[ CAS No. 343788-51-2 ] {[proInfo.proName]}

Name: 343788-51-2|8-(Benzyloxy)-2-chloroquinoline|98%
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SKU: A264315
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Quality Control of [ 343788-51-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 343788-51-2 ]

SDS Specification

Alternatived Products of [ 343788-51-2 ]

Product Details of [ 343788-51-2 ]

CAS No. :	343788-51-2	MDL No. :	MFCD09261075
Formula :	C₁₆H₁₂ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NIEHWTGNWJVDEU-UHFFFAOYSA-N
M.W :	269.73	Pubchem ID :	22042234
Synonyms :

Calculated chemistry of [ 343788-51-2 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.06
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	77.73
TPSA :	22.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.82
Log Po/w (XLOGP3) :	4.47
Log Po/w (WLOGP) :	4.32
Log Po/w (MLOGP) :	3.38
Log Po/w (SILICOS-IT) :	4.52
Consensus Log Po/w :	3.9

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.75
Solubility :	0.00476 mg/ml ; 0.0000176 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.65
Solubility :	0.00598 mg/ml ; 0.0000222 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.98
Solubility :	0.0000283 mg/ml ; 0.000000105 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 343788-51-2 ]

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 [ 343788-51-2 ]

* 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 [ 343788-51-2 ]
Downstream synthetic route of [ 343788-51-2 ]

[ 343788-51-2 ] Synthesis Path-Upstream 1~9

1
[ 63404-84-2 ]
[ 343788-51-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With oxalyl dichloride In 1,1-dichloroethane at 85℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	Step IB: Preparation 8-(benzyloxy)-2-chloroquinoline:; A flask was charged with 8-(benzyloxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, followed by a few drops of DMF (0.5 ml, 105 mmol), and the reaction mixture was heated to 85 °C overnight. The reaction was cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil and the organic layer was washed with 300 ml of saturated NaHCC>₃. The layers were separated and the organic phase was dried over Na₂SC>₄₅ filtered and concentrated to an oil. The oil was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).; Step 2B: Preparation 8 -(benzyloxy)-2-chloro quino Line:; A flask was charged with 8-(benzyloxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, and then a couple of drops of DMF (0.5 ml, 105 mmol) were added. The reaction was heated to 85 °C overnight, then cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil, and the organic layer was washed with 300 ml of saturated NaHCO₃. The layers were separated and the organic phase was dried over Na₂SO₄, filtered and concentrated to an oil. The oil was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).
85%	at 90℃; for 16 h;	8-(benzyloxy)quinolin-2-ol (6.6 g, 26.3 mmol) was dissolved in POCI₃ (50 mL). The mixture was stirred at 90 °C for 16 h. The POCI₃ was evaporated and to the residue was added EtOAc (100 mL) and the solution was washed with a.q. NaHC0₃ (80 mL) and H₂0 (80 mL). The EtOAc was removed under vacuum to give the desired compound (6.0 g, yield 85 percent). LCMS (m/z): 270.1 [M+H]⁺

Reference： [1] Patent: WO2008/124323, 2008, A1, . Location in patent: Page/Page column 50; 57
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 78 - 83
[3] Patent: WO2014/100730, 2014, A1, . Location in patent: Paragraph 00348
[4] Patent: WO2004/2490, 2004, A2, . Location in patent: Page/Page column 42
[5] Patent: WO2004/2992, 2004, A1, . Location in patent: Page 51
[6] Patent: WO2004/20431, 2004, A2, . Location in patent: Page 34
[7] Patent: WO2006/21448, 2006, A1, . Location in patent: Page/Page column 143

2
[ 79-37-8 ]
[ 63404-84-2 ]
[ 343788-51-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N,N-dimethyl-formamide In 1,1-dichloroethane at 85℃;	A 500 mL flask was charged with 8-(benzyIoxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, then add a couple of drops of DMF (0.5 ml, 105 mmol) were added. The reaction was heated to 85 °C overnight. The reaction was cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil and the organic layer was washed with 300 ml of saturated NaHCψ₃. The layers were separated, the organic phase was dried over Na₂SO₄, filtered and concentrated to an oil. The residue was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).

Reference： [1] Patent: WO2008/121687, 2008, A2, . Location in patent: Page/Page column 62

3
[ 15450-76-7 ]
[ 343788-51-2 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 78 - 83
[2] Patent: WO2014/100730, 2014, A1,
[3] Patent: WO2008/124323, 2008, A1,
[4] Patent: WO2008/121687, 2008, A2,

4
[ 100-39-0 ]
[ 343788-51-2 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 78 - 83
[2] Patent: WO2014/100730, 2014, A1,
[3] Patent: WO2008/124323, 2008, A1,
[4] Patent: WO2008/121687, 2008, A2,

5
[ 63404-84-2 ]
[ 343788-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 7, p. 1667 - 1687
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5576 - 5585

6
[ 148-24-3 ]
[ 343788-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5576 - 5585

7
[ 1127-45-3 ]
[ 343788-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5576 - 5585

8
[ 15450-72-3 ]
[ 343788-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5576 - 5585

9
[ 15450-76-7 ]
[ 343788-51-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5576 - 5585

[ 343788-51-2 ] Synthesis Path-Downstream 1~64

1
[ 63404-84-2 ]
[ 343788-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1667 - 1687
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

2
[ 98-80-6 ]
[ 343788-51-2 ]
[ 687637-87-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1667 - 1687

3
[ 343788-51-2 ]
[ 6961-25-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1667 - 1687

4
[ 343788-51-2 ]
[ 146830-22-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1667 - 1687

5
[ 124-41-4 ]
[ 343788-51-2 ]
[ 642477-85-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	In methanol; toluene; at 70℃;	The crude <strong>[343788-51-2]2-chloro-8-benzyloxyquinoline</strong> from above was dissolved in toluene (lOmL) and added to a stirred 25 wt% solution of NaOMe in MeOH (50 mL). The reaction solution was heated with stirring overnight at 70 C. After cooling to room temperature, the reaction solution was poured onto ice and extracted with toluene. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a colorless oil (6.14 g, 92%). The product was used without further purification. LC/MS : (ES) m/z 266 (M+H) +.
92%	In methanol; toluene; at 70℃;	8-Benzyloxyquinolin-2-ol (a) (6 g, 23.9 mmol) was added to [POC13] (45 mL) and heated with stirring at [80 C] for 10 hours. The reaction was allowed to cool to room temperature and the excess [POC13] was decomposed by slowly pouring the mixture into water at [30 C.] The product was then extracted into toluene and the combined organic layers were washed with saturated aqueous [NAHC03] and dried over [MGSO4.] Concentration provided 6.9 g of a colorless oil which was dissolved in toluene [(LOML)] and added to a stirred 25 wt% solution [OF NAOME] in MeOH (50 mL). The reaction solution was heated overnight at [70 C.] After cooling to room temperature, the reaction solution was poured onto ice and extracted with toluene. The combined organic extracts were dried [(MGSO4)] and concentrated in vacuo to give a colorless oil (6.14 g, 92%). [LC/MS] : [(ES)] [MLZ 266] (M+H) +.
79%	In methanol; at 70℃; for 16h;	To a solution of MeONa (400 mg, 7.43 mmol) in MeOH (20 mL) was added 8- (benzyloxy)-2-chloroquinoline (2.0 g, 7.43 mmol). The mixture was stirred at 70 C for 16 h. To the mixture was added H20 (20 mL) and the product extracted with toluene (30 mL x 3). The combined organic layers were dried with Na2S04 and evaporated to give the desired compound (1.5 g, yield 79%). LCMS (m/z): 266.1 [M+H]+

79%	In methanol; at 70℃; for 16h;	To a solution of 373 MeONa (400 mg, 7.43 mmol) in 18 MeOH (20 mL) was added 371 <strong>[343788-51-2]8-(benzyloxy)-2-chloroquinoline</strong> (2.0 g, 7.43 mmol). The mixture was stirred at 70 C. for 16 h. To the mixture was added 92 H2O (20 mL) and the product extracted with toluene (30 mL×3). The combined organic layers were dried with Na2SO4 and evaporated to give the desired 374 compound (1.5 g, yield 79%). LCMS (m/z): 266.1 [M+H]+
	In toluene; at 20 - 70℃; for 14h;	108c) 8-Benzyloxy-2-methoxyguinolineA solution of chloroquinoline (108b) (28.3 g) in dry toluene (40ml) was added dropwise to a stirred 25 wt% solution of sodiummethoxide (300 ml) at room temperature. The resulting solutionwas heated at 70C for 14 hours, cooled, quenched with ice (300g) and extracted with toluene {4 x 150 ml). The combined organicextracts were dried over sodium sulfate, filtered and evaporatedto give the desired product (27 g), which was used directly forthe next reaction without purification.

Reference： [1]Patent: WO2004/2490,2004,A2 .Location in patent: Page/Page column 42-43
[2]Patent: WO2004/2992,2004,A1 .Location in patent: Page 51
[3]Patent: WO2014/100730,2014,A1 .Location in patent: Paragraph 00349
[4]Patent: US2019/83482,2019,A1 .Location in patent: Paragraph 0446-0447
[5]Patent: WO2006/21448,2006,A1 .Location in patent: Page/Page column 143-144

6
[ 63404-84-2 ]
[ 343788-51-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step IB: Preparation 8-(benzyloxy)-2-chloroquinoline:; A flask was charged with 8-(benzyloxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, followed by a few drops of DMF (0.5 ml, 105 mmol), and the reaction mixture was heated to 85 C overnight. The reaction was cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil and the organic layer was washed with 300 ml of saturated NaHCC>3. The layers were separated and the organic phase was dried over Na2SC>45 filtered and concentrated to an oil. The oil was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).; Step 2B: Preparation 8 -(benzyloxy)-2-chloro quino Line:; A flask was charged with 8-(benzyloxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, and then a couple of drops of DMF (0.5 ml, 105 mmol) were added. The reaction was heated to 85 C overnight, then cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil, and the organic layer was washed with 300 ml of saturated NaHCO3. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated to an oil. The oil was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).
85%	With trichlorophosphate; at 90℃; for 16h;	8-(benzyloxy)quinolin-2-ol (6.6 g, 26.3 mmol) was dissolved in POCI3 (50 mL). The mixture was stirred at 90 C for 16 h. The POCI3 was evaporated and to the residue was added EtOAc (100 mL) and the solution was washed with a.q. NaHC03 (80 mL) and H20 (80 mL). The EtOAc was removed under vacuum to give the desired compound (6.0 g, yield 85 %). LCMS (m/z): 270.1 [M+H]+
85%	With trichlorophosphate; at 90℃; for 17h;	8-(benzyloxy)quinolin-2-ol (6.6 g, 26.3 mmol) was dissolved in 242 POCl3 (50 mL). The mixture was stirred at 90 C. for 16 h. The POCl3 was evaporated and to the residue was added 121 EtOAc (100 mL) and the solution was washed with a.q. NaHCO3 (80 mL) and 92 H2O (80 mL). The EtOAc was removed under vacuum to give the desired 371 compound (6.0 g, yield 85%). LCMS (m/z): 270.1 [M+H]+

	With trichlorophosphate; at 80℃; for 10h;	8-Benzyloxyquinolin-2-ol (a) (6 g, 23.9 mmol) was added to POC13 (45 mL) and heated with stirring at 80 C for 10 h. The reaction was allowed to cool to room temperature and the excess POC13 was decomposed by slowly pouring the mixture into water at 30 C. The product was then extracted into toluene and the combined organic layers were washed with saturated aq. NaHC03 and dried over MgSO4. Concentration provided 6.9 g of a colorless oil, crude 2-chloro-8-benzyloxyquinoline, which was directly used in the next reaction step. LC/MS : (ES) into 270 (M+H) +.
	With trichlorophosphate; at 80℃; for 10h;	8-Benzyloxyquinolin-2-ol (a) (6 g, 23.9 mmol) was added to [POC13] (45 mL) and heated with stirring at [80 C] for 10 hours. The reaction was allowed to cool to room temperature and the excess [POC13] was decomposed by slowly pouring the mixture into water at [30 C.] The product was then extracted into toluene and the combined organic layers were washed with saturated aqueous [NAHC03] and dried over [MGSO4.] Concentration provided 6.9 g of a colorless oil which was dissolved in toluene [(LOML)] and added to a stirred 25 wt% solution [OF NAOME] in MeOH (50 mL). The reaction solution was heated overnight at [70 C.] After cooling to room temperature, the reaction solution was poured onto ice and extracted with toluene. The combined organic extracts were dried [(MGSO4)] and concentrated in vacuo to give a colorless oil (6.14 g, 92%). [LC/MS] : [(ES)] [MLZ 266] (M+H) +.
		NOVEL [BENZOIMIDAZOLE DERIVATIVES] USEFUL AS ANTIPROLIFERATIVE AGENTS Background of the Invention This invention relates to novel benzimidazole derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds. It is known that a cell may become cancerous by virtue of the transformation of a portion [ OF ITS DNA INTO AN ONCOGENE (,] a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. Receptor tyrosine kinases are enzymes which span the cell membrane and possess an [EXTRACELLULAR] binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, [PDGFR,] [FGFR,] and VEGFR. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma that does not express the EGF receptor. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, in particular [PDGFR,] are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently, five European patent publications, namely EP 0 566 226 A1 (published October 20,1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25,1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30,1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published November 26,1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications [W096/16960] (published June 6,1996), WO 96/09294 (published March 6,1996), WO [97/30034] (published August 21,1997), WO 98/02434 (published January 22,1998), WO [98/02437] (published January 22,1998), and WO 98/02438 (published January 22,1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose. Also see WO 99/16755, J. Med. Chem. 1998, 41,5457-5465 and J. Med. Chem. 1999,42, 2373-2382. Summary of the Invention The present invention relates to compounds of the the formula 1 or a [PHARMACEUTICALLY] acceptable salt, prodrug, hydrate or solvate thereof, wherein each [R',] [R2,] and R3 is independently selected from [H, C1-C6 ALKYL, C3-C6 CYCLOALKYL, HALO,] cyano, [CF3,] [DIFLUOROMETHOXY,] [TRIFLUOROMETHOXY,] [OC,-C6] alkyl, OC3-C6 cycloalkyl, and [NR7R8] ; wherein [R4 IS-(CR5R6) NH, OR-(CR5R6)] m (4 to 10 membered heterocyclic), wherein n is an integer ranging from 1 to 5, wherein m is an integer ranging from 0 to 5, wherein said 4 to 10 membered heterocyclic when aromatic is optionally substituted by 1 to 3 R1 substituents, and wherein said 4 to 10 membered heterocyclic when non-aromatic is optionally substituted by 1 to 3 [R7 SUBSTITUITENTS] at any position and optionally substituted by 1 to 3 R9 substituents at any position not adjacent to or directly attached to a heteroatom; wherein each R5 and [R6] is independently selected from H or [C-C6] alkyl wherein each [R7 AND R8] is independently selected from H, [CI-CG] alkyl, and C3-C6 cycloalkyl ; and wherein each R9 is indepe...
		108b) 8-Benzyloxy-2-chloroguinolineQuinolinol (108a) (31.6 g) was added to phosphorus oxychloride(225 ml) and the solution was stirred at room temperature for 48hours. The excess phosphorus oxychloride was evaporated and theresidue dissolved in toluene (500 ml). The organic layer waswashed with saturated bicarbonate solution (3 x 150 ml) andwater (150 ml), dried over sodium sulfate, filtered andevaporated. The residue was triturated with cyclohexane. Thesolid was filtered off, washed with cyclohexane and dried togive desired product (29.2 g).XH NMR (300MHz, d6-DMSO) : 6: 8.38 (d, 1H) , 7.59-7.51 (m, 5H)7.43-7.39 (m, 2H), 7.36-7.33 (m, 2H), 5.31 (s, 2H)MS (El): m/z: 292 [M+Na]+

Reference： [1]Patent: WO2008/124323,2008,A1 .Location in patent: Page/Page column 50; 57
[2]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83
[3]Patent: WO2014/100730,2014,A1 .Location in patent: Paragraph 00348
[4]Patent: US2019/83482,2019,A1 .Location in patent: Paragraph 0444-0445
[5]Patent: WO2004/2490,2004,A2 .Location in patent: Page/Page column 42
[6]Patent: WO2004/2992,2004,A1 .Location in patent: Page 51
[7]Patent: WO2004/20431,2004,A2 .Location in patent: Page 34
[8]Patent: WO2006/21448,2006,A1 .Location in patent: Page/Page column 143

7
4-(3-methyloxetan-3-ylmethoxy)-2-nitroaniline [ No CAS ]
[ 343788-51-2 ]
(8-benzyloxyquinolin-2-yl)(4-(3-methyloxetan-3-ylmethoxy)-2-nitrophenyl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.37%	With palladium diacetate; potassium carbonate; 1,2-bis-(diphenylphosphino)ethane; In toluene; at 98 - 100℃;	The compound 8 - benzyloxy quinoline -2 - chloro 47.2 g, A1 50 g, potassium carbonate 80 g, DIPHOS4 . 3g, toluene 700 ml is added to the 2 L in the [...], palladium acetate is added 0.9 g, stir. Heating as stirring, the temperature in 98 - 100 C reaction 24 - 30 of H. After the reaction is finished, lowering the temperature to 55 C added dichloroethane 700 ml. Stirring 10 min, adding diatomaceous earth filtration of the reaction solution in the solid, cake 500 ml dichloroethane flushing. The filtrate is concentrated to dry, adding ethyl acetate 480 ml, heating to reflux, cooling to 20 - 25 C crystallization 10 - 20 the H. Filtering the separated solid, 50 C blast drying, to obtain the orange solid is the A2, 79.69g, 96.37%.
77%	With caesium carbonate;palladium diacetate; 1,2-bis-(diphenylphosphino)ethane; In toluene; at 100℃; for 24 - 30h;	The compound, 8-BENZYLOXY-QUINOLIN-2-OL (5 g, 18.5 m, mol, 1.0 equivalent), 4- (3- Methyl-oxetan-3-ylmethoxy)-2-nitro-phenylamine (5.3 g, 22.2 mmol, 1.2 equivalents), cesium carbonate (8.46 g, 26 mmol, 1.4 equivalents), DIPHOS (1,2-Bis (diphenylphosphino) ethane; 443 mg, 111 LIMOL, 0.06 equivalents) and toluene (75 mL, 15 volumes) were charged to a 100 mL round bottom flask. The reaction was deoxygenated. Palladium acetate (83 mg, 37 mumol, 0.02 equivalents) was added and the reaction was deoxygenated again. The reaction was heated to 100 C for 24-30 hours. At reaction completion, the reaction was cooled to 55 C and dichloroethane ("DCE"; 75 mL, 15 volumes) was charged. The slurry was filtered through a pad of Celite and then the flask and filter were rinsed once with additional DCE (50 mL, 10 volumes). The organics were concentrated to low volume and ethyl acetate (50 mL, 10 volumes) was added. The reaction was heated to reflux and allowed to cool to 20-25 C. The solids were granulated for 10-20 hours, filtered, and dried under vacuum at 40 C with a slight NITROGEN BLEED TO YIEID 6. 72 G (8-BENZYLOXY-QUINOLIN-2-YL)- [4- (3-METHYL-OXETAN-3-YLMETHOXY)-2- NITRO-PHENYL1-ANNINE AS an orange solid (77% yield). The material was judged to be about 95% pure by NMR, with -5% of the DIPHOS bis-oxide

Reference： [1]Patent: CN107382983,2017,A .Location in patent: Paragraph 0013
[2]Patent: WO2004/113322,2004,A1 .Location in patent: Page 13

8
[ 79-37-8 ]
[ 63404-84-2 ]
[ 343788-51-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N,N-dimethyl-formamide; In 1,1-dichloroethane; at 85℃;	A 500 mL flask was charged with 8-(benzyIoxy)quinolin-2-ol (26.5 g, 105 mmol) and DCE (105 ml, 105 mmol). Oxalyl chloride (18.4 ml, 211 mmol) was added dropwise, then add a couple of drops of DMF (0.5 ml, 105 mmol) were added. The reaction was heated to 85 C overnight. The reaction was cooled to ambient temperature and concentrated to an oil. DCM (300 mL) was added to the oil and the organic layer was washed with 300 ml of saturated NaHCtheta3. The layers were separated, the organic phase was dried over Na2SO4, filtered and concentrated to an oil. The residue was crystallized from toluene to yield 28.4 g of desired product (quantitative yield).

Reference： [1]Patent: WO2008/121687,2008,A2 .Location in patent: Page/Page column 62

9
[ 1067914-34-4 ]
[ 343788-51-2 ]
[ 1067914-77-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium carbonate;palladium diacetate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;	Step 2C: Preparation of 8-fbenzyloxy)-2-('7-f2-methoxyethoxyVimidazori.2- a1pyridrn-3-yl)quinoline:; 8-(Benzyloxy)-2-chloroquinoline (5.0 g, 18.5 mmol), 7-(2- methoxyethoxy)-imidazo[l,2-a]pyridine (3.56 g, 18.5 mmol), Pd(PPh3)4 (1.07 g, 0.927 mmol), K2CO3 (5.12 g, 37.1 mmol), and Pd(OAc)2 (0.208 g, 0.927 mmol) were added into dioxane (74.1 ml, 18.5 mmol) and water (0.735 ml, 40.8 mmol) and heated to 100 0C overnight under nitrogen. The reaction was diluted with DCM and carbon (5 g) was added, followed by filtration. The filtrate was concentrated and then triturated with 1:1 EtOAc/MTBE (30 mL). The resulting solids were allowed to stir for 5 hours and then filtered to isolate of the desired product as a solid (5.4 g, 69% yield).; Step 1C: Preparation of 8-fbenzyloxyV2-(7-('2-methoxyethoxyVimidazori.2- a]pwidin-3-vDquinoline:; 8-(Benzyloxy)-2-chloroquinoline (5.0 g, 18.5 mmol), 7-(2- methoxyethoxy)-imidazo[l,2-a]pyridine (3.56 g, 18.5 mmol), Pd(PPh3)4 (1.07 g, 0.927 mmol), K2CO3 (5.12 g, 37.1 mmol), and Pd(OAc)2 (0.208 g, 0.927 mmol) were added to dioxane (74.1 ml, 18.5 mmol) and water (0.735 ml, 40.8 mmol) and the reaction mixture was heated to 100 0C overnight under nitrogen. The reaction was diluted with DCM and 5 g of carbon were added followed by filtration. The slurry was concentrated and the filtrate was triturated with 1:1 <n="59"/>EtOAc/MTBE (30 mL). The resulting solids were stirred for 5 hours and then filtered to isolate the desired product as a solid (5.4 g, 69 % yield).
69%	With potassium carbonate;palladium diacetate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;	8-(Benzyloxy)-2-chloroquinoline (5.0 g, 18.5 mmol), 7-(2- methoxyethoxy)-imidazo[l,2-a]pyridine (3.56 g, 18.5 mmol), Pd(PPh3)4 (1.07 g, 0.927 mmol), K2CO3 (5.12 g, 37.1 mmol), and Pd(OAc)2 (0.208 g, 0.927 mmol) were added to dioxane (74.1 ml, 18.5 mmol) and water (0.735 ml, 40.8 mmol) and heated to 100 0C overnight under nitrogen. The reaction was then diluted with DCM and carbon (5 g) was added. The reaction mixture was filtered and the filtrate was triturated with 1:1 EtOAc/MTBE (30 mL). The resulting solids were allowed to stir for 5 hours and were then filtered to isolate the desired product as a solid (5.4 g, 69 % yield).

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83
[2]Patent: WO2008/124323,2008,A1 .Location in patent: Page/Page column 50; 57-58
[3]Patent: WO2008/121687,2008,A2 .Location in patent: Page/Page column 62

10
[ 1036990-92-7 ]
[ 343788-51-2 ]
[ 1070897-01-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;palladium diacetate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water;Heating / reflux;	Step IB: Preparation of 8-(benzyloxy)-2-(7-ethylimidazo["1.2-alpyridin-3- yDquinoline:; A mixture of 7-ethylimidazo[l,2-a]pyridine (1.18 g, 8.06 mmol), 8-benzyloxy-2- chloroquinoline (2.17 g, 8.06 mmol), potassium carbonate (2.23 g, 16.2 mmol), palladium (II) acetate (90.5 mg, 0.40 mmol), tetrakis(triphenylphosphuie)palladium (0) (466 mg, 0.40 mmol), 1,4-dioxane (33 ml) and water (0.33 ml) was heated under a nitrogen atmosphere overnight. The reaction mixture was diluted with water, extracted with CH2Cl2 and EtOAc, and the combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the desired product (3.45 g) as a solid. MS APCI (+) m/z 380.2 (M+l) detected.

Reference： [1]Patent: WO2008/124323,2008,A1 .Location in patent: Page/Page column 64

11
[ 62230-88-0 ]
[ 343788-51-2 ]
[ 1456528-56-5 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 8755 - 8757

12
[ 15450-76-7 ]
[ 343788-51-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83
[2]Patent: WO2014/100730,2014,A1
[3]Patent: WO2008/124323,2008,A1
[4]Patent: WO2008/121687,2008,A2
[5]Patent: US2019/83482,2019,A1

13
[ 100-39-0 ]
[ 343788-51-2 ]

14
[ 343788-51-2 ]
[ 1067914-75-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83
[2]Patent: WO2008/124323,2008,A1
[3]Patent: WO2008/121687,2008,A2

15
[ 343788-51-2 ]
[ 1070896-55-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83
[2]Patent: WO2008/124323,2008,A1

16
[ 343788-51-2 ]
2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline bis(2,2,2-trifluoroacetate) [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83

17
[ 343788-51-2 ]
(trans)-tert-butyl 3-fluoro-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83

18
[ 343788-51-2 ]
8-(trans)-(3-fluoropiperidin-4-yloxy)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolone [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 78 - 83

19
[ 343788-51-2 ]
[ 74668-72-7 ]

Reference： [1]Patent: WO2014/100730,2014,A1
[2]Patent: US2019/83482,2019,A1

20
[ 343788-51-2 ]
[ 1616077-67-8 ]

Reference： [1]Patent: WO2014/100730,2014,A1
[2]Patent: US2019/83482,2019,A1

21
[ 343788-51-2 ]
[ 1616075-64-9 ]

Reference： [1]Patent: WO2014/100730,2014,A1
[2]Patent: US2019/83482,2019,A1

22
[ 343788-51-2 ]
8-(benzyloxy)-2-fluoroquinoline [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 12137 - 12145

23
[ 148-24-3 ]
[ 343788-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

24
[ 1127-45-3 ]
[ 343788-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

25
[ 15450-72-3 ]
[ 343788-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

26
[ 15450-76-7 ]
[ 343788-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

27
[ 50982-75-7 ]
[ 343788-51-2 ]
C₂₅H₂₃N₃O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5576 - 5585

28
[ 1036990-92-7 ]
[ 343788-51-2 ]
[ 1070897-02-7 ]