4-amino-N-methylbenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5° C. and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C., and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H). to warm 25° C. it was mixed at 25° C. for 20 hours the fraction eluting 0-10% methanol/DCM was collected concentrated The resultant residue was triturated with water filtered to provide B20

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

Procedure: A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A, 4-amino-N-methylbenzamide (37 mg) and acetic acid (13 μL) in ethanol (2 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3 mL) was added 1M hydrochloric acid (230 μL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (65 mg). the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) To a solution of the residue (87 mg) in ethanol (3 mL) was added 1M hydrochloric acid (230 μL) the solvent was evaporated under reduced pressure The residue was recrystallized (diisopropyl ether/ethanol)

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

Procedure: A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A, 4-amino-N-methylbenzamide (37 mg) and acetic acid (13 μL) in ethanol (2 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3 mL) was added 1M hydrochloric acid (230 μL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (65 mg). the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) To a solution of the residue (87 mg) in ethanol (3 mL) was added 1M hydrochloric acid (230 μL) the solvent was evaporated under reduced pressure The residue was recrystallized (diisopropyl ether/ethanol)

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

Procedure: A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), 4-amino-N-methylbenzamide (32 mg) and acetic acid (12 μL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg). The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate) recrystallized (hexane/ethyl acetate)

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

Procedure: A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), 4-amino-N-methylbenzamide (32 mg) and acetic acid (12 μL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg). The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate) recrystallized (hexane/ethyl acetate)

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

Procedure: To a suspension of 4-(methylcarbamoyl)aniline (1.0 g) in 1,4-dioxane (10 ml) were added 1N sodium hydroxide solution (13.4 ml) and phenyl chloroformate (1.26 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give phenyl 4-(methylcarbamoyl)phenylcarbamate (1.70 g) as pale yellow crystals. cooling extracted with a mixture of chloroform and methanol The extract was washed with water dried over magnesium sulfate evaporated in vacuo The residue was crystallized from ethyl acetate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-6-(3-(4-fluorophenoxy) azetidin-1-yl)pyridine (500 mg, 1.79 mmoL) and 4-amino-N-methylbenzamide (270 mg, 1.79 mmol) in dimethylacetamide (5 mL, 3 mL/mmol) was added cesium carbonate (873 mg, 2.68 mmol) and the reaction was degassed for 15 min. Pd2(dba)3 (81 mg, 0.089 mmol) and BINAP (55 mg, 0.089 mmol) were added and the reaction was allowed to heat at 120° C. in the microwave. The reaction was quenched with water and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to afford 3-(6-(3-(4-fluorophenoxy) azetidin-1-yl)pyridin-2-ylamino)-N-methylbenzamide (61 mg, 13%) as a solid. Observed mass (M+1): 393.1. The following compounds were prepared as described in Example V above using appropriate starting materials. the reaction was degassed for 15 min The reaction was quenched with water extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over sodium sulfate concentrated under reduced pressure purified by silica gel column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-6-(3-(4-fluorophenoxy) azetidin-1-yl)pyridine (500 mg, 1.79 mmoL) and 4-amino-N-methylbenzamide (270 mg, 1.79 mmol) in dimethylacetamide (5 mL, 3 mL/mmol) was added cesium carbonate (873 mg, 2.68 mmol) and the reaction was degassed for 15 min. Pd2(dba)3 (81 mg, 0.089 mmol) and BINAP (55 mg, 0.089 mmol) were added and the reaction was allowed to heat at 120° C. in the microwave. The reaction was quenched with water and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to afford 3-(6-(3-(4-fluorophenoxy) azetidin-1-yl)pyridin-2-ylamino)-N-methylbenzamide (61 mg, 13%) as a solid. Observed mass (M+1): 393.1. The following compounds were prepared as described in Example V above using appropriate starting materials. the reaction was degassed for 15 min The reaction was quenched with water extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over sodium sulfate concentrated under reduced pressure purified by silica gel column chromatography

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

Procedure: To a solution of 2, 4-dichloropyridine (0.500 g, 3.39 mmoL) and 4-amino-N-methylbenzamide (0.510 g, 3.39 mmoL) in dimethylacetamide (1 mL) was added cesium carbonate (1.6 g, 5.08 mmoL) and the reaction mixture was degassed for 15 min. Pd2(dba)3 (0.154 g, 0.169 mmol) and BINAP (105 mg, 0.169 mmol) were added and the reaction mixture was irradiated in the microwave at 120° C. for 1 h. Then reaction was quenched with water and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 38%) as a solid. Observed mass (M+1): 262.1 the reaction mixture was degassed for 15 min the reaction mixture was irradiated in the microwave at 120° C. for 1 h Then reaction was quenched with water extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography