394-50-3 ]
2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In chlorobenzene; at 130℃;	Compound 43: 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanone; 4-Chloro-6,7-dimethoxyquinoline (111 mg), <strong>[394-50-3]3-fluorosalicylaldehyde</strong> (280 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130°C overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde. 2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added thereto at 0°C, and the mixture was stirred at 0°C for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol. 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml). Sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0°C, and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (2 mg, yield 1percent). 1H-NMR (CDCl3, 400 MHz): delta 1.03 (t, J = 7.2 Hz, 3H), 2.84 (q, J = 7.2 Hz, 2H), 4.05 (s, 6H), 6.34 (d, J = 5.4 Hz, 1H), 7.32 - 7.42 (m, 2H), 7.45 (s, 1H), 7.56 (s, 1H), 7.63 - 7.67 (m, 1H), 8.48 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 356 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 70-71

38
[ 35654-56-9 ]
[ 93249-62-8 ]
2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In chlorobenzene; at 130℃;	Compound 51: 1-[2-(6,7-Dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl]-1-propanone; 4-Chloro-6,7-dimethoxyquinoline (111 mg), <strong>[93249-62-8]5-trifluoromethoxysalicylaldehyde</strong> (412 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130C overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde. 2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenz-aldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0C, and the mixture was stirred at 0C for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanol. 1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution, a sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0C, and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (18 mg, yield 8%). 1H-NMR (CDCl3, 400 MHz): delta 1.06 (t, J = 7.2 Hz, 3H), 2.91 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.47 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 7.38 (dd, J = 3.0 Hz, 9.0 Hz, 1H), 7.45 (s, 1H), 7.46 (s, 1H), 7.73 (d, J = 2.9 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 422 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 74

39
[ 35654-56-9 ]
[ 14770-96-8 ]
{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	at 180℃; for 9h;	Compound 74: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-(phenyl)methanone Compound 74: {2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-(phenyl)methanone; A mixture of 4-chloro-6,7-dimethoxyquinoline (93 mg) with 2-hydroxy-5-methoxybenzophenone (462 mg) was stirred at 180°C for 9 hr. The reaction solution was cooled to room temperature and was purified by column chromatography on silica gel using acetone-hexane to give the title compound (14 mg, yield 8%). 1H-NMR (CDCl3, 500 MHz): δ 3.87 (s, 3H), 3.89 (s, 3H), 4.00 (s, 3H), 6.42 (d, J = 5.5 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.92 (s, 1H), 6.96 (dd, J = 2.4 Hz, 8.6 Hz, 1H), 7.26 - 7.29 (m, 3H), 7.31 (s, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 5.5 Hz, 1H) Mass spectrometric value (FD-MS, m/z): 415 (M+)
8%	With dmap In 1,2-dichloro-benzene at 160℃;

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1548008, 2005, A1 Location in patent: Page/Page column 80
[2]Shimizu, Toshiyuki; Kimura, Kaname; Sakai, Teruyuki; Kawakami, Kazuki; Miyazaki, Tetsuko; Nakouji, Masayoshi; Ogawa, Akira; Ohuchi, Hitomi; Shimizu, Kiyoshi [Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3326 - 3329]

40
[ 35654-56-9 ]
[ 6555-40-4 ]
Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-6-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; In 1,2-dichloro-benzene; at 120 - 140℃;	Compound 92: Ethyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]-6-methylbenzoate; 4-Chloro-6,7-dimethoxyquinoline (112 mg), <strong>[6555-40-4]ethyl 6-methylsalicylate</strong> (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120C overnight and was further stirred at 140C for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (168 mg, yield 91%). 1H-NMR (CDCl3, 400 MHz): delta 0.96 (t, J = 7.1 Hz, 3H), 2.44 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H), 4.10 (q, J = 7.1 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.52 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 368 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 85

41
[ 1990-24-5 ]
[ 35654-56-9 ]
1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-propylphenyl}-1-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With dmap; In 1,2-dichloro-benzene; at 130℃; for 8.0h;	Compound 173: 1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-propyl-phenyl]-ethanone; 4-n-Propylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (862 mg) and acetyl chloride (692 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 4-n-propylphenyl acetate (1.09 g, yield 100%). 4-n-Propylphenyl acetate (1.07 g) and scandium trifluoromethanesulfonate (345 mg) were suspended in toluene (10 ml), and the suspension was stirred at 120C for 7 hr. The reaction solution was cooled to room temperature, and the cooled reaction solution was then filtered. The solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give <strong>[1990-24-5]2-hydroxy-5-n-propylacetophenone</strong> (276 mg, yield 26%). 2-Hydroxy-5-n-propylacetophenone (276 mg), 4-chloro-6,7-dimethoxyquinoline (117 mg), and 4-dimethylaminopyridine (191 mg) were suspended in o-dichlorobenzene (6.5 ml), and the suspension was stirred at 130C for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (50 mg, yield 26%). 1H-NMR (CDCl3, 400 MHz): delta 0.90 (t, J = 7.2 Hz, 3H), 1.61 (qt, J = 7.2 Hz, J = 7.6 Hz, 2H), 2.44 (s, 3H), 2.59 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 3.97 (s, 3H), 6.35 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.30 - 7.37 (m, 2H), 7.48 (s, 1H), 7.65 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 366 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 106
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3326 - 3329

42
[ 74115-12-1 ]
[ 35654-56-9 ]
4-(5-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; In 1,2-dichloro-benzene; at 140℃; for 6h;	Compound 208: 4-(5-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline; 4-Chloro-6,7-dimethoxyquinoline (245 mg), 3-chloro-5-pyridinol (277 mg), and 4-dimethylaminopyridine (377 mg) were suspended in o-dichlorobenzene (13 ml), and the mixture was stirred at 140C for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (283 mg, yield 81%). 1H-NMR (CDCl3, 400 MHz): delta 4.04 (s, 3H), 4.06 (s, 3H), 6.56 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.46 (s, 1H), 7.53 (m, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.58 (d, J = 5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 317 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 117

43
[ 1122-43-6 ]
[ 35654-56-9 ]
4-(2,6-dimethyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; In 1,2-dichloro-benzene; at 130℃;	Compound 209: 4-(2,6-Dimethyl-pyrridin-3-yloxy)-6,7-dimethoxy-quinoline; <strong>[1122-43-6]2,6-Dimethylpyridin-3-ol</strong> (165 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)-pyridine (164 mg) were dissolved in 1,2-dichlorobenzene (4.5 ml) to prepare a solution which was then stirred at 130C overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (116 mg, yield 83%). 1H-NMR (CDCl3, 400 MHz): delta 2.41 (s, 3H), 2.60 (s, 3H), 4.08 (s, 6H), 6.30 (d, J = 5.6 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.59 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 311 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 117

44
[ 35654-56-9 ]
[ 86-48-6 ]
6,7-dimethoxy-4-(1-naphthyloxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap In 1,2-dichloro-benzene at 150℃; for 2h;	Compound 16: 6,7-Dimethoxy-4-(1-naphthyloxy)quinoline Compound 16: 6,7-Dimethoxy-4-(1-naphthyloxy)quinoline; 4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-naphthonic acid (252 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150°C for 2 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (119 mg, yield 80%). 1H-NMR (CDCl3, 400 MHz): δ 3.96 (s, 6H), 6.22 (d, J = 5.2 Hz, 1H), 7.22 (m, 1H), 7.31 - 7.40 (m, 4H), 7.64 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.0 Hz, 2H), 8.31 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 332 (M+1)+

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 64

45
[ 1121-25-1 ]
[ 35654-56-9 ]
6,7-Dimethoxy-4-(2-methyl-pyridin-3-yloxy)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; In 1,2-dichloro-benzene; at 135℃; for 48h;	Compound 202: 6,7-Dimethoxy-4-(2-methyl-pyridin-3-yloxy)-quinoline; 4-Chloro-6,7-dimethoxyquinoline (245 mg), <strong>[1121-25-1]2-methyl-3-pyridinol</strong> (227 mg), and 4-dimethylaminopyridine (420 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 135C for 2 days. The reaction solution was cooled to room temperature. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (324 mg, yield 100%). 1H-NMR (CDCl3, 400 MHz): delta 2.48 (s, 3H), 4.07 (s, 3H), 4.07 (s, 3H), 6.28 (d, J = 5.4 Hz, 1H), 7.27 (m, 1H), 7.42 - 7.46 (m, 2H), 7.56 (d, J = 1.7 Hz, 1H), 8.48 - 8.50 (m, 2H) Mass spectrometric value (ESI-MS, m/z): 297 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 116

46
[ 35654-56-9 ]
[ 28480-70-8 ]
1-{5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methylphenyl}-1-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With dmap In 1,2-dichloro-benzene at 150℃; for 2h;	Compound 37: 1-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methyrlphenyl}-1-ethanone Compound 37: 1-{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methyrlphenyl}-1-ethanone; 4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxy-4-methylacetophenone (248 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150°C for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (71 mg, yield 45%). 1H-NMR (CDCl3, 400 MHz): δ 2.32 (s, 3H), 2.42 (s, 3H), 3.97 (s, 6H), 6.39 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 7.43 (s, 1H), 7.47 (s, 1H), 7.83 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 372 (M+1)+
	With dmap In 1,2-dichloro-benzene at 130℃;

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 69
[2]Shimizu, Toshiyuki; Kimura, Kaname; Sakai, Teruyuki; Kawakami, Kazuki; Miyazaki, Tetsuko; Nakouji, Masayoshi; Ogawa, Akira; Ohuchi, Hitomi; Shimizu, Kiyoshi [Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3326 - 3329]

47
[ 26278-79-5 ]
[ 35654-56-9 ]
6-(6,7-dimethoxyquinolin-4-yloxy)benzo[d]thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; copper; In dichloromethane; at 100℃; for 0.166667h;Microwave irradiation;	Example 1; (2-Chlorobenzyl)- [6- (6, 7- dimethoxy-quinolin-4-yloxy)- benzothiazol-2-yl-amine; (a) 6- (6, 7-Dimethoxy-quinolin-4-yloxy)-benzothiazol-2-ylamine.; To a microwave vial was added 4-chloro-6,7-dimethoxy-quinoline prepared by the method of Miwa, et al. , (WO 03/33472) (0.300 g, 1.3 mmol), 2-amino-benzothiazol-6-ol (0. 334 g, 2.0 mmol) and KOH pellets (0.140 g, 2.6 mmol), followed by 4% by weight of Cu powder in 3 mL of dry CH2C12. The sealed vial was microwaved for 10 min at 100 C and 60 W. (Powermax, CEM). The mixture was diluted with CH2C12 and transferred to a separation funnel. NaOH (40 mL) was added and the organic layer was extracted 3X with CH2C12. The organics were combined, dried over Na2S04, filtered, and concentrated in-vacuo. The crude compound was purified by crystallization from 10% CH2C12/Hexanes to give the titled compound as a light purple powder. MS (ESI pos. ion) m/z: 354 (M+H). Calc'd Exact Mass for C18Hl5N303S : 353.08.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1442 - 1445
[2]Patent: WO2005/73224,2005,A2 .Location in patent: Page/Page column 52

48
[ 87-17-2 ]
[ 35654-56-9 ]
N-Phenyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; In 1,2-dichloro-benzene; at 140℃; for 4h;	Compound 104: N-Phenyl-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzamide; 4-Chloro-6,7-dimethoxyquinoline (56 mg), <strong>[87-17-2]salicylanilide</strong> (213 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140C for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (86 mg, yield 86%). 1H-NMR (CDCl3, 400 MHz): delta 3.82 (s, 3H), 4.02 (s, 3H), 6.41 (m, 1H), 6.98 (m, 2H), 7.06 (d, J = 4.9 Hz, 1H), 7.09 (s, 1H), 7.18 - 7.28 (m, 4H), 7.33 - 7.38 (m, 2H), 7.45 (s, 1H), 8.66 (d, J = 4.9 Hz, 1H), 10.50 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 399 (M-1)-

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 88

49
[ 85-19-8 ]
[ 35654-56-9 ]
{5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound 68: {5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanone; 4-Chloro-6,7-dimethoxyquinoline (57.5 mg), <strong>[85-19-8]5-chloro-2-hydroxybenzophenone</strong> (309 mg), and 4-dimethylaminopyridine (173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160C for 5 hr. The mixture was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 114 mg of the title compound. 1H-NMR (CDCl3, 400 MHz): delta 3.82 (s, 3H), 3.99 (s, 3H), 6.44 (d, J = 5.1 Hz, 1H), 6.90 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.31 - 7.37 (m, 3H), 7.46 - 7.51 (m, 1H), 7.58 (dd, J = 2.7 Hz, 8.8 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 7.68 - 7.72 (m, 2H), 8.45 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 420 (M+1)+

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 3326 - 3329
[2]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 78

50
[ 85-19-8 ]
[ 35654-56-9 ]
{5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		Compound 69: {5-Chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-(phenyl)methanone hydrochloride 4-Chloro-6,7-dimethoxyquinoline (1.00 g) and <strong>[85-19-8]5-chloro-2-hydroxybenzophenone</strong> (1.46 g) were stirred at 170C for one hr, and the reaction solution was cooled to room temperature. Chloroform was then added to the reaction solution, and separation was carried out with a 10% aqueous sodium hydroxide solution. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using hexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) was added to the product, followed by concentration. The concentrate was suspended in ether, and the suspension was filtered to give the title compound (225 mg, yield 11%). 1H-NMR (CDCl3, 400 MHz): delta 3.91 (s, 3H), 4.12 (s, 3H), 6.68 (d, J = 5.6 Hz, 1H), 7.11 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.54 - 7.60 (m, 1H), 7.66 - 7.74 (m, 4H), 8.08 (s, 1H), 8.48 (brs, 1H) Mass spectrometric value (ESI-MS, m/z): 420 (M-HCl+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 78-79

51
[ 41288-96-4 ]
[ 35654-56-9 ]
[ 666731-22-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; In 1,2-dichloro-benzene; at 140℃; for 2h;	Compound 206: 4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline; 2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline (861 mg), and 4-dimethylaminopyridine (283 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140C for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (164 mg, yield 67%). 1H-NMR (CDCl3, 400 MHz): delta 4.00 (s, 3H), 4.02 (s, 3H), 6.45 (d, J = 5.2 Hz, 1H), 7.31 - 7.49 (m, 4H), 8.31 (d, J = 3.2 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 317 (M+1)+
64.8%		<strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (310 mg, 2.3 mmol) and TEA (5 mL, 28.7 mmol) were added sequentially to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (354 mg, 1.58 mmol) in chlorobenzene (3 mL). The resulting solution was heated to 140 C for 12 h. The reaction mixture was quenched with H20 (100 mL), and EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eluting with 0No.10% CH30H in EtOAc) to give 4-[(6-chloropyridin-3- yl) oxy]-6,7-dimethoxyquinoline as a light brown yellow oil (324.2 mg; 1.02 mmol; 64.8% yield) ; MS (APCI) (M+H)(at) 317. 'H NMR (400 MHz, CDCls) 6 ppm 4.00 (s, 3 H) 4.01 (s, 3 H) 6.45 (d, .1=5.3 Hz, 1 H) 7.44 (m, 4 H) 8.32 (d, J=2.5 Hz, 1 H) 8.51 (d, J=5.1 Hz, 1 H).
1.16g	With triethylamine; In chlorobenzene; at 140℃; for 120h;Inert atmosphere;	In the nitrogen flow, the 4-chloro -6,7-dimethoxy-quinoline (1.00g) (CAS Denn segni: 35654-56-9) in chlorobenzene (9 ml) of the solution in the, 6-chloro-pyridine-3-ol (0.65g) and triethylamine (11.3 ml) in 100 ml flask in four necks, and the mixture is in the bath temperature (140 C) stirring five days. The cup the obtained solution to room temperature, adding water and ethyl acetate, and the solution separation. The aqueous layer is extracted once again with ethyl acetate, the combined organic layer with saturated aqueous salt solution washing, drying with anhydrous sodium sulfate. The solvent is distilled under reduced pressure. The resulting residue with silica gel column chromatography (hexane: ethyl acetate = 1:8) purification, to obtain the title compound (1.16g), which has the following physical property value.

28 g

With dmap; In chlorobenzene; at 140℃; for 42h;Inert atmosphere;

Example 1 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxy quinoline Under a stream of nitrogen, a solution of 4-chloro-6,7-dimethoxy quinoline (39 g) (CAS registration No.: 35654-56-9) in chlorobenzene (400 mL), <strong>[41288-96-4]6-chloropyridine-3-ol</strong> (25 g), and 4-dimethylaminopyridine (DMAP) (64 g) were placed into a 2-L four-necked flask, and the mixture was stirred at a bath temperature (140C) for 42 hours. The resulting solution was allowed to cool to room temperature, water (700 mL) and ethyl acetate (1 L) were added thereto, and the solution was separated. The water layer was extracted again with ethyl acetate (1 L). The combined organic layer was washed with a saturated saline solution (500 mL), and dried over anhydrous sodium sulfate, and a solvent was removed by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1:8) to obtain the title compound (28 g) having the following physical property values. TLC: Rf 0.22 (hexane : ethyl acetate = 1:3); 1H-NMR (DMSO-d6): delta 8.52, 8.48, 7.87 - 7.85, 7.66, 7.49, 7.43, 6.65, 3.95, 3.93.

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 117
[2]European Journal of Medicinal Chemistry,2008,vol. 43,p. 1321 - 1329
[3]Patent: WO2005/121125,2005,A1 .Location in patent: Page/Page column 42-43
[4]Patent: CN105408312,2016,A .Location in patent: Paragraph 0274; 0275; 0276; 0277; 0278
[5]Patent: EP3239147,2017,A1 .Location in patent: Paragraph 0128
[6]Patent: US2019/389837,2019,A1 .Location in patent: Paragraph 0125-0127

52
[ 35654-56-9 ]
[ 6921-66-0 ]
1-[4-Chloro-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With dmap; In 1,2-dichloro-benzene; at 120 - 140℃;	Compound 181: 1-[4-Chloro-2-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-ethanone; 4-Chloro-2-hydroxyacetophenone (45 mg), 4-chloro-6,7-dimethoxyquinoline (60 mg), and 4-dimethylaminopyridine (95 mg) are suspended in o-dichlorobenzene (10 ml) to prepare a suspension which was then stirred at 120C overnight and then at 140C for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (11 mg, yield 12%). 1H-NMR (CDCl3, 400 MHz): delta 2.54 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H), 6.51 (d, J = 5.4 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 2.0 Hz, 8.6 Hz, 1H), 7.48 (m, 2H), 7.91 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 358 (M+1)+

Reference： [1]Patent: EP1548008,2005,A1 .Location in patent: Page/Page column 108-109

53
[ 35654-56-9 ]
[ 2052-14-4 ]
Butyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With dmap In 1,2-dichloro-benzene at 120 - 140℃;	Compound 98: Butyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate Compound 98: Butyl 2-[(6,7-dimethoxy-4-quinolyl)oxy]benzoate; 4-Chloro-6,7-dimethoxyquinoline (100 mg), butyl salicylate (388 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120°C overnight and at 140°C for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (106 mg, yield 57%). 1H-NMR (CDCl3, 400 MHz): δ 0.66 (t, J = 7.3 Hz, 3H), 1.06 (m, 2H), 1.24 (m, 2H), 4.03 (m, 8H), 6.28 (d, J = 5.3 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.37 - 7.43 (m, 2H), 7.63 (m, 2H), 8.07 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 8.45 (d, J = 5.3 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 382 (M+1)+

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1548008, 2005, A1 Location in patent: Page/Page column 87

54
[ 35654-56-9 ]
[ 5930-28-9 ]
[ 286371-47-9 ]

Yield	Reaction Conditions	Operation in experiment
22%	With dimethyl sulfoxide; In water;	Production Example 4: 3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline Sodium hydride (60 wtpercent, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50°C for 30 min and was then cooled to room temperature. 4-Amino-2,6-dichlorophenol (1.59 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100°C overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give 0.35 g (yield 22percent) of the title compound. 1H-NMR (CDCl3, 400 MHz): delta 3.84 (s, 2H), 4.05 (s,3H), 4.08 (s, 3H), 6.28 (d, J = 5.4 Hz, 1H), 6.74 (s, 2H), 7.43 (s, 1H), 7.64 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H)

Reference： [1]Patent: EP1153920,2001,A1

55
[ 35654-56-9 ]
[ 3096-71-7 ]
[ 286371-46-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfoxide; In water;	Production Example 3: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline Sodium hydride (60 wt%, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50C for 30 min and was then cooled to room temperature. 4-Amino-2,5-dimethylphenol (1.23 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100C overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give the title compound.

Reference： [1]Patent: EP1153920,2001,A1

56
[ 156-38-7 ]
[ 35654-56-9 ]
[ 948570-72-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With caesium carbonate In N,N-dimethyl-formamide at 170℃; for 9h;
46%	Stage #1: 4-hydroxyphenylacetate With hydrogenchloride; caesium carbonate In dimethyl sulfoxide at 100℃; for 0.833333h; Stage #2: 6,7-dimethoxy-4-chloroquinoline In dimethyl sulfoxide at 100℃; for 2h;	32.2 Step 2. 2-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)acetic acid (73) A suspension of cesium carbonate (0.728 g, 2.236 mmol) in DMSO (2.236 mL) was heated at 100° C. under atmosphere of nitrogen for 20 mins. 4-hydroxyphenyacetic acid (0.136 g, 0.894 mmol) was added and the mixture was stirred for an additional 30 mins followed by the addition of compound 4 (0.200 g, 0.894 mmol). The reaction mixture was stirred at 100° C. for a further 2 h. The reaction mixture was diluted with water, washed with EtOAc then acidified (pH~4) by addition of 2N HCl and filtered. The precipitate was dried overnight under vacuum to afford crude compound 73 (0.140 g, 46% yield) as a brown solid that was used in the next step without further purification. MS (m/z): 340.2 (M+H).
	Stage #1: 4-hydroxyphenylacetate; 6,7-dimethoxy-4-chloroquinoline With caesium carbonate In N,N-dimethyl-formamide for 7h; Heating / reflux; Stage #2: With acetic acid In water	1 The 2- [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl] acetic acid used as a starting materialI5 was prepared as follows:- A mixture of 4-chloro-6,7-dimethoxyquinoline (1.28 g; International Patent Application WO 98/13350, Example 2 thereof), 2-(4-hydroxyphenyl)acetic acid (1.73 g), caesium carbonate (7.46 g) and DMF (12.5 ml) was stirred and heated to reflux for 7 hours. The mixture was cooled to ambient temperature and diethyl ether was added. The gummy 0 precipitated solid was dissolved in water and washed with methylene chloride. The aqueous solution was acidified to pH4.5 by the addition of glacial acetic acid. The resultant precipitate was isolated, washed with water and with diethyl ether and dried under vacuum. There was thus obtained the required starting material (1.57 g); 1H NMR: (DMSOd6) 3.64 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.46 (d, IH), 7.21 (d, 2H), 7.39 (s, IH), 7.41 (d, 2H), 7.49 (s, IH), 8.48 5 (d, IH); Mass Spectrum: M+H+ 340.

With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 7h;

Reference： [1]Location in patent: scheme or table Plé, Patrick A.; Jung, Frédéric; Ashton, Sue; Hennequin, Laurent; Laine, Romuald; Lambert-Van Der Brempt, Christine; Morgentin, Rémy; Pasquet, Georges; Taylor, Sian [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3050 - 3055]
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2008/4273, 2008, A1 Location in patent: Page/Page column 77
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2007/99326, 2007, A1 Location in patent: Page/Page column 102
[4]Location in patent: scheme or table Plé, Patrick A.; Jung, Frédéric; Ashton, Sue; Hennequin, Laurent; Laine, Romuald; Morgentin, Rémy; Pasquet, Georges; Taylor, Sian [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 262 - 266]

57
[ 35654-56-9 ]
[ 185220-68-2 ]
[ 417722-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; ethyl acetate;	Production Example 222-2 4-(2-Chloro-6-iodopyridin-3-yloxy)-6,7-dimethoxyquinoline 4-Chloro-6,7-dimethoxyquinoline (2.23 g, 10.0 mmol), <strong>[185220-68-2]2-chloro-6-iodopyridin-3-ol</strong> (2.55 g, 22.0 mmol) and diisopropylethylamine (1.29 g, 10.0 mmol) were heated and stirred in dimethylformamide (5 ml) at 130 C. for 3 hours. The reaction solution was distributed between an ethyl acetate-tetrahydrofuran mixed solvent and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (2.16 g, 4.88 mmol, 49%) as colorless crystals. 1H-NMR Spectrum (CDCl3) delta (ppm): 4.05 (3H, s), 4.06 (3H, s), 6.39 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=8.2 Hz), 7.45 (1H, s), 7.48 (1H, s), 7.75 (1H, d, J=8.2 Hz), 8.55 (1H, d, J=5.2 Hz).

Reference： [1]Patent: US2004/53908,2004,A1

58
[ 35654-56-9 ]
[ 2437-17-4 ]
[ 861881-26-7 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1649 - 1667
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 1668 - 1680

59
[ 35654-56-9 ]
[ 399-95-1 ]
[ 228559-74-8 ]

Yield	Reaction Conditions	Operation in experiment
65.1%		To a 250 ml three-necked flask, 4-amino 3-fluorophenol [compound (III)] (4.0 g, 31.4 mmol), NaH (content 60percent, 1.26 g, 31.4 mmol) and dimethyl sulfoxide 50 ml were mixed and stirred. 50 ml of dimethyl sulfoxide was mixed with 4-chloro-6,7-dimethoxyquinoline [compound (II)] (5 g, 22.4 mmol).Adding to the above reaction solution to control the temperature below 25 ° C,After the completion of the dropwise addition, the temperature was raised to 100 ° C, the reaction was stopped for 2 hours, the reaction was stopped, and the mixture was cooled to 15 to 20 ° C. The reaction mixture was poured into 100 ml of ice water, the temperature was controlled at 15 to 30 ° C, 20 ml of ethyl acetate was added, and the solid was separated and stirred. The solid was washed once with 10 ml of ethyl acetate and dried under vacuum at 40 ° C for 12 hours to give a brown solid, 4.58 g (65.1percent), which is compound (IV)
31%		To a solution of <strong>[399-95-1]4-amino-3-fluorophenol</strong> (65.9mg, 0.52 mmol) in DMSO (1OmL) was added KOf-Bu (84 mg, 0.75 mmol) and the reaction mixture was stirred at rt for 30 min. Then 4-chloro-6,7-dimethoxyquinoline (116 mg, 0.519 mmol) was added, and the reaction mixture was stirred at 9O0C for an additional 16 h. The reaction mixture was cooled to rt and diluted with ethyl acetate. The organic mixture was then washed successively with water and K2CO3 (10percent aqueous solution), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 50 to 100percent ethyl acetate in hexanes) to give 50 mg (31 percent) of the title compound. 1H NMR (400 MHz, CD3CN) delta <n="51"/>8.45 (d, 1 H), 7.57 (s, 1 H), 7.39 (s, 1 H), 6.98-6.86 (m, 3 H), 6.49 (d, 1 H), 4.27 (bs, 2 H), 3.99 (s, 3 H)1 3.97 (s, 3 H); ES-MS m/z 315.3 [M+H]+, LCMS RT (min) 2.08.

Reference： [1]Patent: CN108358840,2018,A .Location in patent: Paragraph 0038; 0039
[2]Patent: WO2008/48375,2008,A1 .Location in patent: Page/Page column 49-50

60
[ 35654-56-9 ]
[ 904326-92-7 ]
[ 1119718-03-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In 1,2-dimethoxyethane; water; at 80℃;	To 100 mL round-bottomed flask was added 4-chloro-6,7-dimethoxyquinoline (0.1125 g, 0.503 mmol), <strong>[904326-92-7]6-fluoro-5-methylpyridin-3-ylboronic acid</strong> (0.1075 g, 0.629 mmol), and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.0321 g, 0.0402 mmol) in 1,2-dimethoxyethane. An aqueous solution of sodium carbonate (27 g, 257 mmol) was added and the temperature was brought to 80 C. stir overnight. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluding with a gradient of 10% to 70% ethyl acetate in hexane, to provide 4-(6-fluoro-5-methylpyridin-3-yl)-6,7-dimethoxyquinoline (0.059 g).

Reference： [1]Patent: US2009/62277,2009,A1 .Location in patent: Page/Page column 15

61
[ 35654-56-9 ]
[ 849217-68-1 ]

Reference： [1]Patent: WO2012/109510,2012,A1
[2]Patent: WO2013/59788,2013,A1
[3]Patent: WO2013/43840,2013,A1
[4]Patent: WO2013/70890,2013,A1
[5]Patent: WO2013/166296,2013,A1
[6]Patent: WO2013/166296,2013,A1
[7]Patent: WO2014/165786,2014,A1
[8]Patent: WO2014/165779,2014,A1
[9]Patent: WO2015/164869,2015,A1
[10]Patent: WO2016/19285,2016,A1
[11]Patent: WO2016/19285,2016,A1
[12]Patent: WO2016/19285,2016,A1
[13]Patent: WO2016/19285,2016,A1
[14]Patent: US2016/772,2016,A1
[15]Patent: TWI516477,2016,B
[16]Patent: CN103664776,2016,B
[17]Heterocycles,2016,vol. 93,p. 323 - 332
[18]Patent: EP2758057,2017,B1
[19]Patent: CN103664778,2017,B
[20]Patent: CN103664778,2017,B
[21]Patent: CN106632028,2017,A
[22]Patent: WO2018/136796,2018,A1
[23]Patent: WO2018/227119,2018,A1
[24]Patent: WO2018/227119,2018,A1
[25]Organic Preparations and Procedures International,2019,vol. 51,p. 381 - 387
[26]Patent: CN109988107,2019,A
[27]Patent: CN109988107,2019,A
[28]Patent: CN109836382,2019,A
[29]Patent: WO2019/234761,2019,A1
[30]Patent: US2020/255382,2020,A1

62
[ 35654-56-9 ]
[ 1140909-48-3 ]

Reference： [1]Patent: WO2012/109510,2012,A1
[2]Patent: WO2013/59788,2013,A1
[3]Patent: WO2013/43840,2013,A1
[4]Patent: WO2013/43840,2013,A1
[5]Patent: WO2013/166296,2013,A1
[6]Patent: WO2013/166296,2013,A1
[7]Patent: WO2014/165786,2014,A1
[8]Patent: WO2015/164869,2015,A1
[9]Patent: WO2015/164869,2015,A1
[10]Patent: WO2016/22697,2016,A1
[11]Patent: US2016/772,2016,A1
[12]Patent: TWI516477,2016,B
[13]Patent: WO2018/227119,2018,A1
[14]Patent: WO2018/227119,2018,A1
[15]Patent: CN109836382,2019,A

63
[ 13425-93-9 ]
[ 1634-04-4 ]
[ 96042-30-7 ]
[ 35654-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; trichlorophosphate; In dichloromethane; water; acetonitrile;	Preparation of 4-Chloro-6,7-dimethoxy-quinoline A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 C. and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77 C. The reaction was deemed complete (approximately 13 hours) when less than 3 percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7 C. and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to 25 C. and held for 2.5 hours. This resulted in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 C. under nitrogen to afford the title compound. (35.6 kg).

Reference： [1]Patent: US2012/252840,2012,A1

64
[ 13425-93-9 ]
[ 67000-01-5 ]
[ 35654-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; trichlorophosphate; In dichloromethane; acetonitrile;	Preparation of 4-Chloro-6,7-dimethoxy-quinoline A reactor was charged sequentially with <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 C. and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 80 C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 C. and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30 percent NH4OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 C., and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation with the removal of solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 C., during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 C. to afford the title compound (8.0 kg).

Reference： [1]Patent: US2012/252840,2012,A1

65
[ 35654-56-9 ]
[ 123-30-8 ]
[ 849217-68-1 ]

Reference： [1]Patent: US2012/252840,2012,A1
[2]Patent: CN109988108,2019,A

66
[ 55717-45-8 ]
[ 35654-56-9 ]
[ 1355031-22-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With dmap; In chlorobenzene; at 100℃;	4-Chloro-6,7-dimethoxyquinoline (1.12 g) obtained according to J. Med. Chem., 2006, 49, 2186-2192 was dissolved in chlorobenzene (50 mL), and <strong>[55717-45-8]6-bromopyridin-3-ol</strong> (1.74 g) and dimethylaminopyridine (1.83 g) were added thereto, followed by stirring at 100C overnight. After the completion of the reaction, the solvent was distilled off from the resulting reaction mixture under reduced pressure. The resulting residue was purified by silica gel column chromatography using chloroform and methanol as the eluents to give the titled compound A16 (1.57 g, yield: 87%).
47%	With dmap; In toluene; at 100℃; for 16h;	<strong>[55717-45-8]6-bromopyridin-3-ol</strong> (1.74 g, 10.0 mmol, 1.0 eq), 4-chloro-6,7-dimethoxybenzopyridine (2.24 g, 10.0 mmol, 1.0 eq), and 4-dimethyl Aminopyridine (3.67g, 30.0mmol, 3.0eq) was dissolved in toluene (50mL), and the temperature was raised to 100 C for 16 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated, and the crude product was subjected to silica gel column chromatography (DCM: MeOH = 50: 1 20: 1).Purified to give 4-((6-bromopyridin-3-yl) oxy) -6,7-dimethoxyquinoline (1.70 g, yield: 47%) as a white solid

Reference： [1]Patent: EP2594566,2013,A1 .Location in patent: Paragraph 0204
[2]Patent: CN110041316,2019,A .Location in patent: Paragraph 0397; 0401-0403

67
[ 35654-56-9 ]
[ 5847-59-6 ]
[ 1437323-80-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With dmap; In chlorobenzene; at 140℃; for 48h;Inert atmosphere;	A mixture of 4-chloro- 6,7-dimethoxyquinoline (0.82 g, 3.67 mmol), <strong>[5847-59-6]2-bromo-4-nitrophenol</strong> (0.80 g, 3.67 mmol) and 4-dimethylaminopyridine (0.067 g, 0.549 mmol) in chlorobenzene (8 mL) was heated at 140 C for 2 days under an argon atmosphere. The crude product was purified by silica gel column chromatography followed by crystallization from a mixture of CH2CI2, MeOH, ether, and hexane to produce 4-(2-bromo-4-nitrophenoxy)-6,7-dimethoxyquinoline (0.74 z = 406 (M + 1).

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 77

68
[ 35654-56-9 ]
[ 16292-95-8 ]
[ 1431697-97-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; In chlorobenzene; at 140℃;	A solution of 4-chloro-6,7-dimethoxyquinoline (0.4 g, 2 mmol) , 3-methoxy-4- nitrophenol (0.30 g, 1.8 mmol) , and 4-dimethylaminopyridine (0.011 g, 0.089 mmol) in chlorobenzene (5 mL) was stirred at 140 C overnight. After cooling to rt the solid that formed was filtered and dried to yield pure product 0.48 g (75%), MS: 357 (M+H).

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 120

69
[ 35654-56-9 ]
[ 16292-95-8 ]
4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenylamine [ No CAS ]

Reference： [1]Patent: WO2013/74633,2013,A1

70
[ 35654-56-9 ]
[ 399-96-2 ]
[ 347161-74-4 ]

Yield	Reaction Conditions	Operation in experiment
70%		Sodium hydride (60% disp. in mineral oil; 1.3 g, 33.5 mmol) was added to 4-amino-2- fluoro-phenol in dry N,N-dimethylformamide (50 mL) and stirred at rt for 30 min under an atmosphere of nitrogen. Then solid 4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.4 mmol) was added and the reaction stirred at 100C for 30 h. The mixture was concentrated, dissolved in EtOAc (100 mL) and washed with IN Na2C03, water and brine, then dried over MgSC^. The product was chromatographed on silica gel (5%methanol/dichloromethane (MeOH/DCM)) to give a tan solid 4.9 g, 70%. mp = 172-5 C; LCMS m/z = 315 (M + 1); 1H NMR (DMSO) ?: 8.48 (d, 1H, J = 5.4 Hz), 7.50 (s, 1H), 7.38 (s, 1H), 7.07 (t, 1H, J = 8.6 Hz), 6.53,6.56 (dd, 1H, J = 2.6, 13.4 Hz), 6.45, 6.47 (dd, 1H, J = 2, 8 Hz), 6.38, 6.39 (dd, 1H, J = 1, 5.4 Hz), 5.48 (s, 2H), 3.94 (s, 6H).
66%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1.5h;Microwave irradiation;	The compound 4-chloro-6,7-dimethoxyquinoline (110 mg, 0.5 mmol)<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (127 mg, 1 mmol) was dissolved in 1 ml of DMF,Potassium tert-butoxide (112 mg, 1 mmol) was added with vigorous stirring,Then microwave reaction at 80 C for 1.5 h,After completion of the reaction, dry DMF, dissolved in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil,Brown powder 3a (100 mg, 66%) was obtained by column chromatography (ethyl acetate: petroleum ether = 1: 1).
1.50 g	With sodium t-butanolate; In N,N-dimethyl acetamide; at 105℃; for 12h;	Take a 100ml three-necked flask, add 2.23g 4-chloro-6,7-dimethoxyquinoline, 1.91g <strong>[399-96-2]4-amino-2-fluorophenol</strong>, 1.44g sodium tert-butoxide, 10ml DMAC, and react at 105 C for 12h. The basic reaction of the raw materials was complete, poured into 100 ml of water, and filtered with suction to obtain a brown-black solid. Column chromatography gave 1.50 g of compound I-2-1.

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 50
[2]Patent: CN107151240,2017,A .Location in patent: Paragraph 0154; 0155; 0156
[3]Patent: CN110330479,2019,A .Location in patent: Paragraph 0087-0089

71
[ 35654-56-9 ]
[ 3964-52-1 ]
[ 286371-44-6 ]

Yield	Reaction Conditions	Operation in experiment
49%		To a suspension of <strong>[3964-52-1]4-amino-2-chlorophenol</strong> (474 mg, 3.3 mmol) in DMSO (7 mL) was added NaH (264 mg, 6.6 mmol, 60% in mineral oil). The mixture was stirred at rt for 15 minutes, followed by the addition of 4-chloro-6,7-dimethoxyquinoline (671 mg, 3.0 mmol). The reaction was heated to 160 C for 2 hours in microwave, then cooled to rt, quenched with water (20 mL), and extracted with EtOAc (60 mL). The organic phase was washed with brine (60 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a purple solid (490 mg, 49%). MS (ESI, pos. ion) m/z: 331.1 [M+H]+; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6): delta 3.93 (d, J = 3.3 Hz, 6H), 5.42 (s, 2H), 6.42 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.98-7.01 (m, 1H), 7.20-7.21 (m, 1H), 7.37 (s, 1H), 7.49 (s, 1H), 8.45 (d, J= 5.2 Hz, 1H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0186

72
[ 35654-56-9 ]
[ 163733-99-1 ]
[ 1437323-99-3 ]

Yield	Reaction Conditions	Operation in experiment
15.8%		To a solution of <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (208 mg, 1.43 mmol) in DMF (4 mL) was added /-BuOK (257 mg, 2.29 mmol). The mixture was stirred at rt for 30 minutes, followed by the addition of 4-chloro-6,7-dimethoxyquinoline (356 mg, 1.59 mmol). The reaction was heated at 120 C for 2 hours in microwave, then cooled to rt, quenched with water (25 mL), and extracted with EtOAC (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a pale yellow solid (75 mg, 15.8%). MS (ESI, pos. ion) m/z: 333.2 [M+H]+; *H NMR (400 MHz, DMSO-i): delta 8.47 (d, J = 5.1 Hz, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 6.99 (m, 1H), 6.76 (m, 1H ), 6.47 (d, J= 4.9 Hz, 1H), 5.90 (s, 2H), 3.94 (s, 6H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0188

73
[ 35654-56-9 ]
[ 163733-99-1 ]
N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2013/180949,2013,A1

74
[ 120103-19-7 ]
[ 35654-56-9 ]
4-((6,7-dimethoxyquinolin-4-yl)oxy)-2.5-difluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydride; In dimethyl sulfoxide; mineral oil; at 150℃; for 2h;Microwave irradiation;	To a suspension of 4-chloro-6,7-dimethoxyquinoline (570 mg, 2.55 mmol) and <strong>[120103-19-7]4-amino-2,5-difluorophenol</strong> (390 mg, 2.60 mmol) in DMSO (5 mL) was added NaH (244 mg, 5.10 mmol, 60% in mineral oil). The reaction was microwaved at 150 C for 2 hours, then cooled to rt, quenched with water (40 mL) and extracted with EtOAc (70 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as an orange solid (210 mg, 25%). MS (ESI, pos. ion) m/z: 333.1 [M+H]+; *H NMR (400 MHz, DMSO-i/6): delta 8.49 (d, J = 5.2 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 6.96 (dd, J= 7.1 Hz, 10.6 Hz, 1H), 6.67 (dd, J = 8.1 Hz, 11.0 Hz, 1H), 6.42 (d, J= 5.2 Hz, 1H), 4.04-4.06 (m, 6H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0190

75
[ 120103-19-7 ]
[ 35654-56-9 ]
N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2013/180949,2013,A1

76
[ 35654-56-9 ]
[ 121219-03-2 ]
4-(4-bromo-3-fluorophenoxy)-6,7-dimethoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		A solution of potassium tert-butoxide in THF (1N, 1.24 mL, 1.24 mmol, 1.05 eq.) was added to a solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (225 mg, 1.18 mmol, 1.0 eq.) in DMF (2 mL). The reaction was stirred at 0 C. for 2 hours, followed by the addition of 4-chloro-6,7-dimethoxy quinoline (264 mg, 1.18 mmol, 1.0 eq.) and potassium carbonate (81 mg, 0.59 mmol, 0.5 eq.). The reaction solution was stirred at 80 C. for 14 hours under nitrogen atmosphere, cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated to give the crude product by by HPLC (C18 reverse phase column, mobile phase: acetonitrile/water, gradient: 10%-100% (volume ratio)) to give the title compound (100 mg, yield: 24%).

Reference： [1]Patent: US2016/200730,2016,A1 .Location in patent: Paragraph 0836; 0837

77
[ 4101-32-0 ]
[ 35654-56-9 ]

Reference： [1]Heterocycles,2016,vol. 92,p. 1882 - 1887
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2801 - 2812
[3]Organic Preparations and Procedures International,2019,vol. 51,p. 381 - 387
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[5]European Journal of Medicinal Chemistry,2020,vol. 193
[6]European Journal of Medicinal Chemistry,2020,vol. 200
[7]Patent: CN111440177,2020,A

78
[ 35654-56-9 ]
[ 666734-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; acetic acid; at 140℃; for 15h;	Weigh the compound having the structure shown in Formula XVIII (1.5 g, 6.7 mmol) into a suffocating can,Then add 15 mL of acetic acid and 15 mL of 40percent hydrobromic acid,Warm to 140°C overnight (about 15 hours). No raw material was detected by LC-MS while part of 6,7-dimethyloxy-4-bromoquinoline was generated.After the reaction solution was directly evaporated, 25 mL of water was added for pulping.Then use a small amount of ammonia to adjust the pH to about 10 and beat it for 1 hour.The solid was collected by suction filtration, and the mixture was azeotropically boiled with absolute ethanol (20 mL) three times.Then pump to constant weight. 1.3 g of a white solid is obtained. FIG. 1 shows the spectrum. Upon analysis, the white solid contained two substances, 6,7-dimethyloxy-4-chloroquinoline (formula XII-1) and 6,7-dimethyloxy-4-bromoquinoline (formula XII-2), based on H-NMR results, see Figure 2, we can see thatThe ratio of the amount of the two substances is approximately 1:1.7. Yield 86.3percent.

Reference： [1]Patent: CN104788372,2018,B .Location in patent: Paragraph 0136; 0137

79
[ 35654-56-9 ]
[ 17609-80-2 ]
[ 286371-44-6 ]

Yield	Reaction Conditions	Operation in experiment
74.6%	With sodium hydride; In dimethyl sulfoxide; at 25 - 100℃; for 9h;	To a 250 ml three-necked flask was added <strong>[17609-80-2]4-amino 3-chlorophenol</strong> [compound (III)] (4.5 g, 31.4 mmol).NaH (content 60%, 1.26g, 31.4mmol) and dimethyl sulfoxide 50ml were mixed and stirred.50 ml of dimethyl sulfoxide was mixed with 4-chloro-6,7-dimethoxyquinoline [compound (II)] (5 g, 22.4 mmol).Adding to the above reaction solution to control the temperature below 25 C,After the addition temperature is increased to 100 C,Reaction for 9 hours,The reaction stops,Cool to 15-20 C,Pour the reaction mixture into 100 ml of ice water.Control temperature 15 ~ 30 C,Add 20 ml of ethyl acetate,Solid separation and suction filtration,The solid was washed once with 10 ml of ethyl acetate.Dry at 40 C for 12 hours under vacuum.Obtaining 5.53 g (74.6%) of brown solid, which is compound (IV);

