[ CAS No. 64465-53-8 ] {[proInfo.proName]}

Name: 64465-53-8|4-Fluoro-3-methoxyaniline|98%
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Product Details of [ 64465-53-8 ]

CAS No. :	64465-53-8	MDL No. :	MFCD00665789
Formula :	C₇H₈FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XAACOEWSHBIFGJ-UHFFFAOYSA-N
M.W :	141.14	Pubchem ID :	2774533
Synonyms :

Safety of [ 64465-53-8 ]

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 [ 64465-53-8 ]

* 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 [ 64465-53-8 ]
Downstream synthetic route of [ 64465-53-8 ]

[ 64465-53-8 ] Synthesis Path-Upstream 1~8

1
[ 454-16-0 ]
[ 64465-53-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	To a solution of 1-fluoro-2-methoxy-4-nitrobenzene (101) (5.0 g, 29.0 mmol) in methanol (25 mL) was added 10 percent Pd/C (500 mg) at room temperature under H2 atmosphere. After reaction completion (monitored by TLC), the mixture was filtered and the filtrate was evaporated under vacuo to afford title compound 202 (4.0 g, 97 percent yield). ‘H NIVIR (400 1VIHz, DMSO-d6): 3.72 (s, 3H), 4.93 (s, 2H), 6.02-6.05 (m, 1H), 6.33 (dd, J7.6, 2.4 Hz, 1H),6.81 (dd,J 11.6, 8.8 Hz, 1H).
93%	Stage #1: With hydrogenchloride; iron In ethanol; water at 0 - 20℃; for 18 h; Stage #2: With sodium carbonate In ethanol; water	N-(4-fluoro-3-methoxyphenyl)pivalamide Step 1 : 4-fluoro-3-methoxyanilineNitro compound Il (6.5 g, 0.038 mol) and iron powder (10.6 g, 0.19 mol) were suspended in ethanol (90 ml) at O⁰C. HCI cone. (120 ml) was added drop wise to the reaction mixture. The reaction mixture was stirred at 2O⁰C for 18hr. The reaction mixture was then filtered through celite and washed repeatedly with ethanol. Then ethanol was concentrated and the residue was basified with solid Na2CO3. Then it was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO₄ and concentrated in vacuum to get the product (5 g, Y= 93percent). HPLC-MS: Purity 97percent, M+1 = 142.1

Reference： [1] Patent: WO2017/132928, 2017, A1, . Location in patent: Paragraph 000101
[2] Patent: WO2010/145989, 2010, A1, . Location in patent: Page/Page column 12-13
[3] Patent: US4044049, 1977, A,
[4] Patent: US4044049, 1977, A,

2
[ 3863-11-4 ]
[ 64465-53-8 ]

Reference： [1] Patent: US6136823, 2000, A,

3
[ 3866-16-8 ]
[ 64465-53-8 ]

Reference： [1] Patent: US4145364, 1979, A,

4
[ 3866-16-8 ]
[ 64465-53-8 ]

Reference： [1] Journal of Organic Chemistry, 1981, vol. 46, # 12, p. 2520 - 2528

5
[ 536-90-3 ]
[ 64465-53-8 ]

Reference： [1] Journal of Organic Chemistry, 1981, vol. 46, # 12, p. 2520 - 2528

6
[ 64465-53-8 ]
[ 117902-15-5 ]

Yield	Reaction Conditions	Operation in experiment
46.7%	at 0 - 100℃; for 0.5 h;	To a suspension of compound 202 (4.0 g, 28.0 mmol) in 30 percent sulfuric acid (15mL) was added sodium nitrite (2.15 g, 31.0 mmol) at 0 °C. The reaction was stirred at 0 °Cfor 20 minutes, and then was added to 60percent sulfuric acid (15 mL) at 100 °C and stirred for 30mm. The reaction mixture was neutralized with anhydrous NaHCO3 and extracted with ethylacetate. The organic layer was washed with water and brine, dried over anhydrous sodiumsulfate and evaporated in vacuo. The crude product was purified by column chromatography(hexanes/dichloromethane: 3/1) to afford the title compound 203 (1.84 g, 46.7 percent yield) as acolorless oil. ‘HNIVIR(400 1VIHz, DMSO-d6): 3.76 (s, 3H), 6.24-6.27 (m, 1H), 6.51 (dd, J 6.8, 2.8 Hz, 1H), 6.96 (dd, J 11.2, 8.4 Hz, 1H), 9.36 (s, 1H).

Reference： [1] Patent: WO2017/132928, 2017, A1, . Location in patent: Paragraph 000102

7
[ 64465-53-8 ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 5℃; for 0.25 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20 - 75℃; for 16 h;	Aqueous hydrobromic acid (48percent, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 °C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0-5 ⁰C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 °C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48percent, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70percent yield) of the title compound.: ¹H-NMR (DMSO-J₆): δ 7.36 (dd, J= 7.78, 2.26 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.14-7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) (m/z, percent) 204,206 (100), 189,191 (23), 161,163 (45)

Reference： [1] Patent: WO2007/58602, 2007, A2, . Location in patent: Page/Page column 141
[2] Patent: US4593037, 1986, A,
[3] Patent: WO2007/145568, 2007, A1,
[4] Patent: WO2007/145569, 2007, A1,

8
[ 64465-53-8 ]
[ 100367-48-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With boron tribromide In dichloromethane at 0 - 20℃; Stage #2: With methanol In dichloromethane Stage #3: With sodium hydrogencarbonate In waterSaturated solution	Example 9; Preparation of 1 -(5-tert-butylisoxazol-3-ylV3-D-(6 J-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)urea; [00684] Example 9A Step 1 : To a mixture of 4-fluoro-3-methoxyaniline (2.0 g,14.2 mmol) in CH₂Cl₂ (20 mL) at 0 °C was added 1.0 M solution Of BBr₃ in CH₂Cl₂ (40 mL). It was stirred overnight, at which time the temperature was raised to room temperature. To it was added MeOH and the solvents were removed under reduced pressure. To the residue was added water, basified with saturated NaHCO₃, and extracted with EtOAc. Extracts were washed with brine, dried over MgSO₄, and concentrated under reduced pressure to afford 5-amino-2-fluorophenol as solid (1.3 g, 73percent). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 6.81 (dd, 1H), 6.34 (dd, 1H), 6.04 (dd, 1H), 4.63 (br, 2H).
87.8%	With BCl₃ In dichloromethane; ethyl acetate	b) A solution of 50 g (0.354 mol) of 4-fluoro-3-methoxy-aniline dissolved in methylene chloride (1800 ml) was treated under argon with 163.2 g (0.44 mol) of tetrabutyl-ammonium iodide, cooled to -75° C. and the treated over a period of 25 minutes with 860 ml of 1 M BCl₃ in methylene chloride while keeping the reaction solution between -75° C. and -64° C. The solution was stirred for 15 minutes the cooling bath was removed and stirring was continued for 24 h under argon. The reaction solution was poured into ice water (6 l) with stirring, the layers were separated, the water layer twice extracted with methylene chloride (each 1.5 l). The combined organic layers were washed twice with water (each 2 l) and discarded. The combined aqueous layers were made basic with solid NaHCO₃, saturated with NaCl, extracted 3 times with 2.5 l of ether and twice with 1.5 l of AcOEt. The combined organic layers were tried over magnesium sulphate and concentrated in vacuo to give 43.9 g (87.8percent) of 4-fluoro-3-hydroxy-aniline as light brown crystalline solid. Melting point: 156-157° C.

Reference： [1] Patent: WO2009/117080, 2009, A1, . Location in patent: Page/Page column 171
[2] Patent: US2002/198194, 2002, A1,
[3] Patent: WO2011/119704, 2011, A1, . Location in patent: Page/Page column 45

[ 64465-53-8 ] Synthesis Path-Downstream 1~88

1
[ 3866-16-8 ]
[ 64465-53-8 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 2520 - 2528

2
[ 64465-53-8 ]
[ 321-28-8 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 2520 - 2528

3
[ 64465-53-8 ]
Br^(1-)*C₇H₆FN₂O⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; sodium nitrite; In water; at 0 - 5℃; for 0.25h;	Aqueous hydrobromic acid (48%, 2.41 mL) was added to <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 C. in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0 and 5 C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d6): delta 7.36 (dd, J=7.78, 2.26 Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.09 (m, 1H), 3.86 (s, 3H); MS (EI) m/z 204, 206 [M+].
	With hydrogen bromide; sodium nitrite; In water; at 0 - 5℃; for 0.25h;	Example 1; 4-Bromo- 1 -fluoro-2-methoxybenzene; Aqueous hydrobromic acid (48%, 2.41 mL) was added to <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0-5 0C. The resulting diazoniumsalt solution was added to a suspension of copper (I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with <n="48"/>diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-afo): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) m/z 204, 206 [M+«]
		Example 1; 4-Bromo- 1 -fluoro-2-methoxvbenzeneF; Aqueous hydrobromic acid (48%, 2.41 mL) was added to <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0 - 5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 0C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d«j): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) 0 >«/z 204, 206 [M+»].

Reference： [1]Patent: US2007/299087,2007,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2007/145568,2007,A1 .Location in patent: Page/Page column 46-47
[3]Patent: WO2007/145569,2007,A1 .Location in patent: Page/Page column 45

4
[ 64465-53-8 ]
[ 79099-07-3 ]
C₁₇H₂₃FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃; for 1h;	1 ,1 -Dimethylethyl 4-[4-fluoro-3-(methyloxy)phenyl]amino}-1 - piperidinecarboxylate (D9)A solution of 1 ,1-dimethylethyl 4-oxo-1 -piperidinecarboxylate (1.41g, 7.1mmol) and <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (1g, 7.1mmol) was stirred at room temperature for 1h. Sodium tri(acetoxy)borohydride (1.95g, 9.2mmol) was then added and stirring continued over-weekend. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution, dried and then concentrated in vacuo. Column chromatography eluting with 0-50% Et2C7petroleum ether gave the title compound as a white solid (1.45g). deltaH (CDCI3, 400MHz) 6.89 (1 H1 dd), 6.22 (1 H, dd), 6.09 (1H1 m), <n="30"/>4.03 (2H, br s), 3.84 (3H, s), 3.36 (1 H, br s), 2.92 (2H, m), 2.03 (2H, m), 1.46 (9H, s), 1.32 (2H, m).

Reference： [1]Patent: WO2007/144400,2007,A1 .Location in patent: Page/Page column 28-29

5
[ 934530-42-4 ]
[ 64465-53-8 ]
2-(dimethylamino)-N-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 180℃; for 1h;Microwave;	A CEM microwave reaction vessel was charged with N-(3-(N-(3-chloroquinoxalin- 2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide (62 mg, 0.147 mmol), the desired aniline (0.567 mmol, 4 eq), and 1.0 mL of toluene. The vessel was sealed and the reaction mixture was heated under microwave radiation for 60 min at 180 0C in a CEM Discover microwave instrument. The solvent was removed on a rotary-evaporator. Purification of the final product was done by preparatory HPLC with NH4O Ac/A CN as eluent to yield 2- (dimethylamino)-7V-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl).; Example 417: 2-(dimethylamino)-lambdaV-(3-(N-(3-(4-fluoro-3- methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide. 2-(dimethylamino)- N-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl). 1H-NMR (400MHz5 CDCl3): delta 9.47 (s, IH), 8.36 (s, IH), 8.29 (s, IH), 7.91-7.87 (d, IH), 7.80-7.73 (m, 2H), 7.66-7.63 (d, IH), 7.53-7.47 (t, I H), 7.43-7.30 (m, 4H), 7.10-7.04 (t, IH)3 6.55-5.95 (br s, IH), 3.96 (s, 3H), 3.12 (s, 2H), 2.39 (s, 6H)5 2.08 (s,3H(lambdac0Hj; MS (EI) C25H25FN6O4S: 525 (MH+).

Reference： [1]Patent: WO2008/21389,2008,A2 .Location in patent: Page/Page column 303

6
[ 536-90-3 ]
[ 64465-53-8 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 2520 - 2528

7
[ 2033-24-1 ]
[ 64465-53-8 ]
[ 149-73-5 ]
[ 851985-90-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	In acetonitrile; for 3h;Heating / reflux;	Description 34; 5-[(4-Fluoro-3-methoxvphenvl) aminolmethvlene}-2, 2-dimethvl- 1 3-dioxane-4, 6-dione; To a stirred solution of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (20 g, 142 mmol) in acetonitrile (200 ml) was added 2, 2-dimethyl-1, 3-dioxane-4,6-dione (Meldrum's acid) (22.5 g, 156 mmol) followed by trimethyl orthoformate (18.6 ml, 170 mmol). The mixture was heated to reflux for 3 hours. The cooled mixture was filtered to give the title compound (30.9 g, 74%). 1H NMR (400 MHz, CDCl3) 1.76 (6 H, s), 3.94 (3 H, s), 6.76-6. 83 (2 H, m), 7.14 (1 H, dd, J10. 5 and 8.4), 8.56 (1 H, d, J14. 4), 11.23 (1 H, d, J14.4).
	In acetonitrile; at 80℃; for 16h;	[0579] Procedure: To a stirred solution of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (3 g, 21.25 mmol) in ACN (30 mL), Meldrum's acid (3.9 g, 27.63 mmol) and trimethyl orthoformate (3.25 mL, 29.75 mmol) were added at room temperature. The resulting mixture was heated to 80 C for 16 h. The progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature and evaporated the solvent under reduced pressure. The crude product was triturated with n-pentane (3 x 50 mL) and decanted, dried to afford 5-(((4-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as brown solid (6 g , crude). LC-MS (ES) m/z = 293.9 [M-H]+.

Reference： [1]Patent: WO2005/47279,2005,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2019/46778,2019,A1 .Location in patent: Paragraph 0579

8
[ 64465-53-8 ]
[ 327021-81-8 ]

Yield	Reaction Conditions	Operation in experiment
67%		To stirred hydrochloric acid (100 mL) at 0 C. was added <strong>[64465-53-8]3-methoxy-4-fluoroaniline</strong> (10 g, 71 mmol) followed by water (10 mL) and more hydrochloric acid (10 mL). The mixture was warmed to room temperature, stirred for 20 min then cooled to -5 C. A solution of sodium nitrite (5.14 g, 75 mmol) in water (25 mL) was added dropwise such that the internal temperature remained below 0 C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was cooled to -5 C. and a solution of tin(II)chloride dihydrate (64 g, 284 mmol) in hydrochloric acid (200 mL) was added dropwise such that the internal temperature remained below 0 C. The mixture was warmed to room temperature, stirred for 3 h then filtered. The filter cake was washed with hydrochloric acid and dried under vacuum to give a pink solid (7.4 g). The precipitate from the combined filtrates was filtered-off, washed (hydrochloric acid) and dried under vacuum to give a further crop of product (1.8 g. to give a combined yield of 9.2 g, 67%).

Reference： [1]Patent: US6706750,2004,B1 .Location in patent: Page/Page column 15

9
4-chloro-8-methyl-6-(4-morpholinylsulfonyl)-3-quinolinrcarboxamide [ No CAS ]
[ 64465-53-8 ]
4-[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(4-morpholinylsulfonyl)-3-quinolinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 80℃; for 16h;	Intermediate 28 (0.050g) was suspended in acetonitrile (2ML), 4-fluoro-3-(methyloxy)aniline (0.025g) (available from Aldrich) was added and the mixture heated at 80C for 16h. The mixture was cooled to room temperature and the solvent blown off under a stream of nitrogen. Purification by mass directed HPLC gave a yellow oil. This was loaded onto an SPE cartridge (1G Varian Bond Elut, aminopropyl solid phase) and eluted with methanol to give the title compound as a yellow solid (0. 018G). LC/MS Rt 2.58min M/Z 475 [MH+]

Reference： [1]Patent: WO2005/30212,2005,A1 .Location in patent: Page/Page column 48

10
4-chloro-6-([2-(4-morpholinyl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide [ No CAS ]
[ 64465-53-8 ]
C₂₃H₂₆FN₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	pyridine hydrochloride; In ethanol; for 5h;Heating / reflux;	4-Fluoro-3-methoxyaniline (Apollo-Chem, 0.0085g) was added to intermediate 30 (0. 021 G) in ethanol (3ML), pyridine hydrochloride 0.012g) was added, and the mixture was heated under reflux for 5h. The solvent was evaporated to give a brown gum (0.033g), which was purified by mass directed preparative HPLC (Method A); 2N hydrochloric acid (1ML) was added to the product fractions, and the solvents evaporated to give the title compound (0.0067g). LC/MS Rt 1. 91min m/z 504 [MH+]

Reference： [1]Patent: WO2005/30212,2005,A1 .Location in patent: Page/Page column 50-51

11
4-chloro-6-[(methylamino)sulfonyl]-3-quinolinecarboxamide [ No CAS ]
[ 64465-53-8 ]
C₁₈H₁₇FN₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In DMF (N,N-dimethyl-formamide); acetonitrile; at 80℃; for 18h;	To a solution of intermediate 33 (0. 011G) in acetonitrile (2ML) and N,N-dimethylformamide (1. 5ml) was added 4-FLUORO-3-METHOXYANILINE (APOLLO-CHEM, 0.007g), and the mixture was heated at 80 with stirring under nitrogen for 18h. The solvents were evaporated to give a brown gum, which was purified by mass directed preparative HPLC (Method A); 2N hydrochloric acid (0. 5ml) was added to the product fractions, and the solvents evaporated to give the title compound as a pale yellow solid (0.0058g). LC/MS Rt 2.17min M/Z405 [MH+]

Reference： [1]Patent: WO2005/30212,2005,A1 .Location in patent: Page/Page column 52

12
[ 64465-53-8 ]
[ 773855-64-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		Dissolve 4-fluoro-3-methoxyphenylamine (5. 0 g, 35 mmol) in water (25 mL) and concentrated sulfuric acid (8 mL). Cool to less than 0 C in an ice/methanol bath and add sodium nitrite (2. 7 g, 39 mmol) dropwise in a solution in water (20 mL) and stir one h. Dissolve potassium iodide (9. 9 g, 60 mmol) in water (35 mL) and add dropwise. Warm to room temperature and stir 18 h. Extract with ethyl acetate (300 mL), wash with water (200 mL), saturated aqueous sodium thiosulfate (300 mL), and saturated aqueous sodium chloride (300 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as an orange oil (8. 8 g, 99%). H NMR (300 MHz, CDCl3) 6 3. 88 (s, 3H), 6. 77-6. 87 (m, 1H), 7. 16-7. 26 (m, 2H).

Reference： [1]Patent: WO2005/94822,2005,A1 .Location in patent: Page/Page column 47

13
[ 64465-53-8 ]
[ 887266-97-9 ]

Yield	Reaction Conditions	Operation in experiment
		4-Fluoro-3-methoxyaniline (0.5 g, 3.55 mmol) in suspension in glacial acetic acid (15ml) is treated with a concentrated HCI (5 ml). The resulting solution is then cooled approximately to 0 0C and treated dropwise with a solution of sodium nitrite (0.245 g, 3.55 mmol) in water (2 ml). After 10 minutes the reaction mixture is added to a stirred solution of SO2/AcOH/CuCI2/H2O (40 ml) (the preparation of the reagent is described below). The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then poured into water (250 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers are washed with water (2 x 100 ml) followed by brine (100 ml) and dried over MgSO4. After filtration the solvent is removed in vacuo to give the titled product which is used crude in the next step.Preparation of the reagent SO2/AcOH/CuCI2/H2O:According to the reported procedure (E. E. Gilbert, Synthesis 1969, 1-10, p6), glacial acetic acid (100 ml), vigorously stirred at room temperature, is treated by bubbling SO2 gas. Once a saturated solution is achieved (approximately 10 g per 100 ml), the solution is treated with copper (II) chloride (4 g) in water (5 ml). The resulting mixture is allowed to settle to give a green solution.
		4-Fluoro-3-methoxy-benzenesulfonyl chloride: 4-Fluoro-3-methoxyaniline (0.5 g, 3.55 mmol) in suspension in glacial acetic acid (15ml) is treated with a concentrated HCI (5 ml). The resulting solution is then cooled approximately to 0 C and treated dropwise with a solution of sodium nitrite (0.245 g, 3.55 mmol) in water (2 ml). After 10 minutes the reaction mixture is added to a stirred solution of S02/AcOH/CuCI2/H20 (40 ml) (the preparation of the reagent is described below). The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then poured into water (250 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers are washed with water (2 x 100 ml) followed by brine (100 ml) and dried over MgS04. After filtration the solvent is removed in vacuo to give the titled product which is used crude in the next step. Preparation of the reagent SO2/AcOH/CuCl2/H2O: According to the reported procedure (E. E. Gilbert, Synthesis 1969,1-10, p6), glacial acetic acid (100 ml), vigorously stirred at room temperature, is treated by bubbling S02 gas. Once a saturated solution is achieved (approximately 10 g per 100 ml), the solution is treated with copper (II) chloride (4 g) in water (5 ml). The resulting mixture is allowed to settle to give a green solution.

Reference： [1]Patent: WO2007/68418,2007,A1 .Location in patent: Page/Page column 63-64
[2]Patent: WO2005/123731,2005,A2 .Location in patent: Page/Page column 68-69

14
[ 64465-53-8 ]
[ 77168-31-1 ]
[ 438249-13-9 ]

Yield	Reaction Conditions	Operation in experiment
78%		EXAMPLE 177 4-(4-Fluoro-3-methoxyanilino)-6-methyl-2-(2-pyridinyl)pyrimidine The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (56.4 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (96.7 mg, 78%). 1H NMR (CDCl3): 8.63 (d, J=4.2 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.42 (s, 1H), 7.20 (m, 1H), 7.0 (d, J=7.5 Hz, 1H), 6.90 (m, 1H), 6.69 (m, 1H), 3.71 (s, 3H), 2.30 (s, 3H),

Reference： [1]Patent: US2003/69239,2003,A1

15
[ 64465-53-8 ]
[ 100367-48-4 ]

Yield	Reaction Conditions	Operation in experiment
73%		Example 9; Preparation of 1 -(5-tert-butylisoxazol-3-ylV3-D-(6 J-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)urea; [00684] Example 9A Step 1 : To a mixture of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (2.0 g,14.2 mmol) in CH2Cl2 (20 mL) at 0 C was added 1.0 M solution Of BBr3 in CH2Cl2 (40 mL). It was stirred overnight, at which time the temperature was raised to room temperature. To it was added MeOH and the solvents were removed under reduced pressure. To the residue was added water, basified with saturated NaHCO3, and extracted with EtOAc. Extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford 5-amino-2-fluorophenol as solid (1.3 g, 73%). 1H NMR (300 MHz, DMSO-d6) delta 9.26 (s, 1H), 6.81 (dd, 1H), 6.34 (dd, 1H), 6.04 (dd, 1H), 4.63 (br, 2H).
43.9 g (87.8%)	With BCl3; In dichloromethane; ethyl acetate;	b) A solution of 50 g (0.354 mol) of <strong>[64465-53-8]4-fluoro-3-methoxy-aniline</strong> dissolved in methylene chloride (1800 ml) was treated under argon with 163.2 g (0.44 mol) of tetrabutyl-ammonium iodide, cooled to -75 C. and the treated over a period of 25 minutes with 860 ml of 1 M BCl3 in methylene chloride while keeping the reaction solution between -75 C. and -64 C. The solution was stirred for 15 minutes the cooling bath was removed and stirring was continued for 24 h under argon. The reaction solution was poured into ice water (6 l) with stirring, the layers were separated, the water layer twice extracted with methylene chloride (each 1.5 l). The combined organic layers were washed twice with water (each 2 l) and discarded. The combined aqueous layers were made basic with solid NaHCO3, saturated with NaCl, extracted 3 times with 2.5 l of ether and twice with 1.5 l of AcOEt. The combined organic layers were tried over magnesium sulphate and concentrated in vacuo to give 43.9 g (87.8%) of 4-fluoro-3-hydroxy-aniline as light brown crystalline solid. Melting point: 156-157 C.
	With boron tribromide; In dichloromethane; at 0℃;	INTERMEDIATE PREPARATION 145-a nolTo a solution of 4-fluoro-3-(methyloxy)aniline (3.8 g, 26.92 mmol) in methylene chloride (50 mL) at 0C was added boron tribromide (20.2 g, 80.77 mmol). The mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in methanol and reconcentrated two times. The residue was dissolved in water and NaHC03 was added. The resulting solution was extracted with ethyl acetate, washed with brine, dried over MgS04, filtered and concentrated to afford 5-amino-2-fluorophenol (3.0 g).

Reference： [1]Patent: WO2009/117080,2009,A1 .Location in patent: Page/Page column 171
[2]Patent: US2002/198194,2002,A1
[3]Patent: WO2011/119704,2011,A1 .Location in patent: Page/Page column 45

16
tin(II)chloride dihydrate [ No CAS ]
[ 64465-53-8 ]
[ 327021-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In hydrogenchloride; water;	4-Fluoro-3-methoxyphenylhydrazine Hydrochloride To stirred hydrochloric acid (100 mL) at 0 C. was added <strong>[64465-53-8]3-methoxy-4-fluoroaniline</strong> (10 g, 71 mmol) followed by water (10 mL) and more hydrochloric acid (10 mL). The mixture was warmed to room temperature, stirred for 20 min then cooled to -5 C. A solution of sodium nitrite (5.14 g, 75 mmol) in water (25 mL) was added dropwise such that the internal temperature remained below 0 C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was cooled to -5 C. and a solution of tin(II)chloride dihydrate (64 g, 284 mmol) in hydrochloric acid (200 mL) was added dropwise such that the internal temperature remained below 0 C. The mixture was warmed to room temperature, stirred for 3 h then filtered. The filter-cake was washed with hydrochloric acid and dried in vacuo to give a pink solid (7.4 g). The emerging precipitate from the combined filtrates was filtered-off, washing with hydrochloric acid, to give a further crop of product (1.8 g. Combined yield 9.2 g, 67%); m.p. 250+ C. (dec.); NMR: (400 MHz, DMSO-d6) deltaH10.17 (3H, s, NH3), 8.14 (1H, s, NH), 7.15 (1H, dd,J 11.6, 8.6 Hz), 6.95 (1H, dd, J 7.6, 3.0 Hz), 6.54 (1H, dt, J 8.6, 3.0 Hz), 3.83 (3H, s, MeO).

Reference： [1]Patent: US6479534,2002,B1

17
[ 910817-92-4 ]
[ 64465-53-8 ]
[ 910817-43-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		1E. Preparation of (3R,4R)-4-amino-1-((4-(4-fluoro-3-methoxyphenylamino) quinazolin-5-yl)methyl)piperidin-3-ol To a suspension mixture of 1D (82.6 mg, 0.25 mmol) and <strong>[64465-53-8]4-fluoro-3-methoxy-aniline</strong> (53 mg, 0.375 mmol) in CH3CN (3 ml) was added AgNO3 (63.7 mg, 0.375 mmol). The reaction mixture was heated at 70 C. for 30 min. After cooling to room temperature, the solid was removed by filtration through a pad of Celite. The filtrate was concentrated, and the residue was dissolved in EtOAc, washed twice with water. The organic layer was concentrated to give a crude intermediate, which was used without further purification. The above intermediate was dissolved in a mixture of THF/H2O (2 ml/0.2 ml) and PPH3 (131 mg, 0.5 mmol) was added. The mixture was heated at 70 C. for 2 h. After cooling to room temperature, the reaction mixture was purified by SCX column (2 g), followed by silica gel flash column (DCM/MeOH/NH4OH=90/10/1) to give 1E (33.0 mg, 33%) as a solid.

Reference： [1]Patent: US2006/217369,2006,A1 .Location in patent: Page/Page column 11

18
[ 3863-11-4 ]
[ 64465-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; water;	Referential Example 32 Synthesis of 4-Fluoro-3-methoxyaniline 3,4-Difluoroaniline (2.6 g) was added to a 28% methanol solution of sodium methoxide, and the mixture was heated for 2 days at about 60 C. and for 4 days at 110 C. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml). A chloroform layer was washed with distilled water (20 ml) and then dried over anhydrous magnesium sulfate. The dry chloroform layer was concentrated under reduced pressure to obtain the title compound (2.8 g) as a dark brown oil. 1 H-NMR (CDCl3) delta: 3.54(br,2H), 3.84(s,3H), 6.17(dt,J=8 Hz,3 Hz,1H), 6.31(dd,J=3 Hz,7 Hz,1H), 6.86(dd,J=8 Hz,11 Hz,1H).

Reference： [1]Patent: US6136823,2000,A

19
[ 112822-88-5 ]
ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-methylbenzoyl)acrylate [ No CAS ]
[ 64465-53-8 ]
ethyl 6,7-Difluoro-1-(4-fluoro-3-ethoxyphenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; chloroform; water; N,N-dimethyl-formamide;	Referential Example 18 Synthesis of Ethyl 6,7-Difluoro-1-(4-fluoro-3-ethoxyphenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate 4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-methylbenzoyl)acrylate synthesised from ethyl 2,4,5-trifluoro-3-methylbenzoylacetate (2.6 g) in accordance with a method known per se in the art. The mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (3.0 g) and N,N-dimethylformamide (7 ml) were added to the residue, followed by stirring at 90 C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (100 ml) and distilled water (250 ml) were added to the mixture, thereby conducting liquid separation. A chloroform layer was then washed twice with distilled water (250 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.59 g) as a colorless powder. Melting point: 273-277 C. 1 H-NMR (CDCl3) delta: 1.40(t,J=7 Hz,3H), 1.76(d,J=3 Hz,3H), 3.94(s,3H), 4.39(q,J=7 Hz,2H), 6.97(m,2H), 7.25(dd,J=8 Hz,10 Hz,1H), 8.23(t,J=9 Hz,1H), 8.43(s,1H).

Reference： [1]Patent: US6136823,2000,A

20
[ 64465-53-8 ]
[ 101987-86-4 ]
[ 208166-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; chloroform; water; N,N-dimethyl-formamide;	Referential Example 33 Synthesis of Ethyl 8-Chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) with ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate synthesised from ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (2.8 g) in accordance with a method known per se in the art dissolved therein. The reaction mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (2.7 g) and N,N-dimethylformamide (6 ml) were added to the residue, followed by stirring at 90 C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (80 ml) and distilled water (300 ml) were added to the reaction mixture, thereby conducting liquid separation. A chloroform layer was washed twice with distilled water (300 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.98 g) as a colorless powder. Melting point: 245-246 C. 1 H-NMR (CDCl3) delta: 1.40(t,J=7 Hz,3H), 3.92(s,3H), 4.39(q,J=7 Hz,2H), 6.95(m,2H), 7.23(dd,J=8 Hz,11 Hz,1H), 8.33(t,J=9 Hz,1H), 8.45(s,1H).

Reference： [1]Patent: US6136823,2000,A

21
[ 15568-85-1 ]
[ 64465-53-8 ]
[ 851985-90-5 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 70℃; for 0.5h;	4-Fluoro-3-methoxyaniline (1.0 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.62 g) were suspended in 2-propanol (40 ml), and the mixture was stirred at 70C for 30 min. The reaction mixture was cooled to room temperature, and the precipitated crystal was collected by filtration and was washed with methanol and then with ether. The crystal thus obtained as such was used in the next reaction without further purification. The crystal prepared above and biphenyl (6.1 g) were suspended in diphenyl ether (25 ml), and the suspension was stirred at 220C for one hr. The reaction mixture was cooled to room temperature, and the precipitated crystal was collected by filtration and was washed with chloroform. The crystal thus obtained as such was used in the next reaction without further purification. The residue was suspended in diisopropylethylamine (7 ml). Phosphorus oxychloride (2 ml) was added to the suspension, and the mixture was stirred at 100C for 30 min. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an ethyl acetate-hexane system to give 4-chloro-6-fluoro-7-methoxy-quinoline (550 mg, yield 37%) (3 steps).

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 61

22
concentrated hydrofluoric acid [ No CAS ]
[ 3866-16-8 ]
[ 64465-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; dichloromethane; water;	Step B: Preparation of 3-methoxy-4-fluoroaniline A solution of 10.73g. (0.07 mole) of 3-methoxyphenylazide in 100 ml. of hexane was added to 20 ml. of concentrated hydrofluoric acid and the reaction mixture, contained in a bomb, was aged for 10 hours at room temperature with agitation. The reaction mixture was then cooled, vented, and poured from the bomb. The bomb was then rinsed with 50 ml. of water, followed by 20 ml. of dichloromethane. The reaction mixture poured from the bomb was blown down under nitrogen, and then combined with the bomb rinsings, and this mixture was cooled and brought to a pH of about 12 with KOH pellets. The mixture was extracted three times with 50 ml. of dichloromethane per extraction, and the combined extracts were dried over MgSO4 and concentrated to 7.31g. (53%) of a dark oil. An aliquot of this product was distilled under reduced pressure to obtain a pale yellow oil with a b.p. of 150-152 C. at 50 mm. Hg.

Reference： [1]Patent: US4145364,1979,A

23
[ 454-16-0 ]
[ 64465-53-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	To a solution of 1-fluoro-2-methoxy-4-nitrobenzene (101) (5.0 g, 29.0 mmol) in methanol (25 mL) was added 10 percent Pd/C (500 mg) at room temperature under H2 atmosphere. After reaction completion (monitored by TLC), the mixture was filtered and the filtrate was evaporated under vacuo to afford title compound 202 (4.0 g, 97 percent yield). ?H NIVIR (400 1VIHz, DMSO-d6): 3.72 (s, 3H), 4.93 (s, 2H), 6.02-6.05 (m, 1H), 6.33 (dd, J7.6, 2.4 Hz, 1H),6.81 (dd,J 11.6, 8.8 Hz, 1H).
93%		N-(4-fluoro-3-methoxyphenyl)pivalamide Step 1 : 4-fluoro-3-methoxyanilineNitro compound Il (6.5 g, 0.038 mol) and iron powder (10.6 g, 0.19 mol) were suspended in ethanol (90 ml) at O0C. HCI cone. (120 ml) was added drop wise to the reaction mixture. The reaction mixture was stirred at 2O0C for 18hr. The reaction mixture was then filtered through celite and washed repeatedly with ethanol. Then ethanol was concentrated and the residue was basified with solid Na2CO3. Then it was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuum to get the product (5 g, Y= 93percent). HPLC-MS: Purity 97percent, M+1 = 142.1
	palladium-carbon; In 1,4-dioxane;	C. 4-Fluoro-3-methoxyaniline A suspension of 10 grams of 2-fluoro-5-nitroanisole and 100 ml. of dioxane is reduced catalytically under 40 p.s.i. of hydrogen and 1.0 gram of 5percent Pd/C. After the uptake of hydrogen ceases, the catalyst is filtered, and the filtrate is concentrated in vacuo to yield 4-fluoro-3-methoxyaniline. Alternatively, the compound may be prepared as follows:

With hydrogenchloride; In methanol;

B. 4-Fluoro-3-methoxyaniline A solution of 5.4 grams 2-fluoro-5-nitroanisole in 125 ml. methanol is reduced by hydrogen at room temperature and 40 p.s.i. pressure using 100 mg. platinum oxide catalyst. After the required uptake of hydrogen, the mixture is filtered, 50 ml. 2.5 N hydrochloric acid added and the resulting solution is evaporated in vacuo. After washing the residue with ether, it is dissolved in methanol, filtered and diluted with excess ether. The precipitate is filtered, washed with ether and dried in vacuo at room temperature. The 4-fluoro-3-methoxyaniline hydrochloride darkens at 250° C. and melts 260° - 265° C. Calculated for C7 H8 FNO.HC1: C, 47.33; H, 5.11; N, 7.89; F, 10.70; Cl, 19.96. Found: C, 47.35; H, 5.14; N, 7.66; F, 10.9; Cl, 20.05.

Reference： [1]Patent: WO2017/132928,2017,A1 .Location in patent: Paragraph 000101
[2]Patent: WO2010/145989,2010,A1 .Location in patent: Page/Page column 12-13
[3]Patent: US4044049,1977,A
[4]Patent: US4044049,1977,A

24
[ 935292-33-4 ]
[ 64465-53-8 ]
4-[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(methylsulfonyl)-3-cinnolinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 80℃;	To 4-chloro-8-methyl-6-(methylsulfonyl)-3-cinnolinecarboxamide (40mg) (for example as prepared for Intermediate 14) in acetonitrile (3ml) was added 4-fluoro-3-(methyloxy)aniline (19mg, available from Fluorochem) and the mixture heated under nitrogen at 80C over the weekend, then allowed to cool to room temperature. The mixture was filtered and filtrate concentrated in vacuo. The residue was purified mass directed preparative HPLC to give the title compound as a pale yellow solid (12mg). LC/MS Rt 2.76min m/z 405 [MH+].

Reference： [1]Patent: WO2007/45861,2007,A1 .Location in patent: Page/Page column 91

25
[ 64465-53-8 ]
[ 32779-36-5 ]
[ 1123515-71-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of -5-bromo 2-chloropyrimidine 4 (1.1 mmol) and 4-fluoro-3- methoxyaniline (1.1 mmol) in 5 mL of 1,4-dioxane is added p-TSA (1.0 mmol). The reaction mixture is heated at 105 0C for 4 h. After this time, the reaction mixture is diluted with a 2M <n="92"/>Na2CO3 solution and extracted with DCM (3 x 50 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated. Purification prep HPLC (ACN gradient 20-70%) 5-bromo- N-(4-fluoro-3-methoxyphenyl)pyrimidin-2-amine 44 as brown solid. MS (m/z) (M+l)+: 299.1.

Reference： [1]Patent: WO2009/26276,2009,A1 .Location in patent: Page/Page column 90-91

26
[ 801315-28-6 ]
[ 64465-53-8 ]
C₁₉H₁₈FN₃O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

27
C₁₂H₁₁ClN₂O₄S [ No CAS ]
[ 64465-53-8 ]
C₁₉H₁₈FN₃O₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

28
[ 801315-33-3 ]
[ 64465-53-8 ]
[ 807325-86-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

29
[ 801315-34-4 ]
[ 64465-53-8 ]
[ 807325-99-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

30
[ 801315-32-2 ]
[ 64465-53-8 ]
[ 807325-77-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

31
[ 801315-20-8 ]
[ 64465-53-8 ]
C₁₈H₁₆FN₃O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1380 - 1385

32
[ 98-98-6 ]
[ 64465-53-8 ]
[ 1103665-24-2 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20 - 50℃;	General procedure: The synthesis was carried out by using the synthetic method a. To a solution of 2-picolinic acid (0.871 g,7.08 mmol), N-hydroxybenzotriazolehydrate (HOBt.H2O,1.084 g, 7.08 mmol), diisopropylethylamine(DIPEA, 1.83 g, 14.17mmol) and N-(3-methylaminopropyl)-N?-ethylcarbodiimidehydrochloride (EDCHCl, 2.036 g, 10.63mmol) in anhydrous 1,4-dioxane (60 mL) was added 3-fluoro-3-methoxyanilline (1.00 g, 7.08 mmol) at room temperature. The mixture was heated to 50 oC and stirred overnight. To the reaction mixture was added 300 mL of dichloromethane, and sequentially washed with water (3 x100 mL). After the organic layer was separated and concentrated, the reaction mixture was purified by silica-gel chromatography (hexane/ethyl acetate) to give the product as a pale-yellow solid (1.559 g, 6.33mmol, 89.4% yield).mp: 100-102 oC; 1H NMR (500MHz, CDCl3)delta ppm 10.01 (s, 1H), 8.62 (d, J = 4.8Hz, 1H), 8.29 (d, J = 7.7 Hz, 1H),7.92(t, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.50 (m, 1H), 7.07 (d, J = 8.5 Hz, 2H), 3.95 (s, 3H);13C NMR (125 MHz, CDCl3)delta ppm161.91, 149.07 (d, J = 243.5 Hz), 149.59, 147.96 (d, J = 2.4 Hz), 147.74 (d, J = 11.4 Hz),137.72, 134.26, 126.51,122.29, 115.90 (d, J = 19.5 Hz), 111.45 (d, J = 6.5 Hz), 105.63 (d, J = 5.7 Hz), 56.21;19F NMR (470 MHz, CDCl3)delta ppm -139.84; LC-MS, calculated for C13H11FN2O2:246.08; observed:247.1 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4115 - 4118
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960

33
[ 208994-11-0 ]
[ 64465-53-8 ]
[ 122-51-0 ]
[ 1258078-04-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3199 - 3203

34
[ 872889-99-1 ]
[ 64465-53-8 ]
[ 1258078-04-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3199 - 3203

35
[ 1139717-28-4 ]
[ 64465-53-8 ]
[ 1139717-32-0 ]

Yield	Reaction Conditions	Operation in experiment
23%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 2-chloro-5-(4-fluorophenoxy)pyridine (180 mg, 0.807 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (170 mg, 1.210 mmol), tris(dibenzylideneacetone)palladium(0) (36.9 mg, 0.040 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.7 mg, 0.080 mmol) and cesium carbonate (526 mg, 1.614 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC (ethyl acetate:hexane 1:1) to afford (4-fluoro-3-methoxyphenyl)-[5-(4-fluorophenoxy)pyridin-2yl]amine as a beige solid (60 mg, 23%). ES+ 329 (M+H)+ deltaH (d6-DMSO) 3.80 (3H, s), 6.86 (1H, d), 6.8-7.4 (2H, m), 7.08 (1H, dd), 7.20 (2H, t), 7.16-7.24 (1H, m), 7.38 (1H, dd), 7.49 (1H, dd), 7.97 (1H, dd) and 9.15 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 12

36
[ 1139717-39-7 ]
[ 64465-53-8 ]
[ 1139717-41-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 2-chloro-5-(3,4-difluorophenoxy)pyridine (180 mg, 0.743 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (157 mg, 1.11 mmol), tris(dibenzylideneacetone)palladium(0) (35.0 mg, 0.037 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43.0 mg, 0.074 mmol) and cesium carbonate (485 mg, 1.487 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC (ethyl acetate:hexane 1:1) to afford [5-(3,4-difluorophenoxy)-pyridin-2-yl]-(4-fluoro-3-methoxyphenyl)amine as a beige solid (55 mg, 21%). ES+ 347 (M+H)+ deltaH (d6-DMSO) 3.82 (3H, s), 6.81 (1H, m), 6.88 (1H, d), 7.08 (1H, dd), 7.15 (1H, m), 7.23 (1H, m), 7.43 (2H, d +dd), 7.51 (1H, dd), 8.02 (1H, d) and 9.17 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 14

