4-fluoro-N-phenylbenzamide

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

Procedure: Into a 500-mL 3-necked round-bottom flask, was placed 4-fluoro-N-phenylbenzamide (50 g; 233 mmol) and thionyl chloride (200 mL). The mixture was stirred at refluxed for 3 h and then the solvent was evaporated to dryness to afford (Z)-4-fluoro-N-phenylbenzimidoyl chloride as white solid. The solid was dissolved into chlorobenzene and SnCl4 (39.0 mmol) and ethyl cyanoformate (39.0 mmol) were added. The reaction mixture was heated at 140° C. for 1 hour and concentrated to get black oil. The black oil was added into water, made alkaline with 20% NaOH, and extracted with 2×300 mL of dichloromethane. The organic layer was washed with 1×100 mL of brine and dried over sodium sulphate and concentrated to get the crude product, which was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to afford ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate as white solid (8.1 g, 11.7%, 2 steps). MS (ESI) m/z 297 ([M+H]+). Into a 500-mL 3-necked round-bottom flask, was placed at refluxed for 3 h the solvent was evaporated to dryness

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

Procedure: Into a 5000-mL 4-necked round-bottom flask, was placed aniline (93 g, 1.0 mol, 1.0 equiv.), triethylamine (202 g, 2.0 mol, 2.0 equiv.) and dichloromethane (2,000 mL). This was followed by the addition of 4-fluorobenzoyl chloride (174 g, 1.1 mol, 1.1 equiv.) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated under vacuum. The solid was filtered out. The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water. This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid. MS (ESI) m/z 216 ([M+H]+). Into a 5000-mL 4-necked round-bottom flask, was placed The mixture was stirred at room temperature for 3 hours The resulting solution was concentrated under vacuum The solid was filtered out The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid

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

Procedure: Into a 500-mL 3-necked round-bottom flask, was placed 4-fluoro-N-phenylbenzamide (50 g; 233 mmol) and thionyl chloride (200 mL). The mixture was stirred at refluxed for 3 h and then the solvent was evaporated to dryness to afford (Z)-4-fluoro-N-phenylbenzimidoyl chloride as white solid. The solid was dissolved into chlorobenzene and SnCl4 (39.0 mmol) and ethyl cyanoformate (39.0 mmol) were added. The reaction mixture was heated at 140° C. for 1 hour and concentrated to get black oil. The black oil was added into water, made alkaline with 20% NaOH, and extracted with 2×300 mL of dichloromethane. The organic layer was washed with 1×100 mL of brine and dried over sodium sulphate and concentrated to get the crude product, which was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to afford ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate as white solid (8.1 g, 11.7%, 2 steps). MS (ESI) m/z 297 ([M+H]+). Into a 500-mL 3-necked round-bottom flask, was placed at refluxed for 3 h the solvent was evaporated to dryness

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

Procedure: Into a 5000-mL 4-necked round-bottom flask, was placed aniline (93 g, 1.0 mol, 1.0 equiv.), triethylamine (202 g, 2.0 mol, 2.0 equiv.) and dichloromethane (2,000 mL). This was followed by the addition of 4-fluorobenzoyl chloride (174 g, 1.1 mol, 1.1 equiv.) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated under vacuum. The solid was filtered out. The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water. This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid. MS (ESI) m/z 216 ([M+H]+). Into a 5000-mL 4-necked round-bottom flask, was placed The mixture was stirred at room temperature for 3 hours The resulting solution was concentrated under vacuum The solid was filtered out The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid