N-(2-cyanophenyl)-N-methylmethanesulfonamide

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

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

Procedure: N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+. The mixture was degassed filtered through a plug of diatomaceous earth rinsed with dichloromethane The filtrate was evaporated under reduced pressure

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

Procedure: N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+. The mixture was degassed filtered through a plug of diatomaceous earth rinsed with dichloromethane The filtrate was evaporated under reduced pressure

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

Procedure: To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+. The mixture was cooled to room temperature The mixture was extracted with ethyl acetate (75 mL) The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL) dried over magnesium sulfate filtered evaporated to a waxy solid The recovered solid was triturated with hexane filtered dried

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

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

Procedure: To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+. 147b) N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+. 147c) N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.74 g, 3.2 mmol) and N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamide (0.76 g, 3.5 mmol) in a manner analogous to Example 2d. Product isolated as a white foam (0.847 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.87 (d, J=6.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.40-7.28 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.38 (t, J=5.4 Hz, 1H), 4.73 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.00 (s, 3H). MS=366 (MH)+. 147d) N-Methyl-N-[2-({2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.053 g, 50%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79 (d, J=6.6 Hz, 1H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.38-7.28 (m, 3H), 6.95 (d, J=8.8 Hz, 2H), 6.65 (t, J=7.5 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J=7.7 Hz, 1H), 5.21 (t, J=6.0 Hz, 1H), 4.71 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.18-3.12 (m, 4H), 3.00 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+. The mixture was degassed filtered through a plug of diatomaceous earth rinsed with dichloromethane The filtrate was evaporated under reduced pressure

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

Procedure: To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+. 147b) N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+. 147c) N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.74 g, 3.2 mmol) and N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamide (0.76 g, 3.5 mmol) in a manner analogous to Example 2d. Product isolated as a white foam (0.847 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.87 (d, J=6.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.40-7.28 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.38 (t, J=5.4 Hz, 1H), 4.73 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.00 (s, 3H). MS=366 (MH)+. 147d) N-Methyl-N-[2-({2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.053 g, 50%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79 (d, J=6.6 Hz, 1H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.38-7.28 (m, 3H), 6.95 (d, J=8.8 Hz, 2H), 6.65 (t, J=7.5 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J=7.7 Hz, 1H), 5.21 (t, J=6.0 Hz, 1H), 4.71 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.18-3.12 (m, 4H), 3.00 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+. The mixture was cooled to room temperature The mixture was extracted with ethyl acetate (75 mL) The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL) dried over magnesium sulfate filtered evaporated to a waxy solid The recovered solid was triturated with hexane filtered dried

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

Procedure: To a solution of N-(2-cyanophenyl)-N-methylmethanesulfonamide (16.0 g, 76 mmol) in a solution of ammonia in ethanol (500 mL, 4 mol·L−1) was added palladium on carbon (10%, 4 g). The mixture was stirred under an atmosphere of hydrogen for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was washed with ether to give N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide (14.2 g, yield 87.1%). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.55 (m, 1H), 7.36-7.40 (m, 1H), 7.29-7.33 (m, 1H), 7.23-7.25 (m, 1H), 3.97-3.99 (br d, 2H, J=8.0 Hz), 3.27 (s, 3H), 3.00 (s, 3H). N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide was dissolved in ether and bubbled in hydrochloride (gas) to afford the product N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide hydrochloride (15.0 g, yield 90.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.55 (m, 1H), 7.35-7.40 (m, 1H), 7.28-7.33 (m, 1H), 7.24-7.26 (m, 1H), 3.99 (br s, 2H), 3.25 (s, 3H), 2.98 (s, 3H). The catalyst was removed by filtration the filtrate was evaporated The residue was washed with ether

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

Procedure: To a solution of cesium carbonate (55.78 g, 171 mmol) in acetonitrile (500 mL) at room temperature was added N-methylmethane-sulfonamide (14.0 g, 0.128 mol). 2-Fluoro-benzonitrile (10.37 g, 86 mmol) was then added in portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 12 hours. Upon completion, the mixture was filtered and then concentrated. The residue diluted with water and extracted by dichloromethane. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate and evaporated to afford the product N-(2-cyanophenyl)-N-methylmethane-sulfonamide (16.0 g, yield 88.9%). 1H NMR (400 MHz, CDCl3) δ ppm 7.62-7.73 (m, 2H), 7.54-7.56 (m, 1H), 7.45-7.50 (m, 1H), 3.40 (s, 3H), 3.14 (s, 3H). Upon completion, the mixture was filtered concentrated The residue diluted with water extracted by dichloromethane washed by brine dried over anhydrous sodium sulfate evaporated

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

Procedure: N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+. The mixture was degassed filtered through a plug of diatomaceous earth rinsed with dichloromethane The filtrate was evaporated under reduced pressure

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

Procedure: To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+. The mixture was cooled to room temperature The mixture was extracted with ethyl acetate (75 mL) The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL) dried over magnesium sulfate filtered evaporated to a waxy solid The recovered solid was triturated with hexane filtered dried