[ CAS No. 190728-25-7 ] {[proInfo.proName]}

Name: 190728-25-7|4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline|97%
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Quality Control of [ 190728-25-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 190728-25-7 ]

SDS Specification

Alternatived Products of [ 190728-25-7 ]

Product Details of [ 190728-25-7 ]

CAS No. :	190728-25-7	MDL No. :	MFCD19685633
Formula :	C₁₇H₁₆N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VXEQRXJATQUJSN-UHFFFAOYSA-N
M.W :	296.32	Pubchem ID :	11594543
Synonyms :		Chemical Name :	4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline

Calculated chemistry of [ 190728-25-7 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.12
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	85.65
TPSA :	66.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.99 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.71
Log Po/w (XLOGP3) :	2.98
Log Po/w (WLOGP) :	3.63
Log Po/w (MLOGP) :	1.62
Log Po/w (SILICOS-IT) :	2.84
Consensus Log Po/w :	2.76

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.83
Solubility :	0.044 mg/ml ; 0.000148 mol/l
Class :	Soluble
Log S (Ali) :	-4.04
Solubility :	0.0269 mg/ml ; 0.0000908 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.84
Solubility :	0.000423 mg/ml ; 0.00000143 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.33

Safety of [ 190728-25-7 ]

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

Application In Synthesis of [ 190728-25-7 ]

* 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 [ 190728-25-7 ]
Downstream synthetic route of [ 190728-25-7 ]

[ 190728-25-7 ] Synthesis Path-Upstream 1~17

1
[ 190728-24-6 ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium chloride; zinc In tetrahydrofuran; methanol; water for 2 h; Heating / reflux	Step 2: 4-(6,7-dimethoxyquinolin-4-yloxy)aniline (99) To 98 (0.25 g, 0.77 mmol) in 1:1 MeOH/THF (50 mL) was added Zn dust (0.55 g, 8.4 mmol) and ammonium chloride (0.085 g, 1.6 mmol) in water (5 mL). The resulting mixture was heated to reflux for 2 h, then filtered through celite and concentrated. The residue was dissolved in dichloromethane, washed with water, brine, dried (MgSO₄), filtered and concentrated to provide crude 99 (0.25 g, >100percent) which was used without further purification. MS (m/z): 297.1 (M+H).
95%	With raney nickel In methanol at 30℃; for 10 h; Autoclave	Step three:500 ml of methanol was added to the autoclave, and 100 g of intermediate 2 and 25 g of Raney nickel were added.Raise the temperature at 30 ° C for 10 hours;Press filtration, concentration, crystallization, filtration, and drying gave 86 g of Intermediate 3 in a yield of 95percent.
22.4%	With palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 73℃; for 12 h;	To a suspension of 6,7-dimethoxy-4-(4-nitrophenoxy)quinoline (28 g, 85.8 mmol) and HCOOK (50.5 g, 601.1 mmol) in THF (150 niL) and H₂0 (40 niL) was added Pd/C (2.8 g, 10percent). The reaction was heated to 73 °C for 12 hours, and then cooled to rt. The organic phase was separated and concentrated in vacuo. The residue was stirred in EtOH (90 mL) and 0 (30 mL) overnight and then collected through filtration to give the title compound as a pale yellow solid (5.7 g, 22.4percent). MS (ESI, pos. ion) m/z: 297.1 [M + H]⁺; NMR (400 MHz, DMSO-i): δ 3.92 (s, 3H), 3.93 (s, 3H), 5.16 (s, 2H), 6.36 (d, J = 5.2 Hz, 1H), 6.65-6.68 (m, 2H), 6.91-6.93 (m, 2H), 7.36 (s, 1H), 7.50 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H).

3.0 kg	With formic acid; palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 60℃; for 15 h; Large scale	Preparation of 4—(6,7 —Dimethoxy—quinoline-4—yloxy)--phenylamine[00258J A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (TUF, 40.0 kg) that had been heated to approximately 60 °C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 °C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 °C to half of its original volume, which resulted in the precipitation of the product The product was recovered by ifitration, washed with water (12.0 kg), and dried under vacuum at approximately 50 °C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).
3 kg	With formic acid; palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 60℃; for 15 h; Large scale	Preparation of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4 nitro-phenoxy)-quinoline (4.0 kg), 10percent palladium on carbon (50percent water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60° C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60° C. When the reaction was deemed complete as determined using in-process HPLC analysis (<2percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35° C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50° C. to afford the title compound (3.0 kg).
3.0 kg	With formic acid; palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 60℃; for 1.5 h; Large scale	Preparation of 4-(6,7 -Dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (THF, 40.0 kg) that had been heated to approximately 60 °C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 °C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 °C to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 °C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).
86.3 mg	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl acetamide at 30 - 40℃; Autoclave	100 g (0.306 mol) of 6,7-dimethoxy-4-(4-nitrophenoxy) quinoline was treated with 300 g N, N-diethylacetamide was dissolved in an autoclave, and 10percent Pd / C 15g was added to react at 30 to 40 ° C under a hydrogen pressure of 2.8 MPa, and the reaction was complete when no hydrogen was absorbed. After removing most of the solvent, the mixture was poured into 150 ml of water and stirred for 1 hour. The precipitated solid particles were filtered and the cake was washed twice with 100 ml of water, dried at 60 ° C,A solution of 4-(6,7- dimethoxyquinolin-4-oxy)phenylamine (86.3 g), molar yield 95.2percent

Reference： [1] Patent: US2008/4273, 2008, A1, . Location in patent: Page/Page column 86
[2] Patent: CN108264482, 2018, A, . Location in patent: Paragraph 0022; 0027
[3] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292
[6] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0172
[7] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 875 - 879
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[9] Patent: WO2008/48375, 2008, A1, . Location in patent: Page/Page column 48
[10] Patent: WO2010/83414, 2010, A1, . Location in patent: Page/Page column 25
[11] Patent: US2012/70368, 2012, A1,
[12] Patent: US2012/252840, 2012, A1,
[13] Patent: WO2015/164869, 2015, A1, . Location in patent: Paragraph 00255; 00258
[14] Patent: US2016/772, 2016, A1, . Location in patent: Paragraph 0086; 0090
[15] Patent: EP2758057, 2017, B1, . Location in patent: Paragraph 0109
[16] Patent: CN103664778, 2017, B, . Location in patent: Paragraph 0054; 0055; 0056; 0061; 0062

2
[ 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).

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8797 - 8810
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[5] Patent: CN103664776, 2016, B, . Location in patent: Paragraph 0115; 0116; 0117
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[7] Patent: WO2012/109510, 2012, A1, . Location in patent: Page/Page column 28
[8] Patent: US2012/252840, 2012, A1,
[9] Patent: WO2013/59788, 2013, A1, . Location in patent: Paragraph 0061
[10] Patent: WO2013/43840, 2013, A1, . Location in patent: Paragraph 00119; 00121
[11] Patent: WO2013/70890, 2013, A1, . Location in patent: Paragraph 00119-00120
[12] Patent: WO2013/166296, 2013, A1, . Location in patent: Paragraph 00115
[13] Patent: WO2014/165786, 2014, A1, . Location in patent: Paragraph 00197
[14] Patent: WO2014/165779, 2014, A1, . Location in patent: Paragraph 0077; 0078; 0080; 0081; 0082
[15] Patent: WO2015/164869, 2015, A1, . Location in patent: Paragraph 00263; 00265
[16] Patent: WO2016/22697, 2016, A1, . Location in patent: Paragraph 00111; 00112; 00114
[17] Patent: WO2016/19285, 2016, A1, . Location in patent: Paragraph 0096; 0097
[18] Patent: US2016/772, 2016, A1, . Location in patent: Paragraph 0095; 0097
[19] Patent: CN105408312, 2016, A, . Location in patent: Paragraph 0820; 0821; 0822; 0823; 0824
[20] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0213-0216
[21] Patent: TWI516477, 2016, B, . Location in patent: Page/Page column 31; 32
[22] Heterocycles, 2016, vol. 93, # 1, p. 323 - 332
[23] Patent: EP2758057, 2017, B1, . Location in patent: Paragraph 0116
[24] Patent: CN103664778, 2017, B, . Location in patent: Paragraph 0040-0042; 0045; 0046
[25] Patent: WO2018/136796, 2018, A1, . Location in patent: Paragraph 0081; 0082; 0085; 0086; 0087; 0089
[26] Patent: CN108658856, 2018, A, . Location in patent: Page/Page column 8-11
[27] Patent: WO2018/227119, 2018, A1, . Location in patent: Paragraph 00163; 00164; 00167-00168; 00169-00171

3
[ 190728-24-6 ]
[ 190728-25-7 ]

Reference： [1] Patent: US6143764, 2000, A,

4
[ 127285-54-5 ]
[ 190728-25-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[3] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[4] Patent: CN103739550, 2016, B,
[5] Heterocycles, 2016, vol. 93, # 1, p. 323 - 332

5
[ 35654-56-9 ]
[ 190728-25-7 ]

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

6
[ 4101-30-8 ]
[ 190728-25-7 ]

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

7
[ 6315-89-5 ]
[ 190728-25-7 ]

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] Patent: WO2013/180949, 2013, A1,

8
[ 13436-14-1 ]
[ 190728-25-7 ]

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

9
[ 26893-22-1 ]
[ 190728-25-7 ]

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

10
[ 13425-93-9 ]
[ 190728-25-7 ]

Reference： [1] Patent: WO2012/109510, 2012, A1,
[2] Patent: US2012/252840, 2012, A1,
[3] Patent: US2012/252840, 2012, A1,
[4] Patent: US2012/252840, 2012, A1,
[5] Patent: US2012/252840, 2012, A1,
[6] Patent: WO2013/59788, 2013, A1,
[7] Patent: WO2013/43840, 2013, A1,
[8] Patent: WO2013/43840, 2013, A1,
[9] Patent: WO2013/70890, 2013, A1,
[10] Patent: WO2014/165786, 2014, A1,
[11] Patent: WO2013/166296, 2013, A1,
[12] Patent: US2016/772, 2016, A1,
[13] Patent: WO2013/166296, 2013, A1,
[14] Patent: WO2013/180949, 2013, A1,
[15] Patent: WO2014/165779, 2014, A1,
[16] Patent: WO2015/164869, 2015, A1,
[17] Patent: WO2015/164869, 2015, A1,
[18] Patent: WO2016/22697, 2016, A1,
[19] Patent: WO2016/19285, 2016, A1,
[20] Patent: US2016/772, 2016, A1,
[21] Patent: TWI516477, 2016, B,
[22] Patent: EP2758057, 2017, B1,
[23] Patent: EP2758057, 2017, B1,
[24] Patent: CN103664778, 2017, B,
[25] Patent: CN103664778, 2017, B,
[26] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17
[27] Patent: CN108264482, 2018, A,
[28] Patent: WO2018/136796, 2018, A1,
[29] Patent: WO2018/227119, 2018, A1,

11
[ 35654-56-9 ]
[ 123-30-8 ]
[ 14593-46-5 ]
[ 190728-25-7 ]

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

12
[ 26717-39-5 ]
[ 190728-25-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192

13
[ 213699-53-7 ]
[ 190728-25-7 ]

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

14
[ 350-46-9 ]
[ 190728-25-7 ]

Reference： [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17

15
[ 100-02-7 ]
[ 190728-25-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292

16
[ 190728-25-7 ]
[ 97-67-6 ]
[ 1140909-48-3 ]

Yield	Reaction Conditions	Operation in experiment
24 g	Stage #1: With potassium carbonate In tetrahydrofuran; water at 0 - 30℃; for 2 h; Stage #2: at 25 - 75℃; for 1.16667 h;	Thionyl chloride (36.10 kgs) was slowly added to the mixture of l-((4-fluorophenyl) carbamoyl)cyclopropane carboxylic acid (22.60 kgs) and tetrahydrofuran (120 lts) at 25-30°C and stirred for 9 hours at the same temperature. The reaction mixture was slowly added to a pre-cool ed mixture of 4-((6,7-dimethoxyquinolin-4-yloxy)anil me (20.0 kgs), aqueous potassium carbonate solution (83.70 kgs of potassium carbonate in 120 Its of water) and tetrahydrofuran (120 Its) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Both the organic and aqueous layers were separated and water was added to the aqueous layer at 25-30°C. Extracted the aqueous layer with ethyl acetate. Combine the organic layers. Aqueous hydrochloric acid solution (15 lts of HC1 in 145 lts of water) was, added to the organic layer at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the, precipitated solid, washed with tetrahydrofuran and ethyl acetate. To the obtained compound, water (lot-4) was added at 25- ‘30°C and stirred for •2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, water (595 Its) and hydrochloric acid (1 .0 Its) were added at 25-30°C and stirred for.2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, isopropanol (435 Its) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Dimethyl sulfoxide (235 Its) was added to the obtained compound at 25-30°C and stirred for 45 ’iinutes at the same temperature. Filtercd the reaction mixture. Ethyl acetate (720 Its) was added to the obtained filtrate at 2 5-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.Yield: 32.99 kgs; Purity by HPLC: 99.8 5percent.

Reference： [1] Patent: WO2018/104954, 2018, A1, . Location in patent: Page/Page column 28; 29; 32; 33

17
[ 190728-25-7 ]
[ 1140909-48-3 ]

Reference： [1] Patent: WO2012/109510, 2012, A1,
[2] Patent: WO2013/59788, 2013, A1,
[3] Patent: WO2013/43840, 2013, A1,
[4] Patent: WO2013/166296, 2013, A1,
[5] Patent: US2016/772, 2016, A1,
[6] Patent: WO2015/164869, 2015, A1,

[ 190728-25-7 ] Synthesis Path-Downstream 1~84

1
[ 190728-24-6 ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium chloride; zinc; In tetrahydrofuran; methanol; water; for 2h;Heating / reflux;	Step 2: 4-(6,7-dimethoxyquinolin-4-yloxy)aniline (99) To 98 (0.25 g, 0.77 mmol) in 1:1 MeOH/THF (50 mL) was added Zn dust (0.55 g, 8.4 mmol) and ammonium chloride (0.085 g, 1.6 mmol) in water (5 mL). The resulting mixture was heated to reflux for 2 h, then filtered through celite and concentrated. The residue was dissolved in dichloromethane, washed with water, brine, dried (MgSO4), filtered and concentrated to provide crude 99 (0.25 g, >100%) which was used without further purification. MS (m/z): 297.1 (M+H).
95%	With raney nickel; In methanol; at 30℃; for 10h;Autoclave;	Step three:500 ml of methanol was added to the autoclave, and 100 g of intermediate 2 and 25 g of Raney nickel were added.Raise the temperature at 30 C for 10 hours;Press filtration, concentration, crystallization, filtration, and drying gave 86 g of Intermediate 3 in a yield of 95%.
95%	With Raney Nickel; In methanol; at 30℃; for 10h;Autoclave;	500 ml of methanol was added to the autoclave, and 100 g of Intermediate 2 and 25 g of Raney Nickel were added.The temperature is raised at 30 C for 10 hours; the temperature is lowered to room temperature, pressure filtration, concentration, crystallization,Filter, dry,Obtained 86 g of intermediate 3,The yield was 95%.

90.7%		Conc hydrochloric acid (11 mL, 0.2 v/w) and iron powder (56.7 g, 1.0 mol) were sequentially added into 90% ethanol (550 mL, 10 v/w) under stirring for 10 min. Then the reaction mixture was heated to 60oC, the intermediate5(55.0 g, 0.17 mol) was added. After refluxing for 1 h, activated carbon (1.5 g) was added and then reflux for 30 min. The mixture was filtered while hot, the filtrate was cooled to room temperature, adjusted to pH 12 with 10NNaOH, poured into water and stirred for 2 h. The precipitates were collected by filtration and washed with water until the filtrate was nearly neutral to obtain compound6as a pale yellow solid in 90.7% yield.m.p.: 196.4 - 197.2oC;1H-NMR (400 MHz, DMSO-d6) delta 8.43 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 2H), 6.37 (d, J = 5.2 Hz, 1H), 5.18 (s, 2H), 3.93 (s, 6H). MS (ESI) m/z: 297.23 [M+H]+.
82.9%	With iron; acetic acid; In ethanol; water; for 4h;Reflux;	A mixture of 7a (9.6 g, 29.4 mmol), Fe (8.2 g, 0.15 mol) and AcOH(0.5 mL) in 90% EtOH (100 mL) was refluxed with vigorous agitation for 4 h. The hot solution was filtered through celite and the filter cake was washed with hot EtOH (20 mL). The combined filtrate was concentrated under reduced pressure to afford a dark brown solid, which was recrystallized from EtOH to afford 8a as yellow solid (7.2 g,82.9%). HRMS (ESI) m/z: 297.1205 [M+H]+, calcd. for 297.1239.
60%	With tin(II) chloride dihdyrate; In ethanol; at 70℃; for 6h;	6,7-dimethoxy-4-(4-nitrophenyloxy)quinoline (620 mg, 1.9 mmol) was dissolved in ethanol (40 mL). After being dissolved by stirring, tin(II) chloride dihydrate (1.25 g, 4.9 mmol) was added in portions. After the addition was completed, slowly increase to 70 C for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with a 1 N NaOH (10 mL) aqueous solution. It was extracted with ethyl acetate (3 × 15 mL), and the organic layer was combined and washed sequentially with 1 N aqueous NaOH, water and saturated aqueous sodium chloride. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a yellow solid 355 mg, 60% yield.
58.4%	With tin(II) chloride dihdyrate; In ethanol; at 70℃; for 6h;	General procedure: A mixture of nitro compounds 7a-f (2.0 mmol) in EtOH (20 mL) wastreated with tin (II) chloride dihydrate (1.10 g, 4.9 mmol). The resultingyellow slurry was heated at 70 C for 6 h. The yellow mixture was allowedto cool to rt and diluted with NaOH (1 N, 10 mL). The mixturewas extracted with EtOAc (3×15 mL), and the combined organiclayers were washed with NaOH (1 N, 10 mL), H2O, and brine. Afterdrying over Na2SO4, filtering, and concentrating of the organic phase,the resulting yellow solid was used directly in the next step.
22.4%	With palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 73℃; for 12h;	To a suspension of 6,7-dimethoxy-4-(4-nitrophenoxy)quinoline (28 g, 85.8 mmol) and HCOOK (50.5 g, 601.1 mmol) in THF (150 niL) and H20 (40 niL) was added Pd/C (2.8 g, 10%). The reaction was heated to 73 C for 12 hours, and then cooled to rt. The organic phase was separated and concentrated in vacuo. The residue was stirred in EtOH (90 mL) and 0 (30 mL) overnight and then collected through filtration to give the title compound as a pale yellow solid (5.7 g, 22.4%). MS (ESI, pos. ion) m/z: 297.1 [M + H]+; NMR (400 MHz, DMSO-i): delta 3.92 (s, 3H), 3.93 (s, 3H), 5.16 (s, 2H), 6.36 (d, J = 5.2 Hz, 1H), 6.65-6.68 (m, 2H), 6.91-6.93 (m, 2H), 7.36 (s, 1H), 7.50 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H).
	With hydrogen;palladium 10% on activated carbon; In ethanol; N,N-dimethyl-formamide; under 760.051 Torr; for 16h;	To a round bottom flask equipped with stirring bar were added 6,7-dimethoxy- 4-(4-nitrophenoxy)quinoline (534 mg, 1.64 mmol), palladium over carbon (10%, 35 mg), EtOH (4OmL) and DMF (2OmL). The reaction mixture was placed under an atmosphere of H2 (1 atm) and stirred for 16 h. The H2 was thoroughly evacuated from the reaction vessel, and then the reaction mixture was filtered over Celite. The filtrate was concentrated under reduced pressure, and the residue was carried into the next step without further purification. An aliquot was isolated and characterized by 1H NMR. 1H NMR (300 MHz, DMSO-cfe) delta 8.41 (d, 1 H), 7.48 (s, 1 H), 7.34 (s, 1 H), 6.90 (d, 2 H), 6.64 (d, 2 H), 6.34 (d, 1 H), 5.15 (bs, 2 H), 3.92 (s, 3 H), 3.91 (s, 3 H); ES-MS m/z 297 [M+H]+, LCMS RT (min) 1.00.
	With formic acid; potassium formate;palladium 10% on activated carbon; In tetrahydrofuran; water; at 60℃;	A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 6O0C. The addition was carried out such that the temperature of the reaction mixture remained approximately 6O0C. When the reaction was deemed complete as determined using in-process HPLC analysis (<;2% starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 350C to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 5O0C to afford the title compound (3.0 kg; 97% AUC).
	With formic acid; potassium formate;palladium; In tetrahydrofuran; water;	Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1.5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C. to afford the title compound (3.0 kg; 97 percent AUC).
	With formic acid; potassium formate;palladium; In tetrahydrofuran; water;	Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1.5-15 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C. to afford the title compound (3.0 kg; 97 percent AUC).
3.0 kg	With formic acid; palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 60℃; for 15h;Large scale;	Preparation of 4-(6,7 -Dimethoxy-quinoline-4-yloxy)--phenylamine[00258J A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (TUF, 40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C to half of its original volume, which resulted in the precipitation of the product The product was recovered by ifitration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).
3 kg	With formic acid; palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 60℃; for 15h;Large scale;	Preparation of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4 nitro-phenoxy)-quinoline (4.0 kg), 10% palladium on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (<2% starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C. to afford the title compound (3.0 kg).
3.0 kg	With formic acid; palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 60℃; for 1.5h;Large scale;	Preparation of 4-(6,7 -Dimethoxy-quinoline-4-yloxy)-phenylamine A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (THF, 40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).
86.3 mg	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl acetamide; at 30 - 40℃; under 21002.1 Torr;Autoclave;	100 g (0.306 mol) of 6,7-dimethoxy-4-(4-nitrophenoxy) quinoline was treated with 300 g N, N-diethylacetamide was dissolved in an autoclave, and 10% Pd / C 15g was added to react at 30 to 40 C under a hydrogen pressure of 2.8 MPa, and the reaction was complete when no hydrogen was absorbed. After removing most of the solvent, the mixture was poured into 150 ml of water and stirred for 1 hour. The precipitated solid particles were filtered and the cake was washed twice with 100 ml of water, dried at 60 C,A solution of 4-(6,7- dimethoxyquinolin-4-oxy)phenylamine (86.3 g), molar yield 95.2%
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;	[0572] Procedure: To a stirred solution of 6,7-dimethoxy-4-(4-nitrophenoxy)quinoline (3.22 g, 9.86 mmol) in methanol (20 mL) was added 10 % palladium on carbon. The resulting mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was evaporated under reduced pressure to afford 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline as an off-white solid (1.95 g, crude). The crude compound obtained was taken for next step without purification.LC-MS (ES) m/z = 297.3 [M+H]+ .

Reference： [1]Patent: US2008/4273,2008,A1 .Location in patent: Page/Page column 86
[2]Patent: CN108264482,2018,A .Location in patent: Paragraph 0022; 0027
[3]Patent: CN110240563,2019,A .Location in patent: Paragraph 0027
[4]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 5117 - 5133
[5]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[6]Journal of labelled compounds and radiopharmaceuticals,2018,vol. 61,p. 11 - 17
[7]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835
[8]Journal of Medicinal Chemistry,2018,vol. 61,p. 6277 - 6292
[9]Patent: CN109988110,2019,A .Location in patent: Paragraph 0037
[10]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2801 - 2812
[11]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0172
[12]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 875 - 879
[13]Journal of Medicinal Chemistry,2005,vol. 48,p. 1359 - 1366
[14]Patent: WO2008/48375,2008,A1 .Location in patent: Page/Page column 48
[15]Patent: WO2010/83414,2010,A1 .Location in patent: Page/Page column 25
[16]Patent: US2012/70368,2012,A1
[17]Patent: US2012/252840,2012,A1
[18]Patent: WO2015/164869,2015,A1 .Location in patent: Paragraph 00255; 00258
[19]Patent: US2016/772,2016,A1 .Location in patent: Paragraph 0086; 0090
[20]Patent: EP2758057,2017,B1 .Location in patent: Paragraph 0109
[21]Patent: CN103664778,2017,B .Location in patent: Paragraph 0054; 0055; 0056; 0061; 0062
[22]Patent: WO2019/46778,2019,A1 .Location in patent: Paragraph 0572
[23]Archiv der Pharmazie,2019,vol. 352

2
[ 190728-25-7 ]
[ 20651-71-2 ]
N-{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-butylphenyl)carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 5117 - 5133

3
[ 190728-25-7 ]
[ 1498-96-0 ]
N-{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-butoxyphenyl)carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 6h;

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]

4
[ 190728-25-7 ]
[ 2612-57-9 ]
N-(2,4-dichlorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In toluene for 0.5h; Heating;
85%	In toluene	193 N-(2,4-Dichlorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [229] Example 193 N-(2,4-Dichlorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [229] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (115 mg) was added, and the admixture was refluxed with heat for 20 minutes. The separated crystals were filtered and then washed with toluene to obtain 74 mg of the title compound (yield: 85%). 1 H-NMR (DMSO-d6, 500 MHz): δ 3.94 (s, 3H), 3.95 (s, 3H), 6.45 (d, J=4.9Hz, 1H), 7.22 (d, J=8.6Hz, 2H), 7.39 (s, 1H), 7.40 (m, 1H), 7.51 (s, 1H), 7.59 (d, J=9.2Hz, 2H), 7.62 (m, 1 H), 8.21 (d, J=9.2Hz, 1H), 8.40 (s, 1H), 8.46 (d, J=5.5Hz, 1H), 9.56 (s, 1H) Mass spectrometry data (FD-MS, m/z): 483 (M+)
73%	In toluene	199 N-(2,4-Dichlorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [235] Example 199 N-(2,4-Dichlorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [235] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (58 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (93 mg) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 69 mg of the title compound (yield: 73%). 1 H-NMR (CDCl3, 500 MHz): (4.04 (s, 3H), 4.06 (s, 3H), 6.47 (d, J=4.9Hz, 1H), 6.98 (d d, J=2.4, 8.5Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 7.25 (s, 1H), 7.29 (s, 1H), 7.39 (s, 1H), 7.43 (s, 1H), 7.52 (d, J=8.5Hz, 2H), 7.56 (s, 1H), 8.40 (d, J=2.4Hz, 1H), 8.50 (d, J=4.9Hz, 1H) Mass spectrometry data (FD-MS, m/z): 483 (M+)

Reference： [1]Kubo, Kazuo; Shimizu, Toshiyuki; Ohyama, Shin-Ichi; Murooka, Hideko; Iwai, Akemi; Nakamura, Kazuhide; Hasegawa, Kazumasa; Kobayashi, Yoshiko; Takahashi, Noriko; Takahashi, Kazumi; Kato, Shinichiro; Izawa, Toshio; Isoe, Toshiyuki [Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366]
[2]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A
[3]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

5
[ 190728-25-7 ]
[ 39718-32-6 ]
N-(2,5-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In toluene for 0.5h; Heating;
87%	In toluene	237 N-(2,5-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [273] Example 237 N-(2,5-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [273] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,5-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 132 mg of the title compound (yield: 87%). 1 H-NMR (DMSO-d6, 500 MHz): δ 3.94 (s, 3H), 3.95 (s, 3H), 6.46 (d, J=5.5Hz, 1H), 6.80~6.87 (m, 1H), 7.23 (d, J=9.2Hz, 2H), 7.2 7~7.33 (m, 1H), 7.40 (s, 1H), 7.52 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 8.03~8.08 (m, 1H), 8.47 (d, J=5.5Hz, 1H), 8.78 (s, 1H), 9.27 (s, 1H) Mass spectrometry data (FD-MS, m/z): 45 1 (M+)

6
[ 190728-25-7 ]
[ 59025-55-7 ]
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	In toluene for 0.5h; Heating;
84%	In toluene	236 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [272] Example 236 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [272] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,4-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 128 mg of the title compound (yield: 84%). 1 H-NMR (DMSO-d6, 500 MHz): δ 3.94 (s, 3H), 3.95 (s, 3H), 6.46 (d, J=4.9Hz, 1H), 7.03~7.10 (m, 1H), 7.22 (d, J=9.2Hz, 2H), 7.28~7.35 (m, 1H), 7.39 (s, 1H), 7.52 (s, 1H), 7.59 (d, J=9.2Hz, 2H) 8.05~8.12 (m, 1H) 8.47 (d, J=5.5Hz, 1H), 8.52 (s, 1H), 9.15 (s, 1H) Mass spectrometry data (FD-MS, m/z) 451 (M+)

7
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 4442-85-7 ]
1-(2-cyclohexyl-ethyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; bis(trichloromethyl) carbonate With triethylamine In chloroform at 20℃; for 0.166667h; Stage #2: 2-cyclohexylethylamine In chloroform at 20℃; for 1h;

Reference： [1]Furuta, Takayuki; Sakai, Teruyuki; Senga, Terufumi; Osawa, Tatsushi; Kubo, Kazuo; Shimizu, Toshiyuki; Suzuki, Rika; Yoshino, Tetsuya; Endo, Megumi; Miwa, Atsushi [Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192]

8
[ 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

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8797 - 8810
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 2186 - 2192
[3]Patent: CN109836382,2019,A .Location in patent: Paragraph 0072-0077
[4]Patent: CN109988108,2019,A .Location in patent: Paragraph 0034-0038; 0039-0041; 0043-0045
[5]Patent: CN109836381,2019,A .Location in patent: Paragraph 0041-0043
[6]Organic Preparations and Procedures International,2019,vol. 51,p. 381 - 387
[7]Patent: CN109988107,2019,A .Location in patent: Paragraph 0027-0039
[8]Patent: CN106632028,2017,A .Location in patent: Paragraph 0040; 0041; 0042; 0043; 0058; 0059; 0070; 0071
[9]Journal of Medicinal Chemistry,2019,vol. 62,p. 6083 - 6101
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[11]Patent: CN103664776,2016,B .Location in patent: Paragraph 0115; 0116; 0117
[12]Patent: WO2009/136663,2009,A1 .Location in patent: Page/Page column 219-220
[13]Patent: WO2012/109510,2012,A1 .Location in patent: Page/Page column 28
[14]Patent: US2012/252840,2012,A1
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9
[ 4101-30-8 ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: NaOMe / 1,2-dimethoxy-ethane / 1.17 h / 20 °C 1.2: 95 percent / 1,2-dimethoxy-ethane / 2 h / 20 °C 2.1: POCl₃ / Heating 3.1: Heating 4.1: H₂; Et₃N / Pd(OH)2/C / dimethylformamide / 20 °C
	Multi-step reaction with 3 steps 1: sodium methylate 2: trichlorophosphate 3: potassium <i>tert</i>-butylate

Reference： [1]Kubo, Kazuo; Shimizu, Toshiyuki; Ohyama, Shin-Ichi; Murooka, Hideko; Iwai, Akemi; Nakamura, Kazuhide; Hasegawa, Kazumasa; Kobayashi, Yoshiko; Takahashi, Noriko; Takahashi, Kazumi; Kato, Shinichiro; Izawa, Toshio; Isoe, Toshiyuki [Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366]
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN103739550, 2016, B

10
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 367-34-0 ]
[ 144-55-8 ]
N-(2,4,5-trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In toluene;	Example 219 N-(2,4,5-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [255] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. <strong>[367-34-0]2,4,5-Trifluoroaniline</strong> (75 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 58 mg of the title compound (yield: 73percent). 1 H-NMR (DMSO-d6, 500 MHz): delta 3.94 (s, 3H), 3.95 (s, 3H), 6.45 (d, J=5.5Hz, 1H), 7.24 (d, J=8.6Hz, 2H), 7.40 (s, 1H), 7.52 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 7.62~7.70 (m, 1H), 8.17~8.25 (m, 1H), 8.48 (d, J=4.9Hz, 1H), 8.76 (s, 1H), 9.23 (s, 1H) Mass spectrometry data (FD-MS, m/z): 469 (M+)

Reference： [1]Patent: US6143764,2000,A

11
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 3862-73-5 ]
[ 144-55-8 ]
N-(2,3,4-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With triethylamine; In toluene;	Example 221 N-(2,3,4-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [257] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. <strong>[3862-73-5]2,3,4-Trifluoroanilin</strong>e (75 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 18 mg of the title compound (yield: 23%). 1 H-NMR (DMSO-d6, 500 MHz) delta 3.94 (s, 3H), 3.95 (s, 3H), 6.44 (d, J=4.9Hz, 1H), 7.23 (d, J=8.6Hz, 2H), 7.25~7.33 (m, 1H), 7.39 (s, 1 H), 7.52 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 7.85~7.92 (m, 1H), 8.47 (d, J=5.5Hz, 1H), 8.73 (s, 1H), 9.21 (s, 1H) Mass spectrometry data (FD-MS, m/z) 469 (M+)

Reference： [1]Patent: US6143764,2000,A

12
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 6299-67-8 ]
[ 144-55-8 ]
N-(2,3-Dimethoxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In toluene;	Example 232 N-(2,3-Dimethoxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [268] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (74 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,3-Dimethoxyaniline (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 11 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 83 mg of the title compound (yield: 100%). 1 H-NMR (CDCl3, 500 MHz): (3.72 (s, 3H), 3.84 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H), 6.46 (d, J=5.5Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 7.05 (dd, J=8.5, 8.5Hz, 1H), 7.13 (d, J=9.2Hz, 2H), 7.43 (s, 1H), 7.54 (d, J=8.6Hz, 2H), 7.58 (s, 1H), 7.85 (d, J=8.6Hz, 1H), 7.88 (s, 1H), 8.27 (s, 1H), 8.50 (d, J=5.5Hz, 1H) Mass spectrometry data (FD-MS, m/z): 475 (M+)

Reference： [1]Patent: US6143764,2000,A

13
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 144-55-8 ]
[ 67815-56-9 ]
N-(2,3,6-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With triethylamine In toluene	226 N-(2,3,6-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [262] Example 226 N-(2,3,6-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [262] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,3,6-trifluoroaniline (53 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 30 mg of the title compound (yield: 38%). 1 H-NMR (DMSO-d6, 500 MHz): δ 3.93 (s, 3H), 3.94 (s, 3H), 6.44 (d, J=5.5Hz, 1H), 7.15~7.25 (m, 3H), 7.33~7.44 (m, 2H), 7.52 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 8.41 (s, 1H), 8.46 (d, J=4.9Hz, 1H), 9.18 (s, 1H) Mass spectrometry data (FD-MS, m/z): 469 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

14
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 328-93-8 ]
[ 144-55-8 ]
N-(2,5-Bis(trifluoromethyl)phenyl]-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With triethylamine; In toluene;	Example 228 N-(2,5-Bis(trifluoromethyl)phenyl]-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [264] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,5-Bis(trifluoromethyl)aniline (79 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 30 mg of the title compound (yield: 32percent). 1 H-NMR (DMSO-d6, 500 MHz): delta 3.94 (s, 3H), 3.95 (s, 3H), 6.45 (d, J=4.9Hz, 1H), 7.24 (d, J=9.2Hz, 2H), 7.40 (s, 1H), 7.52 (s, 1H), 7.60~7.66 (m, 3H), 7.95 (d, J=7.9Hz, 1H), 8.38 (s, 1H), 8.46~8.52 (m, 2H), 9.70 (s, 1H) Mass spectrometry data (FD-MS, m/z): 551 (M+)

Reference： [1]Patent: US6143764,2000,A

15
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 363-81-5 ]
[ 144-55-8 ]
N-(2,4,6-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine; In toluene;	Example 220 N-(2,4,6-Trifluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [256] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. <strong>[363-81-5]2,4,6-Trifluoroaniline</strong>. (75 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 37 mg of the title compound (yield: 47%). 1 H-NMR (DMSO-d6, 500 MHz): delta 3.94 (s, 3H), 3.95 (s, 3H), 6.4 3 (d, J=5.5Hz, 1H), 7.2 0 (d, J=8.6Hz, 2H), 7.29 (t, J=8.6Hz, 2H), 7.39 (s, 1H), 7.52 (s, 1H), 7.58 (d, J=8.6Hz, 2H), 8.07 (s, 1H), 8.46 (d, J=5.5Hz, 1H), 9.14 (s, 1H) Mass spectrometry data (FD-MS, m/z): 469 (M+)

Reference： [1]Patent: US6143764,2000,A

16
[ 1452-77-3 ]
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 144-55-8 ]
N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-pyridinecarbonyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In toluene	204 N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-pyridinecarbonyl)urea [240] Example 204 N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-pyridinecarbonyl)urea [240] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (75 mg) was dissolved in toluene (7 ml) with heat, after the addition of triethylamine (1.4 ml), triphosgene (201 mg) was added, and the admixture was refluxed with heat for 1 minute. 2-Pyridinecarboxamide (102 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 3 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 86 mg of the title compound (yield: 77%). 1 H-NMR (CDCl3, 500 MHz): δ 4.06 (s, 3H), 4.06 (s, 3H), 6.49 (d, J=4.9Hz, 1H), 7.20 (d, J=9.2Hz, 2H), 7.4 3 (m, 1H), 7.57 (s, 1H), 7.59 (m, 1H), 7.71 (d, J=9.2Hz, 2H), 7.97 (m, 1H), 8.28 (d, J=7.9Hz, 1H), 8.50 (brs, 1H), 8.68 (d, J=4.9Hz, 1H), 10.1 (brs, 1H), 10.7 (brs, 1H) Mass spectrometry data (FD-MS, m/z): 444 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

17
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 32202-61-2 ]
[ 144-55-8 ]
N-(5-Indanyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	In toluene;	Example 114 N-(5-Indanyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [197] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was suspended in toluene (5 ml), triphosgene (54 mg) was added, and the admixture was refluxed with heat for 12 minutes. <strong>[32202-61-2]4-Aminoindan</strong> (36 mg) was added, and the admixture was refluxed with heat for 36 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 13 mg of the title compound (yield: 16percent). 1 H-NMR (CDCl3, 500 MHz): delta 2.04 (m, 2H), 2.82~2.86 (m, 4H), 4.01 (s, 3H), 4.03 (s, 3H), 6.40 (d, J=5.5 Hz, 1H), 7.03 (m, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.13 (m, 1H), 7.32 (s, 1H), 7.40~7.57 (m, 6H), 8.44 (d, J=4.9 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 455 (M+)

Reference： [1]Patent: US6143764,2000,A

18
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 4519-40-8 ]
[ 144-55-8 ]
N-(2,3-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine; In toluene;	Example 224 N-(2,3-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [260] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. <strong>[4519-40-8]2,3-Difluoroaniline</strong> (51 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 60 mg of the title compound (yield: 79percent). 1 H-NMR (DMSO-d6, 500 MHz): delta 3.94 (s, 3H), 3.95 (s, 3H), 6.45 (d, J=4.9Hz, 1H), 7.02~7.08 (m, 1H), 7.11~7.19 (m, 1H), 7.23 (d, J=9.2Hz, 2H), 7.39 (s, 1H), 7.52 (s, 1H), 7.59 (d, J=9.2Hz, 2H), 7.94~7.99 (m, 1H), 8.47 (d, J=4.9Hz, 1H), 8.78 (s, 1H), 9.25 (s, 1H)

Reference： [1]Patent: US6143764,2000,A

19
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 19293-58-4 ]
[ 144-55-8 ]
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(4-dimethylaminophenyl)methyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With triethylamine; In toluene;	Example 215 N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(4-dimethylaminophenyl)methyl]urea [251] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 2 minutes. (4-Dimethylaminophenyl)methylamine (104 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 12 mg of the title compound (yield: 15%). 1 H-NMR (DMSO-d6, 500 MHz): (2.87 (s, 6H), 3.93 (s, 3H), 3.94 (s, 3H), 4.18 (d, J=5.5Hz, 2H), 6.40~6.43 (m, 2H), 6.70 (d, J=9.2Hz, 2 H), 7.1 3 (d, J=8.6Hz, 2H), 7.14 (d, J=8.6Hz, 2H), 7.37 (s, H), 7.51 (s, 1H), 7.52 (d, J=9.2Hz, 2H), 8.44 (d, J=4.9Hz, 1H), 8.57 (s, 1H) Mass spectrometry data (FD-MS, m/z): 472 (M+)

Reference： [1]Patent: US6143764,2000,A

20
[ 190728-25-7 ]
[ 56309-56-9 ]
N-(2-Isopropylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	In toluene	95 N-(2-Isopropylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [166] Example 95 N-(2-Isopropylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [166] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (44 mg) was dissolved in toluene (5 ml) with heat, 2-isopropylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 80 minutes. The resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 14 mg of the title compound (yield: 20%). 1 H-NMR (CDCl3, 500 MHz): δ 1.21 (m, 6H), 3.21 (m, 1H), 4.04 (s, 3H), 4.04 (s, 3H), 6.42 (m, 1H), 6.63 (m, 1H), 7.09-7.55 (m, 11H), 8.46 (m, 1H) Mass spectrometry data (FD-MS, m/z): 457 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

21
[ 190728-25-7 ]
[ 1476-23-9 ]
N-Allyl-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In water; N,N-dimethyl-formamide	102 N-Allyl-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [173] Example 102 N-Allyl-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [173] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in N,N-dimethylformamide (5 ml), allyl isocyanate (0.2 ml) was added, and the admixture was stirred at 80° C. for 15 hours with heat. Water was added to the reaction mixture, the admixture was extracted 2 times with ethyl acetate, and the organic layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 96%). 1 H-NMR (CDCl3, 500 MHz): δ 3.90 (m, 2H), 4.03 (s, 3H), 4.03 (s, 3H), 5.12 (d, J=10.4 Hz, 1H), 5.23 (d, J=1.77 Hz, 1H), 5.62 (s, 1H), 5.88 (m, 1H), 6.41 (d, J=4.9 Hz, 1H), 7.08 (d, J=8.5, 2H), 7.39 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.54 (s, 1H), 7.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 379 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

22
[ 190728-25-7 ]
[ 49647-20-3 ]
N-(4-Acetylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In toluene	80 N-(4-Acetylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}urea [49] Example 80 N-(4-Acetylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}urea [49] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (3 ml) with heat, 4-acetylphenyl isocyanate (210 mg) was added, and the admixture was refluxed with heat for 20 minutes. The resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 50 mg of the title compound (yield: 64%). 1 H-NMR (CDCl3 /CD3 OD, 500 MHz): δ 2.59 (s, 3H), 4.07 (s, 3H), 4.07 (s, 3H), 6.50 (d, J=5.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.36 (s, 1H), 7.58 (s, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.40 (d, J=5.5 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 457 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

23
[ 190728-25-7 ]
[ 55440-54-5 ]
N-(3-Chloro-6-methoxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In toluene	191 N-(3-Chloro-6-methoxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [227] Example 191 N-(3-Chloro-6-methoxyphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [227] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-6-methoxyphenyl isocyanate (111 mg) was added, and the admixture was refluxed with heat for 29 minutes. The resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 84 mg of the title compound (yield: 100%). 1 H-NMR (CDCl3, 500 MHz): δ 3.60 (s, 3H), 3.99 (s, 3H), 4.05 (s, 3H), 6.46 (d, J=4.9Hz, 1H), 6.69 (d, J=8.5Hz, 1H), 6.90 (m, 1H), 7.11 (d, J=9.2Hz, 2H), 7.4 2 (s, 1H), 7.5 3 (d, J=8.5Hz, 2H), 7.58 (s, 1H), 7.82 (s, 1H), 8.32 (m, 1H), 8.48 (d, J=5.5Hz, 1H), 8.52 (s, 1H) Mass spectrometry data (FED-MS, m/z): 479 (M+), 481 (M+ +2)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

24
[ 190728-25-7 ]
[ 23138-50-3 ]
N-(4-Ethylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In toluene	105 N-(4-Ethylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [188] Example 105 N-(4-Ethylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [188] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 4-ethylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 90 minutes. The resulting residue was purified by column chromatography on silica gel eluding with chloroform/acetone (10/1) to obtain 42 mg of the title compound (yield: 56%). 1 H-NMR (CDCl3, 500 MHz): δ 1.18 (m, 3H), 2.58 (m, 2H), 3.99 (s, 3H), 4.02 (s, 3H), 6.39 (d, J=5.5 Hz, 1H), 7.07 (d, J=9.2 Hz, 2H), 7.11 (d, J=7.9 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.40 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.55 (s, 1H), 7.60 (s, 1H), 7.81 (s, 1H), 8.43 (d, J=4.9 Hz, 1H) Mass spectrometry data (FD-MS, m/z): 443 (M+)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

25
[ 190728-25-7 ]
[ 37408-18-7 ]
N-(4-chloro-2-methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In toluene	206 N-(4-Chloro-2-methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [242] Example 206 N-(4-Chloro-2-methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [242] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (55 mg) was dissolved in toluene (5 ml) with heat, 4-chloro-2-methylphenyl isocyanate (90 mg) was added, and the admixture was refluxed with heat for 26 minutes. The separated crystals were filtered and then washed with toluene to obtain 69 mg of the title compound (yield: 80%). 1 H-NMR (DMSO-d6, 500 MHz): δ 2.26 (s, 3H), 3.94 (s, 3H), 3.94 (s, 3H), 6.44 (m, 1H), 7.18~7.20 (m, 3H), 7.25 (s, H), 7.38 (s, 1H), 7.51 (s, 1H), 7.59 (d, J=9.2Hz, 2H), 7.87 (m, 1H), 7.99 (s, 1H), 8.45 (m, 1H), 9.15 (s, 1H) Mass spectrometry data (FD-MS; m/z): 463 (M+), 465 (M+ +2)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD. - US6143764, 2000, A

26
[ 40258-99-9 ]
[ 190728-25-7 ]
1-({4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}carbamoyl)cyclopropane-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.1%	In tetrahydrofuran; at 20℃; for 16h;	To 1,1-cyclopropyldicarboxylic acid (44.9g, 0.345mol) in tetrahydrofuran (350ml)Triethylamine is added to the solution(48.5 mL, 0.345 mol),The solution was stirred at room temperature under nitrogen for 40 minutes.Into thionyl chloride (25mL, 0.344mol),LC/MS monitors the reaction,Monitor the conversion rate of monoacyl chloride (monitor methyl monocarboxylate after reaction quenched with methanol) and stir at room temperature for 3 hours.4-[(6,7-Dimethoxy-4-quinoline)oxy]aniline (102 g, 0.344 mol) was added successivelyAfter stirring at room temperature for 16 hours with tetrahydrofuran (150 ml), ethyl acetate (1000 ml) was added to the thick slurry.After dilution, it was extracted with 1N sodium hydroxide solution. The two-phase slurry is filtered,The aqueous phase was adjusted to pH 6 with hydrochloric acid and filtered. The filter cakes were combined, washed with ethyl acetate, and dried under reduced pressure.The product 1-[4-(6,7-dimethoxyquinoline-4-oxy)benzylcarbamoyl]-cyclopropyl-1-carboxylic acid(98.1 g, yield 70.1%, purity 98%)
68.7%	In tetrahydrofuran; at 20℃; for 16h;	To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THE (3.5 mL) was added TEA (485 iL, 3.45 mmoL). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 jiL, 3.44 mmol). The reaction was monitored by LCMS for the formation of mono acid chloride (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, <strong>[190728-25-7]4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine</strong> (1.02 g, 3.44 mmol) was added as a solid, followed by more TI-IF (1.5 mL). The reaction continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with iN NaOH. The biphasic slurry was filtered, and the aqueous phase was acidified with concentrated HC1 to pH or approximately 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, 1- [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoylj-cyclopropanecarboxylic acid, was obtained (962 mg, 68.7 percent yield, 97 percent pure) as a white solid. ?H NMR (D20/NaOH): 7.97 (d, 1H), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, 1H), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).
68.7%	In tetrahydrofuran; at 20℃; for 16h;	The reaction continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered, and the aqueous phase was acidified with concentrated HC1 to pH or approximately 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, l-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid, was obtained (962 mg, 68.7 percent yield, 97 percent pure) as a white solid. 'H NMR (D20/NaOH): 7.97 (d, 1H), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, lH), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).

68.7%	In tetrahydrofuran; at 20℃; for 16h;	Preparation of 1 - [4-(6,7-dimethoxy-quinolin-4- yloxy)-phenylcarbamoyl] - cyclopropanecarboxylic acid 15. To the cyclopropyl di-carboxylic acid 12a (449 mg, 3.45 mmol) in THF (3.5 mL) was added TEA (485 mu, 3.45 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 uL, 3.44 mmol). The reaction was monitored by LCMS for the formation of mono acid chloride 12 (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, 4-(6,7-dimethoxy-quinolin-4- yloxy)-phenylamine 16 (1.02 g, 3.44 mmol) was added as a solid, followed by more THF (1.5 mL). Continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered and the aqueous phase was acidified with cone. HCI to pH = 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, 1 - [4- (6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl] - cyclopropanecarboxylic acid, 15 was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. NMR (D20 NaOH): 7.97 (d, IH), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, IH), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).
	In tetrahydrofuran; at 20℃; for 16h;	To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THF (3.5 mL) was added TEA (485 muL, 3.45 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 muL, 3.44 mmol). The reaction was monitored by LCMS for the formation of mono acid chloride (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, 4-(6,7-dimethoxy-quinolin-4- yloxy)-phenylamine (1.02 g, 3.44 mmol) was added as a solid, followed by more THF (1.5 mL). Continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered and the aqueous phase was acidified with cone. HCl to pH = 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, l-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]- cyclopropanecarboxylic acid, was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. 1H NMR (D2O/NaOH): 7.97 (d, IH), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, IH), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).

Reference： [1]Patent: CN107556238,2018,A .Location in patent: Paragraph 0015; 0023-0024
[2]Patent: WO2014/145715,2014,A1 .Location in patent: Paragraph 00154; 00155
[3]Patent: WO2015/142928,2015,A1 .Location in patent: Paragraph 00140
[4]Patent: WO2016/19285,2016,A1 .Location in patent: Paragraph 00102; 00103
[5]Patent: WO2006/108059,2006,A1 .Location in patent: Page/Page column 111

27
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 455-01-6 ]
3-(Trifluoromethyl)phenethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 82 3-(Trifluoromethyl)phenethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine = 10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethylphenethyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 76%). 1H-NMR (CDCl3, 400 MHz): 8.42 - 8.49 (1H, m), 8.12 (1H, s), 7.61 (1H, s), 7.42 - 7.59 (6H, m), 7.13 - 7.18 (2H, m), 6.76 (1H, s), 6.66 (1H, d, J = 6.6 Hz), 4.44 (2H, t, J = 6.7 Hz), 4.15 (3H, s), 4.08 (3H, s), 3.07 (2H, t, J = 6.7 Hz) Mass spectrometry value (ESI-MS, m/z): 513 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

28
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 5411-56-3 ]
1-(2-Bromophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 112 1-(2-Bromophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (88 mg) was added to toluene/triethylamine = 10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (145 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, <strong>[5411-56-3]2-bromo-α-methylbenzyl alcohol</strong> (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (89 mg, yield 54%). 1H-NMR (CDCl3, 400 MHz): 8.44 (1H, d, J = 6.7 Hz), 8.12 (1H, s), 6.90 - 7.61 (10H, m), 6.65 (1H, d, J = 6.7 Hz), 6.20 (1H, q, J = 6.4 Hz), 4.14 (3H, s), 4.08 (3H, s), 1.59 (3H, d, J = 6.4 Hz) Mass spectrometry value (ESI-MS, m/z): 524 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

29
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 5339-01-5 ]
1-[3-(Dimethylamino)phenyl]ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	199 Example 199 Example 199 1-[3-(Dimethylamino)phenyl]ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (78 mg) was added to toluene/triethylamine = 10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-dimethylamino-α-methylbenzyl alcohol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected toseparatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 44%). 1H-NMR (CDCl3, 400 MHz): 8.39 (1H, d, J = 5.6 Hz), 7.42 - 7.57 (3H, m), 7.06 - 7.22 (2H, m), 6.54 - 6.74 (5H, m), 6.42 (1H, d, J = 5.6 Hz), 5.80 (1H, q, J = 6.6 Hz), 4.01 (3H, s), 3.99 (3H, s), 2.90 (3H, s), 2.89 (3H, s), 1.56 (3H, d, J = 6.6 Hz) Mass spectrometry value (ESI-MS, m/z): 489 (M+1+1)

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1243582, 2002, A1

30
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 587-03-1 ]
[ 144-55-8 ]
3-Methylbenzyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; In methanol; dichloromethane; chloroform; toluene;	Example 251 3-Methylbenzyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methylphenyl)methanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (146 mg, yield 89%). 1H-NMR (CDCl3-d1, 400 MHz): δ 2.38 (s, 3H), 4.10 (s, 3H), 4.17 (s, 3H), 5.20 (s, 2H), 6.69 (brs, 1H), 6.92 (s, 1H), 7.17 - 7.31 (m, 6H), 7.61 - 7.63 (m, 3H), 8.14 (s, 1H), 8.51 (brs, 1H) Mass spectrometry value (ESI-MS, m/z): 446 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

31
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 144-55-8 ]
[ 100-49-2 ]
cyclohexylmethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With triethylamine; In methanol; dichloromethane; chloroform; toluene;	Example 283 Cyclohexylmethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare asolution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclohexylmethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 61%). 1H-NMR (CDCl3-d1, 400 MHz): delta 1.03 - 1.04 (m, 2H), 1.21-1.27 (m, 4H), 1.78 - 1.80 (m, 5H), 4.02 (d, J = 6.3 Hz, 2H), 4.11 (s, 3H), 4.17 (s, 3H), 6.70 (d, J = 5.9 Hz, 1H), 6.88 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.64 (s, 1H), 8.15 (d, J = 4.1 Hz, 1H), 8.47 (s, 1H) Mass spectrometry value (ESI-MS, m/z): 438 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

32
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 502-41-0 ]
[ 144-55-8 ]
cycloheptyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In methanol; dichloromethane; chloroform; toluene	286 Example 286 Example 286 Cycloheptyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 85%). 1H-NMR (CDCl3-d1, 400 MHz): δ 1.47 - 1.79 (m, 12H), 4.10 (s, 3H), 4.17 (s, 3H), 4.90 - 4.96 (m, 1H), 6.70 (d, J = 5.9 Hz, 1H), 6.83 (s, 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.64 (s, 1H), 8.15 (s, 1H), 8.47 (brs, 1H) Mass spectrometry value (ESI-MS, m/z): 438 (M++1)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1243582, 2002, A1

33
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 402-63-1 ]
1-(3-Fluorophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	97 Example 97 Example 97 1-(3-Fluorophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (97 mg) was added to toluene/triethylamine = 10/1 (10 ml), and the mixture was heated under reflux to prepare asolution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (111 mg, yield 68%). 1H-NMR (CDCl3, 400 MHz): 8.41 - 8.47 (1H, m), 8.12 (1H, s), 7.55 - 7.62 (3H, m), 6.86 - 7.38 (7H, m), 6.65 (1H, d, J = 6.6 Hz), 5.88 (1H, 1, J = 6.6 Hz), 4.14 (3H, s), 4.08 (3H, s), 1.60 (3H, d, J = 6.6 Hz) Mass spectrometry value (ESI-MS, m/z): 463 (M++1)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1243582, 2002, A1

34
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 454-91-1 ]
1-[3-(Trifluoromethyl)phenyl]ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 87 1-[3-(Trifluoromethyl)phenyl]ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (74 mg) was added to toluene/triethylamine = 10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min.Subsequently, 3-trifluoromethyl-alpha-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (81 mg, yield 59%). 1H-NMR (CDCl3, 400 MHz): 8.41 - 8.48 (1H, m), 8.11 (1H, s), 7.45 - 7.68 (7H, m), 7.13 - 7.18 (2H, m), 6.93 (1H, s), 6.65 (1H, d, J = 6.6 Hz), 5.94 (1H, q, J = 6.6 Hz), 4.14 (3H, s), 4.08 (3H, s), 1.63 (3H, d, J = 6.6 Hz) Mass spectrometry value (ESI-MS, m/z): 513 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

35
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 120121-01-9 ]
1-(3-Chlorophenyl)ethyl N-{4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 3 1-(3-Chlorophenyl)ethyl N-{4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine = 10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (109 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-chloro-alpha-methylbenzyl alcohol (46 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed tocool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 70%). 1H-NMR (CDCl3, 400 MHz): 8.44 - 8.50 (1H, m), 8.14 (1H, s), 7.58 - 7.64 (3H, m), 7.26 - 7.42 (4H, m), 7.15 - 7.19 (2H, m), 6.86 (1H, s), 6.67 (1H, d, J = 6.6), 5.88 (1H, q, J = 6.6), 4.16

Reference： [1]Patent: EP1243582,2002,A1

36
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 93-03-8 ]
3,4-Dimethoxybenzyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	62 Example 62 Example 62 3,4-Dimethoxybenzyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (65 mg) was added to toluene/triethylamine = 10/1 (7 ml), and the mixture was heated under reflux to prepare asolution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 60%). 1H-NMR (CDCl3, 400 MHz): 8.49 (1H, s), 8.14 (1H, s), 7.58 - 7.64 (3H, m), 7.17 - 7.22 (2H, m), 6.86 - 7.04 (4H, m), 6.69 (1H, m), 5.17 (2H, s), 4.17 (3H, s), 4.10 (3H, s), 3.92 (3H, s), 3.90 (3H, s) Mass spectrometry value (ESI-MS, m/z): 492 (M++1)

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1243582, 2002, A1

37
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 445-26-1 ]
1-(2-Fluorophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 122 1-(2-Fluorophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (77 mg) was added to toluene/triethylamine = 10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (117 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-fluoro-alpha-methylbenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 78%). Mass spectrometry value (ESI-MS, m/z): 524 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

38
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 614-14-2 ]
1-Phenylbutyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	184 Example 184 Example 184 1-Phenylbutyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (78 mg) was added to toluene/triethylamine = 10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (118 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 1-phenyl-1-butanol (59 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78mg, yield 58%). 1H-NMR (CDCl3, 400 MHz): 8.43 (1H, dd, J = 6.6 Hz), 8.12 (1H, s like), 7.60 (1H, s), 7.53 - 7.58 (2H, m), 7.23 - 7.38 (4H, m), 7.12 - 7.15 (2H, m), 6.80 (1H, s), 6.64 (1H, d, J = 6.6 Hz), 5.72 - 5.78 (1H, m), 4.14 (3H, s), 4.07 (3H, s), 1.75 - 2.03 (2H, m), 1.35 - 1.45 (2H, m), 0.94 (2H, d, J = 7.3 Hz) Mass spectrometry value (ESI-MS, m/z): 474 (M+1+1)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1243582, 2002, A1

39
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 17178-01-7 ]
4-Chloro-2-methylphenyl {4-[(6,7-dimethoxy-4-quinolyl)oxy]anilino}methanethioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	176 Example 176 Example 176 4-Chloro-2-methylphenyl {4-[(6,7-dimethoxy-4-quinolyl)oxy]anilino}methanethioate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (88 mg) was added to toluene/triethylamine = 10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (70 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-methyl-4-chlorothiophenol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (108 mg, yield 70%). Mass spectrometry value (ESI-MS, m/z): 482 (M++1)

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1243582, 2002, A1

40
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 536-50-5 ]
1-(4-Methylphenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine In methanol; dichloromethane; chloroform; water; toluene	132 Example 132 Example 132 1-(4-Methylphenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine = 10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (109 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methyl-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (98 mg, yield 81%). 1H-NMR (CDCl3, 400 MHz): 8.40 - 8.45 (1H, m), 8.11 (1H, s), 7.61 (1H, s), 7.53 - 7.59 (2H, m), 7.10 - 7.32 (6H, m), 6.78 - 6.85 (1H, m), 6.65 (1H, d, J = 6.6 Hz), 5.87 (1H, q, J = 6.6 Hz), 4.14 (3H, s), 4.08 (3H, s), 2.34 (3H, s), 1.60 (3H, d, J = 6.6 Hz) Mass spectrometry value (ESI-MS, m/z): 460 (M++1)

Reference： [1]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1243582, 2002, A1

41
[ 190728-25-7 ]
[ 32315-10-9 ]
[ 52780-14-0 ]
1-(3-Bromophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
584%	With triethylamine; In methanol; dichloromethane; chloroform; water; toluene;	Example 117 1-(3-Bromophenyl)ethyl N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}carbamate 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine = 10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-bromo-alpha-methylbenzyl alcohol (75 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 584%). 1H-NMR (CDCl3, 400 MHz): 8.46 (1H, dd, J = 6.4 Hz), 8.13 (1H, s), 7.16 - 7.64 (9H, m), 7.01 (1H, s), 6.68 (1H, d, J = 6.4 Hz), 5.86 (1H, q, J = 6.4 Hz), 4.16 (3H, s), 4.10 (3H, s), 1.61 (3H, d, J = 6.6 Hz) Mass spectrometry value (ESI-MS, m/z): 524 (M++1)

Reference： [1]Patent: EP1243582,2002,A1

42
[ 868171-67-9 ]
[ 190728-25-7 ]
[ 1021179-16-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;dmap; In N,N-dimethyl-formamide; at 20℃; for 48h;	To a solution of 1 -(4-fluorophenyl)-2-oxo-1 ^-dihydropyridine-S-carboxylic acid (Intermediate E, 531 mg, 2.2 mmol) and 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (Intermediate A, 450 mg, 1.5 mmol) in DMF (20 ml_) were added 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (437 mg, 2.3 mmol), 1 - hydroxybenzotriazole (308 mg, 2.3 mmol), Et3N (231 mg, 2.27 mmol) and DMAP (18.5 mg, 0.15 mmol). The reaction mixture was stirred at rt for 48 h, and then ethyl acetate (50 ml_) was added. The mixture was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was triturated with CH2CI2 and filtered to give 275 mg (35%) of the title compound. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography to give an additional 180 mg (23 %) of the title compound. Total yield: 455 mg (58%).1H NMR (400 MHz, DMSO-cfe) delta 12.00 (s, 1 H), 8.50 (dd, 1 H), 8.46 (d, 1 H), 8.11 (dd, 1 H), 7.82 (d, 2 H), 7.62-7.59 (m, 2 H), 7.49 (s, 1 H), 7.43-7.39 (m, 2 H), 7.38 (s, 1 H), 7.25 (d, 2H), 6.71 (t, 1 H), 6.47 (d, 1 H), 3.93 (s, 3H), 3.91 (s, 3H); ES- MS m/z 512.0 [M+H]+, LCMS RT (min) 2.61.

Reference： [1]Patent: WO2008/48375,2008,A1 .Location in patent: Page/Page column 54-55

43
[ 190728-25-7 ]
[ 598-10-7 ]
1-({4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}carbamoyl)cyclopropane-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.7%		To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THF (3.5 mL) was added TEA (485 PL, 3.45 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 PL, 3.44 mmol). The reaction was monitored by LCMS for the formation of mono acid chloride (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, 4- (6, 7-dimethoxy-quinolin-4- yloxy) -phenylamine (1.02 g, 3.44 mmol) was added as a solid, followed by more THF (1.5 mL). Continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered and the aqueous phase was acidified with conc. HC1 to pH = 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, 1- [4- (6, 7-dimethoxy-quinolin-4-yloxy) -phenylcarbamoyl]- cyclopropanecarboxylic acid, was obtained (962 mg, 68.7% yield, 97% pure) as a white SOLID.
42%	With thionyl chloride; triethylamine; In tetrahydrofuran; for 5h;	In step (1), the reaction vessel C is a 250 ml four-necked bottle, and the holding reaction time is 1 hour;In step (2), stir for 4 hours after the addition is complete;In step (3), the reaction solution was diluted with 500 ml of EA, and extracted with 300 ml of 1N hydrochloric acid.The organic phase was discarded, the aqueous phase was adjusted to pH = 5.5 with 1N hydrochloric acid, and filtered with suction.The filter cake was rinsed with 200ml EA and dried at 50 C to constant weight;The feed ratio of SM3-0, KB-2, SOCl2, Et3N and THF was 13.47g: 30.6g: 12.2g: 10.59g: 150ml.18 g of solid was obtained with a yield of 42% and a purity of 92%.

Reference： [1]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 233
[2]Patent: CN110423218,2019,A .Location in patent: Paragraph 0108-0128

44
[ 190728-25-7 ]
[ 54-60-4 ]
[ 1207980-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;	4-(6,7-Dimethoxyquinolin-4-yloxy)benzenamine (60 mg, 202 μmol), 2-(4- fluorophenylamino)benzoic acid (56 mg, 243 μmol), and HATU (108 mg, 283 μmol) were combined in a resealable tube. DCM (1012 μl, 202 μmol) and N-ethyl-N- isopropylpropan-2-amine (71 μl, 405 μmol) were added, and the reaction mixture in the tube was allowed to stir at RT. Upon completion (as judged by LCMS), the reaction mixture was concentrated in vacuo, dissolved in minimal DMSO and purified by preparative HPLC {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Fractions containing pure product were combined and neutralized with saturated aqueous NaHCO3 then extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo to afford pure N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-2-(4- fluorophenylamino)benzamide as a off-white solid. MS Calcd for C3oH24FN3θ4: [M]+ = 509. Found: [M+H]+= 510.

Reference： [1]Patent: WO2010/19473,2010,A1 .Location in patent: Page/Page column 33

45
[ 190728-25-7 ]
1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carbonyl chloride [ No CAS ]
[ 849217-68-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; water; at 15 - 30℃;	The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 3O0C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-3O0C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a premade solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 650C under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): delta 10.2 (s, IH), 10.05 (s, IH), 8.4 (s, IH), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, IH), 7.35 (s, IH), 7.25 (m, 2H). 7.15(m, 2H). 6.4 (s, IH), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H= 502.
	With potassium carbonate; In tetrahydrofuran; water;	Preparation of N-(4-[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (typically in about 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15 to 30 C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65 C. under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): delta 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Product distribution / selectivity;	The solution from the previous step containing l-(4-fluorc- phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

	With potassium carbonate; In tetrahydrofuran; water;	Preparation of N-(4-[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg), and potassium carbonate (4.0 kg) in THF (27.0 kg), and water (13.0 kg) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (approximately 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15 to 30 C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre made solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65 C. under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): delta 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
	With potassium carbonate; In tetrahydrofuran; water; at 20 - 25℃;Large scale;	Alternative Preparation of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide [0066] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K2C03 in 169 kg water. The acid chloride solution of described in the Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20 to 30 C over a minimum of two hours. The reaction mixture was stirred at 20 to 25 C for a minimum of three hours. The reaction temperature was then adjusted to 30 to 25 C, and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15 to 25 C for a minimum of 16 hours.[0067] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30 to 35 C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours). The mixture was agitated at 15 to 25 C for at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 C.[0068] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10 to 15 C. The recrystallization temperature was changed from 15 to 25 C to 45 to50 C for 1 hour and then cooled to 15 to 25 C over 2 hours.
5.0 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.166667h;Large scale;	The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4- yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (1 1.0 kg) and water (24.0 kg), and dried at approximately 65 C under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). NMR (400 MHz, d6-DMSO): delta 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC MS: M+H= 502.
41 kg	With potassium carbonate; In tetrahydrofuran; water; N,N-dimethyl-formamide; at 30℃; for 0.333333h;Large scale;	[00125] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
41.0 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	Preparation of cyclopropane-1 ,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide[00121] The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
41 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	The solution from the previous step containing l-(4- fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
41 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	The solution from the preyious step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-diniethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (3 1.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 c. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 c for approximately 10 hours, wkich resulted in the precipitation of the product. The product was recoyered by fultration, washed with a pre-made solution of THF (6 8.6 kg) and water (256 L), and dried first on a fulter under nitrogen at approximately 25 c and then at approximately 45 c under yacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
5.0 kg	With potassium carbonate; cyclopropanecarboxylic acid chloride; In tetrahydrofuran; water; at 30℃; for 0.166667h;Large scale;	Preparation of N-(4-{16,7-bis(methyloxy)quinolin-4-yljoxy}phenyl)-N?-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide[002611 The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65 C under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). ?H NMR (400 MHz, do-DMSO): 8 10.2 (s, 1H), 10.05 (s, lH), 8.4 (s, 111), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (ci, 6H), 1.5 (s, 4H). LCIMS: M+H= 502.
	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	[00119] The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in TI-IF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
41 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	10100] The solution from the previous step containing 1 -(4- fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C. and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	Since the steps comprise future 1 - (4-fluoro-phenyl amine formyl )-cyclopropane carbon acyl chlorine of the batch solution so that the temperature does not exceed 30 C added to the compound the rate of 4 - (6,7-dimethoxy-quinolin-4-yloxy)- benzyl amine (23.5 kg) and potassium carbonate (31.9 kg) THF of (245.7 kg) and water (116 L) in the mixture. When the reaction is complete (about 20 minutes), add water (653 L). In 20-25 C stirring the mixture under about 10 hours, resulting in precipitation of the product. Filtering and recycling the product, in order to pre-prepared THF (68.6 kg) and water (256 L) of solution, and about the first 25 C lower, in nitrogen, dry on the filter, and then at about 45 C the lower vacuum drying, the title compound is obtained (to LOD computing, 41.0 kg, 38.1 kg).
5.0 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.166667h;Large scale;	Preparation of N-(4-[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65 C under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): delta 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H= 502.
1589.8 g	With potassium carbonate; In tetrahydrofuran; at -5 - 20℃;Large scale;	A mixture of 4-(6,7-dimethoxyquinolin-4-yloxy)aniline 995.6 g (3.36 mol) after dissolving with 3.6 L (44.39 mol) of tetrahydrofuran, 1210 g (4.03 mol) of potassium carbonate was added,After dissolution dropwise oriented Step l - ((4-fluorophenyl) carbamoyl) cyclopropanecarbonyl chloride solution, the reaction 0.5 ~ 2h at -5 ~ 20 . After completion of the reaction, 1 L of water was added and the solution was stirred at 40 to 45 C for about 2 hours. The crystals were crystallized, filtered and washed three times with 700 ml of water. The filter cake was then dried in vacuo at 45 C to give 1589.8 g (3.17 mol ), molar yield 97.2%.
	With potassium carbonate; In tetrahydrofuran; water; at 20 - 30℃; for 10h;Large scale;	The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
2.93 g	With potassium carbonate; In water; acetone; at 65℃; for 12h;	Add 1.41g of oxalyl chloride to the room temperature 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid1.66 g of a mixed solution of 8.00 g of acetone and 0.03 g of N,N-dimethylformamide,A solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride is obtained;The obtained 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride solution was added at room temperature.2.00 g of 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine and 2.87 g of potassium carbonate in a mixture of 20.00 g of acetone and 8.00 g of water; after completion of the reaction, 20 mL of water was added. ,filter,The resulting solid was dried under vacuum at 65 C for 12 hours.Get the compoundN-(4-[6,7-bis(methoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-Dimethylamide2.93g.
41 kg	With potassium carbonate; In tetrahydrofuran; water; at 30℃; for 0.333333h;Large scale;	[00177] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
11.5 g		To a stirred suspension of 9 (8.4 g, 0.028 mol) in THF (80 mL) was added a solution of K2CO3 (8.3 g, 0.06 mol) in water (40 mL). The mixture was stirred at room temperature for 2 h. Then the carbonyl chloride 10 (0.043 mol) was added at room temperature and the reaction solution was stirred for 3 h. The stirring was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added water(100 mL). Then the mixture was stirred at 15 C for 10 h. The solid was precipitated.The product was filtered and washed with a mixture of 2:1 (v/v) water/THF (20mL2). The crude product was dried at 60 C for 4 h. The dried product was then taken upin EtOAc: EtOH 1:1 (v:v) (50 mL) and heated to reflux for 30 min, then cooled to room temperature for 1 h, the resulting solid was filtered off and washed with EtOAc(20mL 2), dried at 50 C for 3 h to afford 1 (11.5 g, 82%) as an off-white solid. 1HNMR (DMSO-d6): d 1.48 (s, 4H), 3.94 (s, 3H), 3.95 (s, 3H), 6.42 (d, J5.2 Hz, 1H),6.67 (d, J9.2 Hz, 1H), 6.93 (d, J9.2 Hz, 1H), 7.16 (t, J8.8 Hz, 2H), 7.23 (d,J9.6 Hz, 2H), 7.39 (s, 1H), 7.51 (s, 1H), 7.65 (dd, J4.8, 8.8 Hz, 2H), 7.77 (d,J9.6 Hz, 2H), 8.47 (d, J5.2 Hz, 1H), 10.07 (s, 1H), 10.20 (s, 1H). ESI-MS (m/z):502.2 (MH).Anal: Calcd for C28H24FN3O5 : C; 67:06; H; 4:82: Found : C; 67:25; H; 4:78:HPLC Conditions- Column: Acclaim C18 (150mm 2.1mm 5 mm);Detection: 220 nm; Flow rate: 0.8 mL/min; Temperature: 30 C; Injection load: 1 lL;Solvent: methanol; Run time: 15 min; Mobile phase: methanol/water 90/10, tR:4.143 min, purity: 99.1%.

Reference： [1]Patent: WO2010/83414,2010,A1 .Location in patent: Page/Page column 26
[2]Patent: US2012/70368,2012,A1
[3]Patent: WO2012/109510,2012,A1 .Location in patent: Page/Page column 30
[4]Patent: US2012/252840,2012,A1
[5]Patent: WO2013/59788,2013,A1 .Location in patent: Paragraph 0066; 0067; 0068
[6]Patent: WO2013/43840,2013,A1 .Location in patent: Paragraph 00111; 00117
[7]Patent: WO2013/70890,2013,A1 .Location in patent: Paragraph 00124-00125
[8]Patent: WO2013/166296,2013,A1 .Location in patent: Paragraph 00121
[9]Patent: WO2014/165786,2014,A1 .Location in patent: Paragraph 00202
[10]Patent: WO2014/165779,2014,A1 .Location in patent: Paragraph 0077; 0078; 0085; 0086; 0087; 0088
[11]Patent: WO2015/164869,2015,A1 .Location in patent: Paragraph 00255; 00261
[12]Patent: WO2016/22697,2016,A1 .Location in patent: Paragraph 00111; 00119
[13]Patent: US2016/772,2016,A1 .Location in patent: Paragraph 0095; 0100
[14]Patent: TWI516477,2016,B .Location in patent: Page/Page column 31; 35
[15]Patent: EP2758057,2017,B1 .Location in patent: Paragraph 0112
[16]Patent: CN103664778,2017,B .Location in patent: Paragraph 0054; 0056; 0067; 0068
[17]Patent: WO2018/136796,2018,A1 .Location in patent: Paragraph 0081; 0082; 0094; 0095; 0096; 0097; 0098; 0099
[18]Patent: CN104370811,2019,B .Location in patent: Paragraph 0086-0089
[19]Patent: WO2018/227119,2018,A1 .Location in patent: Paragraph 00163; 00176-00177; 00178-00181
[20]Organic Preparations and Procedures International,2019,vol. 51,p. 381 - 387
[21]Patent: US2020/255382,2020,A1 .Location in patent: Paragraph 0111; 0117; 0119; 0127-0130

46
[ 13425-93-9 ]
[ 190728-25-7 ]

Reference： [1]Patent: WO2012/109510,2012,A1
[2]Patent: US2012/252840,2012,A1
[3]Patent: US2012/252840,2012,A1
[4]Patent: US2012/252840,2012,A1
[5]Patent: US2012/252840,2012,A1
[6]Patent: WO2013/59788,2013,A1
[7]Patent: WO2013/43840,2013,A1
[8]Patent: WO2013/43840,2013,A1
[9]Patent: WO2013/70890,2013,A1
[10]Patent: WO2013/166296,2013,A1
[11]Patent: WO2013/166296,2013,A1
[12]Patent: WO2013/180949,2013,A1
[13]Patent: WO2014/165779,2014,A1
[14]Patent: WO2015/164869,2015,A1
[15]Patent: WO2015/164869,2015,A1
[16]Patent: WO2016/22697,2016,A1
[17]Patent: WO2016/19285,2016,A1
[18]Patent: US2016/772,2016,A1
[19]Patent: TWI516477,2016,B
[20]Patent: EP2758057,2017,B1
[21]Patent: EP2758057,2017,B1
[22]Patent: CN103664778,2017,B
[23]Patent: CN103664778,2017,B
[24]Journal of labelled compounds and radiopharmaceuticals,2018,vol. 61,p. 11 - 17
[25]Patent: CN108264482,2018,A
[26]Patent: WO2018/136796,2018,A1
[27]Patent: WO2018/227119,2018,A1
[28]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2801 - 2812
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[31]Archiv der Pharmazie,2019,vol. 352
[32]Patent: CN110240563,2019,A

47
[ 190728-25-7 ]
1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carbonyl chloride [ No CAS ]
[ 1140909-48-3 ]

Reference： [1]Patent: WO2012/109510,2012,A1
[2]Patent: WO2013/59788,2013,A1
[3]Patent: WO2013/43840,2013,A1
[4]Patent: WO2013/166296,2013,A1
[5]Patent: WO2015/164869,2015,A1
[6]Patent: WO2018/227119,2018,A1

48
6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline [ No CAS ]
[ 190728-25-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With formic acid; palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 60℃; for 15h;Large scale;	Preparation of 4-(6,7 -Dimethoxy-q uinoline.-4-yloxy)--phenylamine [00108] A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (TI-IF, 40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).
3.0 kg	With formic acid; palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 60℃; for 1.5h;Large scale;	A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10 percent palladium on carbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (THF, 40.0 kg) that had been heated to approximately 60 C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60 C. When the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35 C to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50 C to afford the title compound (3.0 kg; 97 percent area under curve (AUC)).

Reference： [1]Patent: WO2013/166296,2013,A1 .Location in patent: Paragraph 00108
[2]Patent: WO2013/43840,2013,A1 .Location in patent: Paragraph 00111; 00114

49
[ 190728-25-7 ]
[ 83-10-3 ]
N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux;	To a solution of 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (2 g, 6.7 mmol) and l,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-lH-pyrazole-4-carboxylic acid (1.58 g, 6.8 mmol) in DCM (28 mL) was added EDCI (1.53 g, 8.0 mmol) and HO AT (0.18 g, 1.3 mmol). The reaction was heated to reflux overnight and then washed with water (50 mL x 2). The solution was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by recrystallization (DCM/PE (v/v) = 1/5) to give the title compound as a white solid (1.9 g, 87%). MS (ESI, pos. ion) m/z: 51 1.1 [M+H]+; FontWeight="Bold" FontSize="10" H R (400 MHz, CDC13): delta 10.78 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.77-7.75 (m, 2H), 7.58-7.55 (m, 3H), 7.49-7.47 (m, 1H), 7.42 (s, 1H), 7.39-7.36 (m, 2H), 7.15-7.13 (m, 2H), 6.49 (d, J= 5.3 Hz, 1H), 4.05 (s, 6H), 3.37 (s, 3H), 3.04 (s, 3H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0173

50
[ 190728-25-7 ]
[ 849217-68-1 ]

Reference： [1]Patent: WO2016/19285,2016,A1
[2]Patent: WO2016/19285,2016,A1
[3]Patent: WO2016/19285,2016,A1
[4]Patent: WO2016/19285,2016,A1
[5]Patent: CN103664776,2016,B
[6]Patent: CN109988107,2019,A
[7]Patent: WO2019/234761,2019,A1

51
[ 190728-25-7 ]
[ 113020-21-6 ]
methyl 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g		l-(Methoxycarbonyl)cyclopropanecarboxylic acid (13, 0.2 g, 1.2 mmol), 1,3- diisopropylcarbodiimide (0.2 mL, 1.2 mmol), and 1-hydroxybenzotriazole monohydrate (0.2 g, 1.2 mmol) were added to a 25 mL round bottom flask and dissolved in DMF (3.2 mL). This reaction mixture was allowed to stir at ambient temperature for 10 minutes. To it 4-(6,7- dimethoxyquinolin-3-yloxy)aniline (12, 0.3 g, 1.0 mmol) was added to reaction mixture, and allowed to stir at ambient temperature for 4.5 hours. After this time period, 100 mL of DI water was added and the reaction mixture was extracted with 3 x 50 mL of ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford a yellow/white solid. The crude reaction mixture was purified via flash silica gel column chromatography using ethyl acetate as the mobile phase. Methyl l-(4-(6,7-dimethoxyquinolin-3- yloxy)phenylcarbamoyl)cyclopropanecarboxylate (14, 0.4 g, 0.9 mmol, 89 % yield) was obtained as white solid. NMR (CDC13, 500 MHZ) delta 10.95 (s, 1H); 8.45 (d, 1H, J= 5.5 Hz); 7.67 (d, 2H, J= 6.6 Hz); 7.54 (s, 1H); 7.41(s, 1H); 7.15(d, 2H, J= 6.6 Hz); 6.43(d, 1H, J = 5.5 Hz); 4.04(s, 6H); 3.75(s, 3H); 1.85-1.82 (m, 2H), 1.71-1.69(m, 2H); LCMS (m/z) C23H23N206 (M+H) Calcd: 423.16; Found: 423.1 ; 13C NMR ( CDC13; 125 mHz) delta 174.4, 166.9, 160.9, 152.9, 150.4, 149.5, 148.8, 146.8, 135.6, 121.9, 121.6, 116.1, 107.8, 103.3, 99.5, 56.1, 52.5, 26.5, 20.9.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;	4 - ((6. 7 - Dimethoxy -4 -yl) phenoxy) aniline (11.4g, 0.039 muM, 1.0 eq.), 1, 1 - cyclopropyldicarboxylic acid monomethyl (7.9g, Kunitunit, 0.055 muM eq.) were added to methylene chloride (65 ml unitunito, stirred) with 1.4 ethyl - (1 - dimethylaminopropyl) carbonyldiimine hydrochloride (3 - Kunitunit, 1.5 0.059 muM 11.2g eq.), stirred at room temperature 2h at room temperature. Dichloromethane, concentration and dichloromethane are removed. The concentrate was washed, stirred 50 ml, washed, filtered, and washed 500 ml with water to obtain 5~6h ((1 - (20 ml (4 - 6-dimethoxyquinoline 7 -yloxy) phenyl) aminoformyl) cyclopropanecarboxylate -4 - and gave a unit_, purity Kunitz-like. The 14.1g concentrate was 86.8% obtained by washing 99.7% with water and washing with a purified Kunitz-type aqueous solution.
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	4-[(6,7-Dimethoxyquinolin-4-yl)oxy]aniline (1.0 eq.; A') was added to a stirred solution of HATU (1.05 eq.), l-(methoxycarbonyl)cyclopropanecarboxylic acid (1.0 eq.; B') and DIPEA (1.5 eq.) in DMF and the mixture was stirred at room temperature (RT) for 2 hrs. After complete consumption of the aniline, as monitored by LCMS/TLC, reaction mixture was diluted with water. The resulting solution was extracted in EtOAc. The combined organic extract was dried over anhydrous Na2S04 and concentrated on rotary evaporator. The residue was triturated in diethyl ether to afford compound C.

Reference： [1]Patent: WO2016/19285,2016,A1 .Location in patent: Paragraph 0098
[2]Patent: CN109988107,2019,A .Location in patent: Paragraph 0040-0043
[3]Patent: WO2020/27723,2020,A1 .Location in patent: Page/Page column 36

52
[ 190728-25-7 ]
[ 1005738-45-3 ]
1-tert-butyl 4-methyl 4-({4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}carbamoyl)piperidine-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.9%		The 250 ml round-bottom flask the compound c is added in (5.33g, 18 . 6mmol), DMAP (2.27g, 18 . 7mmol), EDCI (10.7g, 55 . 8mmol), dichloromethane 100 ml, stirring the mixture at room temperature for 20 min the rear, the compound h is added (5g, 16.9mmol), for 45 degrees reflux 7h, dilute hydrochloric acid solution to wash the organic phase 3 times, to yellow oily organic phase evaporation to dryness, with silica gel column chromatography, dichloromethane/methanol elution, the white solid obtained 6g, yield 62.9%.

Reference： [1]Patent: CN105541798,2016,A .Location in patent: Paragraph 0126; 0127

53
[ 190728-25-7 ]
[ 3697-66-3 ]
C₂₄H₂₄N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.2%		To a three-necked flask 250ml tetrahydrofuran 60ml, N, N- dimethylformamide, and 3 drops of 1-(ethoxycarbonyl)Cyclopropanecarboxylic acid 5. 0g (31. 6mmol), control the temperature 0~20 C solution of oxalyl chloride under 5. 3ml (55. 3mmol), Bi drops, control Temperature 10~20 C for 2 hours, the reaction liquid and set aside.To a 250ml three-necked flask was added 4-((6,7-dimethoxy-quinolin-4-yl) oxy)aniline 9. 4g (31. 6mmol), water 30ml, potassium carbonate 13. lg (94. 9mmol), 10~20 C dropwise added step reaction liquid drops Bi, room The reaction temperature of 2 hours, water was added to the reaction solution 300ml, stirred for 5 hours at room temperature, preformulated suction, the filter cake washed with tetrahydrofuranFurans / water (50ml / 100ml) to wash the mixture, suction filtered, the resulting solid was separated by column chromatography (mobile phase V / V: ethyl acetate / diethylDichloromethane = 1/1), desired fractions were collected, the solvent evaporated under reduced pressure to give a pale yellow solid 7. 2g (52. 2%).

Reference： [1]Patent: CN103664776,2016,B .Location in patent: Paragraph 0120; 0121; 0122

54
[ 190728-25-7 ]
[ 1345847-71-3 ]
[ 849217-68-1 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 4h;	4-((6,7-Dimethoxy-4-yl)oxy)aniline (10 g, 0.034 mol, 1.0 eq.),Methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (11.3 g, 0.048 mol, 1.4 eq.) was added to 100 mL of tetrahydrofuran and cooled to 0 C.2M NaHMDS tetrahydrofuran solution (102 mL, 0.204 mol, 6.0 eq.) was added slowly, and the reaction was carried out for 4 h at room temperature.The reaction solution was cooled to 0 C,Slowly add 1200mL of purified water, stir and crystallization for 5-6h,Filter, wash 20 mL of purified water,The biotin of Bobotinib was 16 g, the yield was 94.6%, and the purity was 99.6%.
92.9%	With sodium hexamethyldisilazane; In tetrahydrofuran; at -5 - 5℃;	The compound (II) (200 g, 0.67 muM), compound (VII) (220 g, 0.93 muM), THF (2 L) are added to a reaction in the bottle, lowering the temperature to -5 C -5 C, dropping of the NaHMDS THF (2 mol/L) 2 L solution, then completing, for -5 C -5 C stirring reaction for 1 - 2 hours. (TLC monitoring the reaction is complete, Rf value 0.5 (dichloromethane: methanol=20:1)). To the reaction solution in water (16 L), stirring crystallization 1 - 2 hours, filtration, filtration cake 40 C -50 C vacuum drying 23 - 24 hours to obtain white solid 312 g, yield 92.9%, HPLC purity 99.5%.
62%		A solution of aniline 3 (240 mg, 0.81 mmol) and NaOMe (115 mg, 2.1 mmol) in toluene (15 mL) was stirred under Ar at 100 C (bath temperature), and the MeOH/toluene azeotrop was distilled off at 63 C. In a stream of Ar, toluene (2 mL) was distilled to ensure complete removal of MeOH. To this mixture, methyl ester 4 (230 mg, 0.97 mmol) in toluene (15 mL) was added, and the heating was continued. Again, the MeOH/toluene azeotrop was distilled off, followed by toluene in a stream of Ar at a slightly higher bath temperature. The residue was allowed to cool and was stirred with saturated aqueous NH4Cl solution (30 mL), then extracted with EtOAc (30 mL). The organic phase was filtered, washed with ag. NaHCO3 solution (10 mL), dried over MgSO4 and evaporated. The residue was stirred with t-BuOMe (3 × 3 mL), the insoluble product was collected and dried under reduced pressure to yield an off-white powder (250 mg, 62%); mp 98 C; IR (neat): 1504, 1477, 1211, 831, 516 cm-1; 1HNMR (300 MHz, DMSO-d6) delta 1.49 (s, 4H), 3.93 (s, 3H), 3.94 (s, 3H), 6.43 (d, J = 5.2 Hz, 1H), 7.15 (t, J= 8.8 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.39 (s, 1H), 7.50 (s, 1H), 7.65 (dd, J = 5.1 and 8.8 Hz, 2H), 7.77(d, J = 8.9 Hz, 2H), 8.46 (d, J = 5.2 Hz, 1H), 10.08 (s, 1H), 10.21 (s, 1H); 13C NMR (75 MHz, DMSO-d6)delta 15.4 (2C), 31.5, 55.7 (2C), 99.1, 103.0, 107.8, 115.0 (d, J = 22.0 Hz, 2C), 121.2 (2C), 122.2, 122.4 (d, J= 7.9 Hz, 2C), 135.1, 135.2, 136.4, 146.4, 148.8, 149.3, 149.5, 152.6, 158.3 (d, J = 240.4 Hz), 160.0,168.1, 168.2 ppm; HRMS (FAB) m/z 502.1827 (calcd 502.1778 for C28H25FN3O5, [M+H]+).

62%

4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (240 mg, 0.81 mmol) and sodium methoxide (115mg, 2.1 mmol) in toluene (15 mL) were stirred at 100 00 for 1 hour under inert gas flow whereby the majority of the solvent evaporated. Next, a solution of methyl 1-((4- fluorophenyl)carbamoyl)cyclopropanecarboxylate (230 mg, 0.97 mmol) in toluene (15 mL) was added and toluene/methanol azeotrope distilled off. The bath temperature was raised to 110 00 and stirring under inert gas flow was continued for another 4 hours. Within this periodadditional portions of toluene (3 x 20 mL) were added in order to compensate evaporation. Upon cooling to room temperature the residue was dissolved in ethyl acetate (30 mL) and washed sequentially with saturated aqueous ammonium chloride (30 mL) and bicarbonate (10 mL) solutions. The organic layer was dried over magnesium sulfate und the solvent was evaporated. The residue was extracted with MTBE (3 x 3 mL) providing after drying in vacuo230 mg of pure title compound as a slightly brownish powder in 62 % yield. The respectively obtained material was subjected to 1H-NMR analysis; the 1H-NMR is shown in Fig. 1.

Reference： [1]Patent: CN109988108,2019,A .Location in patent: Paragraph 0057-0061; 0062-0064; 0066-0068; 0070-0072
[2]Patent: CN109836382,2019,A .Location in patent: Paragraph 0081-0087
[3]Heterocycles,2016,vol. 93,p. 323 - 332
[4]Patent: WO2017/29362,2017,A1 .Location in patent: Page/Page column 88

55
[ 95262-10-5 ]
[ 190728-25-7 ]
[ 849217-68-1 ]

Reference： [1]Patent: CN106632028,2017,A

56
[ 95262-10-5 ]
[ 190728-25-7 ]
N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)malonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.7%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 40℃;	3- (4-Fluorophenylamino) -3-oxopropionic acid (18.15 g, 92.04 mmol), 1- (3- dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (21.18 g, 110.45 mmol),1-hydroxybenzotriazole (14.92 g, 110.45 mmol) and4 - [(6,7-dimethoxyquinolin-4-yl) oxy] aniline (30 g, 101.2 mmol)N, N-dimethylacetamide (200 ml),The reaction was stirred at 40 C overnight.The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (2000 ml) and stirred for 1 hour.The mixture was extracted with dichloromethane (2 * 200 ml) and the organic layers were combined and spin-dried to give a solid N- (4 - ((6,7-dimethoxyquinolin-4- yl) oxy) phenyl) 4-fluorophenyl) malonamide(39.3 g, yield: 89.7%).

Reference： [1]Patent: CN106632028,2017,A .Location in patent: Paragraph 0044; 0045; 0046; 0047; 0060; 0061; 0072; 0073

57
[ 190728-25-7 ]
[ 849217-48-7 ]
[ 849217-68-1 ]

Yield	Reaction Conditions	Operation in experiment
93.1%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 60℃;	1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (500 g, 2.24 mol),2-(7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (850 g, 2.24 mol), triethylamine (380 g)And N,N-dimethylacetamide (2L) was added to the reaction flask,Compound (II) (550 g, 1.86 mol) was added with stirring, and the addition was completed.The reaction was stirred at 60 C for 5 to 6 hours. Add water (16L) to the reaction solution,Stir for 10 to 20 hours at 10 to 20 C, and filter.The filter cake was vacuum dried at 40 to 50 C for 23 to 24 hours to obtain 867 g of a white solid.The yield was 93.1%, and the HPLC purity was 99.5%.
86%	With dicyclohexyl-carbodiimide; In dichloromethane; for 10h;Reflux;	Step four:Add 250 dichloromethane to the three-neck bottle.50 g of intermediate 3 and 40 g of 1-(4-fluorophenyl)aminocarbonylcyclopropanecarboxylic acid,Then, 35 g of DCC was added, and the reaction was heated to reflux for 10 hours;Filtered and the filtrate was washed with sodium carbonate solution.The methylene chloride layer was concentrated, crystallized, filtered, dried and recrystallised from ethyl acetate.Get 73gCabotinib,The yield was 86%.
86%	With dicyclohexyl-carbodiimide; In dichloromethane; for 10h;Reflux;	Add 250 dichloromethane to the three-necked flask and add 50g of intermediate 3 and40g1-(4-fluorophenyl)aminocarbonylcyclopropanecarboxylic acid,Then add 35g DCC,Warming reflux reaction for 10 hours;Drop to room temperature, filter, and wash the filtrate with sodium carbonate solution.The methylene chloride layer is concentrated, crystallized, filtered, dried,Recrystallized from ethyl acetate,Get 73g of cabozantini,The yield was 86%.

3.45 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; ethyl 2-cyanoacetate; In N,N-dimethyl-formamide; at 20℃;	At room temperature,0.19 g of ethyl 2-cyanoacetate and 1.58 g of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid a mixed solution of 5.60 g of N,N-dimethylformamide was added to 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine2.00g and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride1.40g of N,N-dimethylformamide 13.20gIn the mixture; after the reaction is completed, adjust the pH to about 9,Add 70 mL of water at room temperature and decanse for 1.5-3 hours.Filtered, washed with water,The obtained solid was vacuum dried at 65 C for 12 hours to give the compound N-(4-[6,7-bis(methoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluoro Phenyl)cyclopropane-1,1-dimethylamide 3.45 g.
	With potassium carbonate; In tetrahydrofuran; water;Large scale;	[00177] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 C and then at approximately 45 C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Reference： [1]Patent: CN109836381,2019,A .Location in patent: Paragraph 0041-0052
[2]Patent: CN110903240,2020,A .Location in patent: Paragraph 0075; 0078-0106
[3]Patent: CN108264482,2018,A .Location in patent: Paragraph 0022; 0028
[4]Patent: CN110240563,2019,A .Location in patent: Paragraph 0028
[5]Journal of labelled compounds and radiopharmaceuticals,2018,vol. 61,p. 11 - 17
[6]Archiv der Pharmazie,2019,vol. 352
[7]Patent: CN104370811,2019,B .Location in patent: Paragraph 0080-0085
[8]Patent: WO2018/227119,2018,A1 .Location in patent: Paragraph 00164

58
[ 190728-25-7 ]
1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carbonyl chloride [ No CAS ]
[ 97-67-6 ]
[ 1140909-48-3 ]

Yield	Reaction Conditions	Operation in experiment
24 g		Thionyl chloride (36.10 kgs) was slowly added to the mixture of l-((4-fluorophenyl) carbamoyl)cyclopropane carboxylic acid (22.60 kgs) and tetrahydrofuran (120 lts) at 25-30C and stirred for 9 hours at the same temperature. The reaction mixture was slowly added to a pre-cool ed mixture of 4-((6,7-dimethoxyquinolin-4-yloxy)anil me (20.0 kgs), aqueous potassium carbonate solution (83.70 kgs of potassium carbonate in 120 Its of water) and tetrahydrofuran (120 Its) at 0-5C. Raised the temperature of the reaction mixture to 25-30C and stirred for 2 hours at the same temperature. Both the organic and aqueous layers were separated and water was added to the aqueous layer at 25-30C. Extracted the aqueous layer with ethyl acetate. Combine the organic layers. Aqueous hydrochloric acid solution (15 lts of HC1 in 145 lts of water) was, added to the organic layer at 25-30C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the, precipitated solid, washed with tetrahydrofuran and ethyl acetate. To the obtained compound, water (lot-4) was added at 25- ?30C and stirred for ?2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, water (595 Its) and hydrochloric acid (1 .0 Its) were added at 25-30C and stirred for.2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, isopropanol (435 Its) was added at 25-30C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Dimethyl sulfoxide (235 Its) was added to the obtained compound at 25-30C and stirred for 45 ?iinutes at the same temperature. Filtercd the reaction mixture. Ethyl acetate (720 Its) was added to the obtained filtrate at 2 5-30C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.Yield: 32.99 kgs; Purity by HPLC: 99.8 5%.

Reference： [1]Patent: WO2018/104954,2018,A1 .Location in patent: Page/Page column 28; 29; 32; 33

59
[ 4101-32-0 ]
[ 190728-25-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2801 - 2812
[2]Organic Preparations and Procedures International,2019,vol. 51,p. 381 - 387
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[4]Patent: CN111440177,2020,A

60
[ 190728-25-7 ]
6-chloro-4-(phenylamino)nicotinic acid [ No CAS ]
6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-(phenylamino)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.7%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: A solution of acid (0.6 mmol), DIPEA (0.75 mmol), HATU(0.6 mmol) and aniline (0.5 mmol) was stirred at rt in DMF (2 mL) for4 h. The solvent was poured into ice water (6 mL), and the crude product was isolated by filtration. After purification on silica gel(eluant: EtOAc: PE=1:1), the desired adducts were obtained.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835

61
[ 190728-25-7 ]
C₁₂H₈ClFN₂O₂ [ No CAS ]
6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-((2-fluorophenyl)amino)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.6%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: A solution of acid (0.6 mmol), DIPEA (0.75 mmol), HATU(0.6 mmol) and aniline (0.5 mmol) was stirred at rt in DMF (2 mL) for4 h. The solvent was poured into ice water (6 mL), and the crude product was isolated by filtration. After purification on silica gel(eluant: EtOAc: PE=1:1), the desired adducts were obtained.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835

62
[ 190728-25-7 ]
C₁₂H₈Cl₂N₂O₂ [ No CAS ]
6-chloro-4-((2-chlorophenyl)amino)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: A solution of acid (0.6 mmol), DIPEA (0.75 mmol), HATU(0.6 mmol) and aniline (0.5 mmol) was stirred at rt in DMF (2 mL) for4 h. The solvent was poured into ice water (6 mL), and the crude product was isolated by filtration. After purification on silica gel(eluant: EtOAc: PE=1:1), the desired adducts were obtained.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835

63
[ 190728-25-7 ]
C₁₂H₈BrClN₂O₂ [ No CAS ]
4-((2-bromophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.6%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: A solution of acid (0.6 mmol), DIPEA (0.75 mmol), HATU(0.6 mmol) and aniline (0.5 mmol) was stirred at rt in DMF (2 mL) for4 h. The solvent was poured into ice water (6 mL), and the crude product was isolated by filtration. After purification on silica gel(eluant: EtOAc: PE=1:1), the desired adducts were obtained.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835

64
[ 190728-25-7 ]
C₁₂H₇BrClFN₂O₂ [ No CAS ]
4-((4-bromo-2-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.0%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: A solution of acid (0.6 mmol), DIPEA (0.75 mmol), HATU(0.6 mmol) and aniline (0.5 mmol) was stirred at rt in DMF (2 mL) for4 h. The solvent was poured into ice water (6 mL), and the crude product was isolated by filtration. After purification on silica gel(eluant: EtOAc: PE=1:1), the desired adducts were obtained.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3825 - 3835

65
[ 190728-25-7 ]
[ 6914-71-2 ]
methyl 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;	4 - ((6. 7 -methoxy -4 - 1 -based) phenoxy) aniline 100 ml 5 2h (11.4g 0.039 muM, 1.0 1 8.6g 0.055 muM 1.4 100 ml 0 C 2 M 0.2 muMAt the end of the reaction, a purified unitz 800 ml stirred crystallization 5~6h, was added. Filter, filter cake, and 20 ml washing, gave 1 - ((4 - ((6, 7 -dimethoxyquinoline -4 -yloxy) phenyl) carbamoyl) cyclopropanecarboxylic acid methyl 14.7g, Bunit_ID, and purity Kunitz. 90.5%. 'unitz 99.8%'.

Reference： [1]Patent: CN109988107,2019,A .Location in patent: Paragraph 0044-0047

66
[ 190728-25-7 ]
(E)-2,2,2-trifluoro-N-phenylacetimidoyl chloride [ No CAS ]
(E)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-2,2,2-trifluoro-N’-phenylacetimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.8%	With triethylamine; In N,N-dimethyl-formamide; at 25℃; for 3h;	General procedure: Triethylamine (0.12 mL, 0.90 mmol) was added to the DMF (10 v/w) which intermediate6(0.2 g, 0.60 mmol) and13a-13j(0.72 mmol) were dissolved in, respectively. After stirring at r.t. for 3 h, the reaction mixture was added to water, and extracted with dichloromethane. The combined organic layer was washed with water, dried over anhydrous Na2SO4and evaporated to dryness to give compounds14a-14j.1.12.1.(E)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-2,2,2-trifluoro-N'-phenylacetimidamide(14a)The title compound was obtained as brown solid in 73.8% yield;m.p.:182.8-185.7oC;1H-NMR (400 MHz,DMSO-d6) delta 9.87 (s, 1H), 8.49 (d,J= 4.9 Hz, 1H), 7.46 -6.83 (m, 12H), 3.93 (d,J= 8.1 Hz, 6H). MS (ESI) m/z: 468.18[M+H]+.