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 6083 - 6101
[2]Patent: CN108358839,2018,A .Location in patent: Paragraph 0013; 0036; 0038; 0039

80
[ 35654-56-9 ]
[ 17609-80-2 ]
1‐(2‐chloro‐4‐((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)‐3‐(4-fluorophenyl)urea [ No CAS ]

Reference： [1]Patent: CN108358839,2018,A

81
[ 489446-42-6 ]
[ 35654-56-9 ]
tert-butyl (4-(6,7-dimethoxyquinolin-4-yl)benzyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	[0596] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (0.5 g, 2.242 mmol), (4-((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.56 g, 2.242 mmol) and potassium carbonate (0.92 g, 6.726 mmol) in 1,4-dioxane ( 10 mL) and water ( 3 mL) was degassed with nitrogen gas for 10 min, then tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.1121 mmol) was added and heated for 12 h at 100 C. The reaction mixture was cooled to room temperature, filtered through celite bed, the filtrate was dried and concentrated to give crude product. The crude was purified by flash column with silica gel pack and 30% ethyl acetate in hexane as eluent. The pure fractions were collected and concentrated to afford tert-butyl (4-(6,7-dimethoxyquinolin-4-yl)benzyl)carbamate as off white solid (0.62 g, 70%).1HNMR (400 MHz, DMSO-d6): delta 8.69 (d, J = 3.6 Hz, 1H), 7.65- 7.55 (m, 1H), 7.55- 7.50 (m, 2H), 7.50- 7.40 (m, 3H), 7.23 (d, J = 3.6 Hz, 1H), 7.15 (s, 1H), 4.23 (d, J = 4.8 Hz, 2H), 3.94 (s, 3H), 3.73 (s, 3H), 1.40 (s, 9H). LC-MS (ES) m/z = 395.1 [M+H]+ .

Reference： [1]Patent: WO2019/46778,2019,A1 .Location in patent: Paragraph 0596

82
[ 489446-42-6 ]
[ 35654-56-9 ]
tert-butyl (4-(6,7-dimethoxyquinolin-4-yl)benzyl)(methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2019/46778,2019,A1

83
[ 35654-56-9 ]
[ 17609-80-2 ]
2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 6083 - 6101

84
[ 35654-56-9 ]
[ 13425-92-8 ]

Reference： [1]Patent: WO2019/177971,2019,A1

85
[ 35654-56-9 ]
[ 109240-30-4 ]
1-(4-bromophenyl)-3-(4-chloro-6,7-dimethoxyquinolin-2-yl)propan-1-one [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2020,vol. 2020,p. 2600 - 2604

86
[ 55717-46-9 ]
[ 35654-56-9 ]
[ 417722-21-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	Stage #1: 6-aminopyridin-3-ol With sodium hydride In dimethyl sulfoxide at 20℃; for 0.166667h; Stage #2: 6,7-dimethoxy-4-chloroquinoline In dimethyl sulfoxide at 90℃; for 1h;

Reference： [1]Karmacharya, Ujjwala; Guragain, Diwakar; Chaudhary, Prakash; Jee, Jun-Goo; Kim, Jung-Ae; Jeong, Byeong-Seon [International Journal of Molecular Sciences, 2021, vol. 22, # 18]

87
[ 55717-46-9 ]
[ 35654-56-9 ]
C₂₇H₂₃FN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.17 h / 20 °C 1.2: 1 h / 90 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C

Reference： [1]Karmacharya, Ujjwala; Guragain, Diwakar; Chaudhary, Prakash; Jee, Jun-Goo; Kim, Jung-Ae; Jeong, Byeong-Seon [International Journal of Molecular Sciences, 2021, vol. 22, # 18]

88
[ 35654-56-9 ]
[ 2243-47-2 ]
N-([1,1'-biphenyl]-3-yl)-6,7-dimethoxyquinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With indium(III) chloride In acetonitrile at 110 - 170℃; Microwave irradiation;	5 General procedure for synthesis of biarylquinoline derivatives General procedure: To a solution of 3-aminobiphenyl derivatives with appropriate substituted group of 4-chloroquinoline in 10-15mL acetonitrile, and added indium (III) chloride as the catalyst in the Glass vial, followed by placing in the microwave reactor. Microwave wattage was between 300 and 900W, heating at 110°C to 170°C for 30min to 3h. After the completion of reaction, the mixture was concentrated under vacuum and then subjected to purify by flash chromatography with different proportion of dichloromethane/methanol. The solid was recrystallized in acetonitrile and filtered to obtained the desired compound.
43%	With indium(III) chloride In acetonitrile at 110 - 170℃; Microwave irradiation;	5 General procedure for synthesis of biarylquinoline derivatives General procedure: To a solution of 3-aminobiphenyl derivatives with appropriate substituted group of 4-chloroquinoline in 10-15mL acetonitrile, and added indium (III) chloride as the catalyst in the Glass vial, followed by placing in the microwave reactor. Microwave wattage was between 300 and 900W, heating at 110°C to 170°C for 30min to 3h. After the completion of reaction, the mixture was concentrated under vacuum and then subjected to purify by flash chromatography with different proportion of dichloromethane/methanol. The solid was recrystallized in acetonitrile and filtered to obtained the desired compound.

Reference： [1]Chang, Chih-Shiang; Chu, Po-Chen; Lin, Tai-Hui; Lu, Meng-Tien; Wu, Yu-Chieh [Bioorganic Chemistry, 2022, vol. 121]
[2]Chang, Chih-Shiang; Chu, Po-Chen; Lin, Tai-Hui; Lu, Meng-Tien; Wu, Yu-Chieh [Bioorganic Chemistry, 2022, vol. 121]

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Code	Phrase
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P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 35654-56-9 ] {[proInfo.proName]}

Quality Control of [ 35654-56-9 ]

Related Doc. of [ 35654-56-9 ]

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Physicochemical Properties

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Lipophilicity

Druglikeness

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[ 35654-56-9 ] Synthesis Path-Upstream 1~21

[ 35654-56-9 ] Synthesis Path-Downstream 1~88

Pharmaceutical Intermediates of [ 35654-56-9 ]

Cabozantinib Intermediates

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Chlorides

Ethers

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Quinolines

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[ 35654-56-9 ]

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[ 35654-56-9 ]

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[ 35654-56-9 ]