37
[ 1139717-48-8 ]
[ 64465-53-8 ]
[ 1139717-50-2 ]

Yield	Reaction Conditions	Operation in experiment
24%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of [3-(6-chloropyridin-3-yloxy)phenyl]-dimethylamine (180 mg, 0.722 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (152.9 mg, 1.08 mmol), tris(dibenzylidene-acetone)palladium(0) (33.0 mg, 0.036 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene(41.8 mg, 0.074 mmol) and cesium carbonate (470 mg, 1.445 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC (ethyl acetate:hexane 1:1) to afford [5-(3-dimethylaminophenoxy)-pyridin-2-yl]-(4-fluoro-3 methoxy-phenyl)amine as a beige solid (60 mg, 24%). ES+ 354 (M+H)+ deltaH (d6-DMSO) 2.85 (6H, s), 3.80 (3H, t), 6.12 (1H, d), 6.30 (1H, br s), 6.42 (1H, d), 6.83 (1H, d), 7.00-7.15 (2H, m), 7.20 (1H, m), 7.33 (1H, dd), 7.47 (1H, br d), 7.93(1H, d) and 9.05 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 16

38
[ 1139717-68-2 ]
[ 64465-53-8 ]
[ 1139717-69-3 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 4-[3-(6-chloropyridin-3-yloxy)phenyl]morpholine (100 mg, 0.343 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (72.8 mg, 0.515 mol), tris(dibenzylidene-acetone)palladium(0) (15.74 mg, 0.017 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (19.9 mg, 0.034 mmol) and cesium carbonate (224 mg, 0.685 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC to afford (4-fluoro-3-methoxyphenyl)-5-(3-morpholin-4-yl-phenoxy)pyridin-2-yl]amine as a brown solid (65 mg, 48%). ES+ 396 (M+H)+ deltaH (d6-DMSO) 3.06(4H, m), 3.68 (4H, m), 3.80 (3H, s), 6.30 (1H, d), 6.52 (1H, br s), 6.63 (1H, d), 6.83 (1H, d), 7.05 (1H, t), 7.15 (2H, m), 7.34 (1H, d), 7.45 (1H, d), 7.91 (1H, d) and 9.10 (1H, br s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 20

39
[ 1139717-78-4 ]
[ 64465-53-8 ]
[ 1139717-80-8 ]

Yield	Reaction Conditions	Operation in experiment
24%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 1-[3-(6-chloropyridin-3-yloxy)phenyl]-4-methylpiperazine (200 mg, 0.658 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (139.3 mg, 0.987 mol), tris(dibenzylidene-acetone)palladium(0) (30.14 mg, 0.032 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (38.09 mg, 0.065 mmol) and cesium carbonate (429 mg, 1.316 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC to afford (4-fluoro-3-methoxyphenyl)-{5-[3-(4-methylpiperazin-1-yl)phenoxy]-pyridin-2-yl}amine as a brown solid (65 mg, 24%). ES+ 409 (M+H)+ deltaH (d6-DMSO) 2.19 (3H, s), 2.40 (4H, m), 3.09 (4H, m), 3.80 (3H, s), 6.25 (1H, d), 6.51 (1H, br s), 6.64 (1H, d), 6.82 (1H, d), 7.04 (1H, t), 7.12 (1H, t), 7.19 (1H, m), 7.33 (1H, d), 7.47 (1H, d), 7.93 (1H, d) and 9.05 (1H, br s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 22; 23

40
[ 1139717-81-9 ]
[ 64465-53-8 ]
[ 1139717-82-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 2-chloro-5-(3-pyrrolidin-1-ylphenoxy)pyridine (150 mg, 0.548 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (116.1 mg, 0.822 mol), tris(dibenzylideneacetone)palladium(0) (25.1 mg, 0.027 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31.73 mg, 0.054 mmol) and cesium carbonate (357 mg, 1.096 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC (ethyl acetate:hexane 1:1) to afford (4-fluoro-3-methoxyphenyl)-[5-(3-pyrrolidin-1-ylphenoxy)-pyridin-2-yl]amine as a beige solid (60 mg, 28%). ES+ 380 (M+H)+ deltaH (d6-DMSO) 1.91 (4H, m), 3.15 (4H, m), 3.80 (3H, s), 6.08 (1H, d), 6.10 (1H, br s), 6.25 (1H, d), 6.82 (1H, d), 7.05 (1H, t), 7.07 (1H, t), 7.19 (1H, m), 7.33 (1H, d), 7.48(1H, d), 7.92 (1H, d) and 9.04 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 23

41
[ 1139717-85-3 ]
[ 64465-53-8 ]
[ 1139717-87-5 ]

Yield	Reaction Conditions	Operation in experiment
10%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of {2-[3-(6-chloropyridin-3-yloxy)phenoxy]ethyl}dimethylamine (164 mg, 0.561 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (118.5 mg, 0.842 mmol), tris(dibenzylidene-acetone)palladium(0) (25.6 mg, 0.028 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (32.4 mg, 0.056 mmol) and cesium carbonate (364 mg, 1.123 mmol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC to afford {5-[3-(2-(dimethylamino)ethoxy)phenoxy]pyridine-2-yl}-(4-fluoro-3-methoxyphenyl)amine as a colourless oil (22 mg, 10%). ES+ 398 (M+H)+ deltaH (d6-DMSO) 2.22 (6H, s), 2.62 (2H, m), 3.83 (3H, s), 4.02 (2H, m), 6.50 (1H, br d), 6.52 (1H, br s), 6.67 (1H, br d), 6.88 (1H, d), 7.08 (1H, dd), 7.22 (1H, m), 7.24 (1H, t), 7.40 (1H, dd), 7.51 (1H, dd), 7.98 (1H, d) and 9.10 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 24

42
[ 1139717-88-6 ]
[ 64465-53-8 ]
[ 1139717-89-7 ]

Yield	Reaction Conditions	Operation in experiment
14%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 4-{2-[3-(6-chloropyridin-3-yloxy)phenoxy]ethyl}morpholine (200 mg, 0.598 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (126 mg, 0.898 mmol), tris(dibenzylidene-acetone)palladium(0) (27.2 mg, 0.029 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.5 mg, 0.059 mmol) and cesium carbonate (390 mg, 1.197 mmol) in degassed 1,4-dioxane (4 ml) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC to afford (4-fluoro-3-methoxyphenyl)-{5-[3-(2-morpholin-4-yl-ethoxy)-phenoxy]-pyridin-2-yl}amine as a brown oil (36 mg, 14%). ES+ 440 (M+H)+ deltaH (d6-DMSO) 2.44 (4H, m), 2.66 (2H, m), 3.55 (4H, m), 4.05 (2H, m), 6.50 (1H, br d), 6.52 (1H, br s), 6.67 (1H, br d), 6.87 (1H, d), 7.08 (1H, m), 7.23 (2H, m), 7.40 (1H, dd), 7.50 (1H, br d), 7.99 (1H, d) and 9.10 (1H, s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 25

43
[ 1139717-90-0 ]
[ 64465-53-8 ]
[ 1139717-91-1 ]

Yield	Reaction Conditions	Operation in experiment
22%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of [3-(6-chloro-5-fluoropyridin-3-yloxy)phenyl]-dimethylamine (200 mg, 0.751 mmol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (166 mg, 0.82 mmol), tris(dibenzylidene-acetone)palladium(0) (27.0 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (43 mg, 0.075 mmol) and cesium carbonate (538 mg, 1.65 mmol) in degassed 1,4-dioxane (5 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluding with ethyl acetate:hexane (1:4) to afford [5-(3-(dimethylaminophenoxy)-3-fluoro-pyridin-2-yl]-(4-fluoro-3-methoxyphenyl)amine as a brown solid. (60 mg, 22%). ES+ 372 (M+H)+ deltaH (d6-DMSO) 2.90 (6H, s), 3.81 (3H, s), 6.20 (1H, d), 6.37 (1H, br s), 6.49 (1H, d), 7.08 (1H, dd), 7.14 (1H, t), 7.40 (1H, m), 7.50 (1H, dd), 7.60 (1H, dd), 7.84 (1H, d) and 8.82 (1H, br s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 25

44
[ 1139717-99-9 ]
[ 64465-53-8 ]
[ 1139718-00-5 ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 48h;	A suspension of 2-chloro-3-fluoro-5-(3-pyrrolidin-1-ylphenoxy)pyridine (0.150 g, 0.51 mol), <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (0.107 g, 0.76 mol), tris(dibenzylideneacetone)-palladium(0) (0.018 g, 0.02 mol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.029 g, 0.05 mol) and cesium carbonate (0.367 g, 1.1 mol) in degassed 1,4-dioxane (4 mL) was heated at 80 C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC eluding with ethyl acetate:hexane (1:1) to afford (4-fluoro-3-methoxy-phenyl)-[3-fluoro-5-(3-pyrrolidin-1-yl-phenoxy)pyridin-2-yl]amine as a pale yellow solid (0.051g, 25%). ES+ 398 (M+H)+ deltaH (d6-DMSO) 1.93 (4H, m), 3.19 (4H, m), 3.80 (3H, s), 6.15 (2H, m), 6.30 (1H, d), 7.05-7.15 (2H, m), 7.40 (1H, m), 7.48 (1H, d), 7.60 (1H, d), 7.84 (1H, d) and 8.82(1H, br s).

Reference： [1]Patent: US2010/298325,2010,A1 .Location in patent: Page/Page column 27

45
[ 64465-53-8 ]
[ 3282-30-2 ]
N-[4-fluoro-3-(methyloxy)phenyl]-2,2-dimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With pyridine; dmap; In dichloromethane; at 0 - 20℃; for 10h;	Step 2: N-(4-fluoro-3-methoxyphenyl)pivalamideCompound III (8.9 g, 0.063 mol) was dissolved in dry dichloromethane (DCM) (90 ml). Pyridine (10.2 ml) was added drop wise to the reaction mixture at 2O0C. Then pivaloyl chloride (8.3 g, 0.069 mol) and 4-dimethylaminopyhdine (76 mg, 0.0006 mol) was added to the reaction mixture at O0C. The reaction was stirred at 2O0C for 10 hrs. Solvent was removed and the residue was washed with aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with Na2CO3 and brine solution. The organic layer was dried over Na2SO4, concentrated in vacuum to get the crude product (13.7 g, Y= 96%). The crude material was used in the next step without further purification. HPLC-MS: Purity 80%, M+1 = 226.2

Reference： [1]Patent: WO2010/145989,2010,A1 .Location in patent: Page/Page column 13

46
[ 302-17-0 ]
[ 64465-53-8 ]
[ 1188354-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydroxylamine hydrochloride; sodium sulfate; In water; at 55℃; for 6h;	118.4 g of sodium sulfate, 26.3 g of hydroxylamine chloride and 20.89 g of chloral hydrate are added, in this order, to a suspension of 14.7 g of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> in 695 ml of water and 35 ml of 2N hydrochloric acid. The reaction mixture is heated at 55 C. for 6 hours. It is cooled to approximately 15 C. The expected compound is obtained and is filtered off, washed and dried. MH+=213; rt=5.94 min; (M 4).

Reference： [1]Patent: US2011/59955,2011,A1 .Location in patent: Page/Page column 11

47
[ 64465-53-8 ]
[ 1188354-73-5 ]

Reference： [1]Patent: US2011/59955,2011,A1

48
[ 64465-53-8 ]
[ 1188354-74-6 ]

Reference： [1]Patent: US2011/59955,2011,A1

49
[ 64465-53-8 ]
[ 1188354-76-8 ]

Reference： [1]Patent: US2011/59955,2011,A1

50
[ 64465-53-8 ]
[ 1344684-79-2 ]

Reference： [1]Patent: US2011/263562,2011,A1

51
[ 600-18-0 ]
[ 454-89-7 ]
[ 64465-53-8 ]
[ 1335116-53-4 ]

Yield	Reaction Conditions	Operation in experiment
53%		EXAMPLE 33-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-r3-(trifluoromethyl)phenyll-A/- r(1 f?)-2,2,2-trifluoro-1-phenylethyll-4-quinolinecarboxamide; 6-fluoro-3-methyl-7-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acidA solution of the 4-fluoro-3-(methyloxy)aniline (1 1.29 g, 80 mmol) and 3- (trifluoromethyl)benzaldehyde (13.93 g, 80 mmol) in ethanol (200 mL) was heated to reflux for 1 h. 2-Oxobutanoic acid (8.17 g, 80 mmol) was added portionwise. The reaction mixture was stirred at reflux for additional 3 h, cooled to room temperature, and stirred at room temperature overnight. The solid was collected by filtration, washed with ethanol, and air dried to give 6- fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (16.05 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) delta 14.35 (br. s., 1 H), 7.93 - 8.00 (m, 2H), 7.85 - 7.91 (m, J = 7.78 Hz, 1 H), 7.74 - 7.81 (m, 1 H), 7.68 - 7.73 (m, J = 8.53 Hz, 1 H), 7.54 (d, J = 12.05 Hz, 1 H), 4.03 (s, 3H), 2.38 (s, 3H); MS (m/z) 380.1 (M+H+).
49%		EXAMPLE 1323-( 1 ,4'-bipiperidin-1 '-ylmethyl)-6-r( 1 -methylethyl)sulfonyll-7-(methyloxy)-A/-( 1 - phenylcvclopropyl)-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxamide6-fluoro-3-methyl-7-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxy acidTo a solution of 4-fluoro-3-(methyloxy)aniline (13.6 g, 96 mmol) in ethanol (200 mL) was added 3-(trifluoromethyl)benzaldehyde (16.78 g, 96 mmol) dropwise. The mixture was stirred at reflux for 1 h, and 2-oxobutanoic acid (9.84 g, 96 mmol) was added portionwise. The reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The mixture was filtered to collect the precipitate, and the solid was washed with ethanol and air dried to give 6-fluoro-3-methyl-7-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (17.9 g, 49% yield). MS (m/z) 380.1 (M+H+).

Reference： [1]Patent: WO2011/119701,2011,A1 .Location in patent: Page/Page column 48
[2]Patent: WO2011/119704,2011,A1 .Location in patent: Page/Page column 62-63

52
[ 64465-53-8 ]
[ 1335116-61-4 ]