4-fluorobenzoyl isothiocyanate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 44%). to prepare a solution The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 44%). to prepare a solution The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 80%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 87%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 85%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 85%). The reaction solution was concentrated the residue was purified by chromatography on silica gel

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of cis-4-(5-Amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (0.069 g, 0.195 mmol) in THF (0.5 mL) was cooled to 0° C. and 4-fluorobenzoyl isothiocyanate (0.053 g, 0.292 mmol) was added as a THF solution. The mixture was stirred at 0° C. for 30 minutes and then was warmed to 20° C. and stirred for 1 hour. To the mixture was added DIPEA (0.051 mL, 0.292 mmol) and EDC (0.056 g, 0.292 mmol), and the reaction was heated at 60° C. for 1 hour. The reaction mixture was diluted with DCM and then washed with water and brine. The organic layer was concentrated under vacuum. The sample was purified by flash chromatography, eluting with 0-70% 90/10/1 DCM/MeOH/NH4OH:DCM to afford impure product as a light yellow solid. The impure material was further purified by preparative TLC, eluting with 90/10/1 DCM/MeOH/NH4OH:DCM to afford (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as a pale yellow solid (0.046 g, 47.1% yield). MS, m/z (C24H28FN5O4S); Calcd, 501.58. found 502.2 [M+H]. was warmed to 20° C. stirred for 1 hour the reaction was heated at 60° C. for 1 hour washed with water and brine The organic layer was concentrated under vacuum The sample was purified by flash chromatography eluting with 0-70% 90/10/1 DCM/MeOH/NH4OH DCM to afford impure product as a light yellow solid The impure material was further purified by preparative TLC eluting with 90/10/1 DCM/MeOH/NH4OH

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)-cyclohexanecarboxamide (100 mg, 0.269 mmol) in EtOH (3 mL) was added tin(II) chloride dihydrate (242 mg, 1.074 mmol). The reaction was stirred at 80° C. After 3 hours, another four equivalents of tin(II) chloride dihydrate (242 mg, 1.074 mmol) was added, and the reaction was stirred at 80° C. for an additional 3 hours, and then at RT overnight. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and 1 N aqueous sodium hydroxide. The aqueous layer was extracted with EtOAc; the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The diamine was dissolved in THF (3 mL), cooled to 0° C., and 4-fluorobenzoyl isothiocyanate (53.5 mg, 0.296 mmol) was added. The reaction was stirred at 0° C. for 30 minutes, then DIPEA (0.070 mL, 0.403 mmol) and EDC (77 mg, 0.403 mmol) were added, and the reaction was stirred for 1 hour at 60° C. The residual material was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 20-100% EtOAc in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as an off-white powder (44 mg, 33.5% yield). MS, m/z (C26H28FN7O2): Calc'd, 489.2. found, 489.9 [M+H]. the reaction was stirred at 80° C. for an additional 3 hours at RT overnight The reaction mixture was concentrated the residue was partitioned between EtOAc and 1 N aqueous sodium hydroxide The aqueous layer was extracted with EtOAc the combined organic layers were dried over anhydrous magnesium sulfate filtered concentrated The diamine was dissolved in THF (3 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 minutes the reaction was stirred for 1 hour at 60° C The residual material was concentrated purified by column chromatography eluting with 20-100% EtOAc in DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from cis-4-(5-amino-2-(3-morpholinopropoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide with 1.3 equivalents of 4-fluorobenzoyl isothiocyanate. Isolated as an off-white solid (98 mg, 104% yield). M/Z calc'd for C30H39FN6O4: 566.67. found 567 [M+H].

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-bath cooled solution of cis-4-(5-amino-2-(2-methoxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (156 mg, 0.445 mmol) in THF (0.8 mL) was added 4-fluorobenzoyl isothiocyanate (161 mg, 0.890 mmol) as a solution in THF (2 mL). The mixture was stirred 15 minutes, and then stirred another 30 minutes at RT. DIPEA (0.194 mL, 1.113 mmol) and EDC (213 mg, 1.113 mmol) were added, and the mixture was heated to 60° C. for 1 hour. The mixture was evaporated, and the residue was dissolved with 5% IPA/EtOAc (5 mL), washed with 1:1 aqueous NH4Cl (sat)/water, [1 mL total volume (×2)], brine, and the organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as a white solid (110 mg, 50% yield). M/Z calc'd for C26H32FN5O4: 497.56. found 498 [M+H]. stirred another 30 minutes at RT The mixture was evaporated the residue was dissolved with 5% IPA/EtOAc (5 mL) washed with 1:1 aqueous NH4Cl (sat)/water, [1 mL total volume (×2)], brine the organic layer was dried over Na2SO4 filtered The mixture was purified via flash chromatography