(3S)-N-methylpyrrolidin-3-amine

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

Procedure: The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]

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

Procedure: The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (109 μl, 1.03 mmol) was added at 140 to 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N-(2-methoxyethyl)-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-122) (314 mg, 855 μmol) and triethylamine (155 μl, 1.11 mmol), followed by stirring at the same temperature for 50 minutes. After cooling, saturated brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=10:1, v/v) to obtain a rough product of the entitled compound. The rough product of the entitled compound was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, then the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (117 mg, 31%) as an amorphous substance. After cooling the mixture liquid was extracted with ethyl acetate Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane methanol=10:1, v/v) to obtain a rough product of the entitled compound washed with an aqueous saturated sodium hydrogencarbonate solution the aqueous layer was extracted with chloroform The combined organic layer was dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure

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

Procedure: 6-(3-Chlorophenyl)-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-311) (500 mg, 1.40 mmol) was dissolved in dimethyl sulfoxide (20 ml), and at room temperature, triethylamine (215 μl, 1.54 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (164 μl, 1.54 mmol) dissolved in dimethyl sulfoxide (3 ml) was added all at a time. After stirred at the same temperature for 30 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was first roughly purified by middle-pressure liquid chromatography using an eluent of chloroform:methanol=95:5 (v/v), and then the roughly-purified product was purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and further the obtained solid was purified in slurry with diisopropyl ether to obtain the entitled compound (250 mg, 41%) as a pale yellow solid. The solution was gradually heated from room temperature up to 150° C. was added all at a time The solvent was evaporated away under reduced pressure The aqueous layer was further extracted twice with chloroform washed with saturated brine dried over anhydrous sodium sulfate The insoluble matter was separated by filtration the solvent was evaporated away the resulting residue was first roughly purified by middle-pressure liquid chromatography methanol=95:5 (v/v), and then the roughly-purified product was purified by preparative TLC (eluent, chloroform 7 N ammonia/methanol solution=95:5, v/v), and further the obtained solid was purified in slurry with diisopropyl ether

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

Procedure: 4-Cyano-7-fluoro-N,N,5-trimethyl-6-(thiophen-2-yl)-1,3-benzoxazole-2-carboxamide (I-308) (160 mg, 0.49 mmol) was dissolved in dimethyl sulfoxide (8.7 ml), and at room temperature, triethylamine (81 μl, 0.58 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (62 μl, 0.58 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. After stirred at the same temperature for 50 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and saturated brine. The aqueous layer was further fractionated twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and the roughly-purified product was again purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v) to obtain the entitled compound (119 mg, 60%) as a yellow amorphous substance. The solution was gradually heated from room temperature up to 150° C. was added all at a time The solvent was evaporated away under reduced pressure washed with saturated brine dried over anhydrous sodium sulfate The insoluble matter was separated by filtration the solvent was evaporated away the resulting residue was roughly purified by preparative TLC (eluent, chloroform 7 N ammonia/methanol solution=95:5, v/v), and the roughly-purified product was again purified by preparative TLC (eluent, chloroform

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

Procedure: Under nitrogen atmosphere at 130° C., (3S)-3-(methylamino)pyrrolidine (85 μl, 801 μmol) was added to a dimethyl sulfoxide (7 ml) solution of 2-cyclopropyl-7-fluoro-5-fluoromethyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-293) (207 mg, 667 μmol) and triethylamine (121 μl, 867 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=5:1, v/v) to obtain a crude product of the entitled compound. The crude product of the entitled compound was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution, then the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (62 mg, 24%) as an amorphous substance. After cooling the mixture liquid was extracted with ethyl acetate Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane methanol=5:1, v/v) to obtain a crude product of the entitled compound washed with an aqueous saturated sodium hydrogencarbonate solution the aqueous layer was extracted with ethyl acetate The combined organic layer was dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Cyclopropyl-7-fluoro-5-methyl-6-phenylbenzoxazole-4-carbonitrile (I-173) (250 mg, 0.86 mmol) was dissolved in dimethyl sulfoxide (5 ml), then at room temperature, triethylamine (155 μl, 1.11 mmol) and (3S)-3-(methylamino)pyrrolidine (119 μl, 1.11 mmol) were added. After stirred under nitrogen atmosphere at 90° C. for 13 hours, this was cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7, v/v) to obtain the entitled compound (201 mg, 63%) as a white solid. this was cooled to room temperature The reaction liquid The aqueous layer was further extracted twice with ethyl acetate washed with saturated brine dried over anhydrous sodium sulfate The insoluble matter was separated by filtration the solvent was evaporated away the resulting residue was purified by preparative TLC (eluent, chloroform

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (67 μl, 633 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (10 ml) solution of 4-cyano-N-ethyl-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-285) (178 mg, 528 μmol) and triethylamine (96 μl, 686 μmol), followed by stirring at the same temperature for 160 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by preparative TLC (eluent, dichloromethane:methanol=10:1, v/v) to obtain the entitled compound (71 mg, 32%) as an amorphous substance. After cooling the reaction liquid was extracted with ethyl acetate Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under the reduced pressure The resulting residue was purified by preparative TLC (eluent, dichloromethane

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-Fluoro-5-methyl-2-(methylamino)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-131) (0.17 g, 0.60 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.17 ml, 1.23 mmol) and (3S)-3-methylaminopyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1), then diisopropyl ether was added, and the insoluble matter was collected by filtration to obtain a beige solid (68.3 mg, 27%). washed with water and brine dried over anhydrous sodium sulfate The solvent was evaporated away under reduced pressure the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1) diisopropyl ether was added the insoluble matter was collected by filtration

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution (3S)-3-methylaminopyrrolidine (139 μl, 1.40 mmol) was added at 150° C. to a dimethyl sulfoxide (18 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (350 mg, 1.08 mmol) and triethylamine (201 μl, 1.30 mmol), followed by stirring at the same temperature for 4 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (4:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (147 mg, 34%) as a pale yellow solid. After cooling the reaction liquid was extracted with ethyl acetate Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Cyclopropyl-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-80) (100 mg, 0.32 mmol) was dissolved in dimethyl sulfoxide (2 ml), triethylamine (112 μl, 0.80 mmol) and (3S)-3-methylaminopyrrolidine (44 μl, 0.42 mmol) were added, followed by stirring at 90° C. for 6 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) followed by recrystallization and purification with a mixed solvent of diethyl ether/ethyl acetate/n-hexane to obtain the entitled compound (22 mg, 17%) as a white solid. After cooling to room temperature The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated away eluted with a mixed solvent of chloroform/methanol (10:1 v/v) followed by recrystallization and purification with a mixed solvent of diethyl ether/ethyl acetate/n-hexane

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (109 μl, 1.03 mmol) was added at 140 to 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N-(2-methoxyethyl)-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-122) (314 mg, 855 μmol) and triethylamine (155 μl, 1.11 mmol), followed by stirring at the same temperature for 50 minutes. After cooling, saturated brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=10:1, v/v) to obtain a rough product of the entitled compound. The rough product of the entitled compound was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, then the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (117 mg, 31%) as an amorphous substance. After cooling the mixture liquid was extracted with ethyl acetate Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane methanol=10:1, v/v) to obtain a rough product of the entitled compound washed with an aqueous saturated sodium hydrogencarbonate solution the aqueous layer was extracted with chloroform The combined organic layer was dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure