4-[(1,3-dioxoisoindol-2-yl)methyl]-N-phenylbenzamide

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide (14 g, 39.28 mmol, 1.00 equiv), POCl3 (140 mL) and PCl5 (8.96 g, 43.03 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted with chlorobenzene (300 mL). To this was added 2-ethoxy-2-oxoacetonitrile (7.7 mL, 2.00 equiv), tetrachlorostannane (15 mL, 1.50 equiv). The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether:tetrahydrofuran (30:6:1). This resulted in 4 g (23%) of ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate as a light yellow solid. MS (ESI) m/z 438 ([M+H]+). Into a 500-mL round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting mixture was concentrated under vacuum The residue was diluted with chlorobenzene (300 mL) to react with stirring, for an additional 2 h while the temperature was maintained at 120° C. in an oil bath The resulting mixture was concentrated under vacuum This resulted in 4 g (23%) of ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate as a light yellow solid

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

Procedure: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed aniline (5.73 g, 61.53 mmol, 1.10 equiv), dichloromethane (100 mL) and triethylamine (11.3 g, 111.67 mmol, 2.00 equiv). This was followed by the addition of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride (16.7 g, 55.72 mmol, 1.00 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 100 mL of hexane. The solids were collected by filtration. The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water. This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid. MS (ESI) m/z 357 ([M+H]+). Into a 500-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was stirred for 3 h at 25° C The solids were collected by filtration The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid

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

Procedure: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed aniline (5.73 g, 61.53 mmol, 1.10 equiv), dichloromethane (100 mL) and triethylamine (11.3 g, 111.67 mmol, 2.00 equiv). This was followed by the addition of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride (16.7 g, 55.72 mmol, 1.00 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 100 mL of hexane. The solids were collected by filtration. The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water. This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid. MS (ESI) m/z 357 ([M+H]+). Into a 500-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was stirred for 3 h at 25° C The solids were collected by filtration The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide (14 g, 39.28 mmol, 1.00 equiv), POCl3 (140 mL) and PCl5 (8.96 g, 43.03 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted with chlorobenzene (300 mL). To this was added 2-ethoxy-2-oxoacetonitrile (7.7 mL, 2.00 equiv), tetrachlorostannane (15 mL, 1.50 equiv). The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether:tetrahydrofuran (30:6:1). This resulted in 4 g (23%) of ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate as a light yellow solid. MS (ESI) m/z 438 ([M+H]+). Into a 500-mL round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting mixture was concentrated under vacuum The residue was diluted with chlorobenzene (300 mL) to react with stirring, for an additional 2 h while the temperature was maintained at 120° C. in an oil bath The resulting mixture was concentrated under vacuum This resulted in 4 g (23%) of ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate as a light yellow solid

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

Procedure: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed aniline (5.73 g, 61.53 mmol, 1.10 equiv), dichloromethane (100 mL) and triethylamine (11.3 g, 111.67 mmol, 2.00 equiv). This was followed by the addition of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride (16.7 g, 55.72 mmol, 1.00 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 100 mL of hexane. The solids were collected by filtration. The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water. This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid. MS (ESI) m/z 357 ([M+H]+). Into a 500-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was stirred for 3 h at 25° C The solids were collected by filtration The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid