N-(3-bromophenyl)-N-methylmethanesulfonamide

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

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

Procedure: 169 b) A suspension of N-(3-bromo-phenyl)-N-methyl-methanesulfonamide (1.0 g, 3.8 mmol) and copper cyanide (0.78 g, 8.7 mmol) in N,N-dimethylformamide (5 mL) was heated at 150° C. for 18 hours. The mixture was cooled to room temperature. A solution of potassium cyanide (5 g) and water (50 mL) was added to the vigorously stirred dark mixture and was stirred for 1 hour. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL) then saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to a yellow oil (1.0 g). The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane). N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a tan solid (0.184 g, 23%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69-7.64 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.54-7.49 (m, 1H), 3.36 (s, 3H), 2.88 (s, 3H). MS=211 (MH)+. The mixture was cooled to room temperature The mixture was extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with water (2×30 mL) saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate filtered The filtrate was evaporated to a yellow oil (1.0 g) The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane)

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

Procedure: To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+. filtered through a plug of diatomaceous earth evaporated under reduced pressure

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

Procedure: To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+. filtered through a plug of diatomaceous earth evaporated under reduced pressure

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

Procedure: A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m). was added dropwise over 5 minutes stirring The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml) The organic layer was dried over sodium sulphate the solvent removed under reduced pressure

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

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

Procedure: A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m). was added dropwise over 5 minutes stirring The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml) The organic layer was dried over sodium sulphate the solvent removed under reduced pressure

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

Procedure: 169 a) To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+. 169 b) A suspension of N-(3-bromo-phenyl)-N-methyl-methanesulfonamide (1.0 g, 3.8 mmol) and copper cyanide (0.78 g, 8.7 mmol) in N,N-dimethylformamide (5 mL) was heated at 150° C. for 18 hours. The mixture was cooled to room temperature. A solution of potassium cyanide (5 g) and water (50 mL) was added to the vigorously stirred dark mixture and was stirred for 1 hour. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL) then saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to a yellow oil (1.0 g). The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane). N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a tan solid (0.184 g, 23%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69-7.64 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.54-7.49 (m, 1H), 3.36 (s, 3H), 2.88 (s, 3H). MS=211 (MH)+. 169 c) -(3-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide (0.184 g, 0.875 mmol) in a manner analogous to Example 156b. Product isolated as a tan viscous oil (0.184 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.39-7.33 (m, 2H), 7.28-7.23 (m, 2H), 3.90 (s, 2H), 3.33 (s, 3H), 2.86 (s, 3H). MS=215 (MH)+. 169 d) N-{3-[(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 (184.0 mg, 0.7915 mmol) and N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide (188.0 mg, 0.8773 mmol) in a manner analogous to Example 2d. Product isolated as a yellow resin (0.082 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.89 (d, J=6.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.33-7.29 (m, 2H), 6.85 (t, J=7.4 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 5.43-5.38 (m, 1H), 4.49 (d, J=5.7 Hz, 2H), 3.32 (s, 3H), 2.83 (s, 3H). MS=366, 368 (MH)+. 169 e) N-Methyl-N-[3-({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-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (82.0 mg, 0.224 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (48.0 mg, 0.251 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.024 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.82 (d, J=6.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.42-7.28 (m, 4H), 6.96 (d, J=8.8 Hz, 2H), 6.65 (t, J=7.2 Hz, 1H), 6.54 (s, 1H), 6.29 (d, J=7.6 Hz, 1H), 5.19 (t, J=5.6 Hz, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.30 (s, 3H), 3.17-3.13 (m, 4H), 2.81 (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 (3×20 mL) The combined organic layers were washed with water (2×30 mL) saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate filtered The filtrate was evaporated to a yellow oil (1.0 g) The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane)

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

Procedure: 169 a) To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+. 169 b) A suspension of N-(3-bromo-phenyl)-N-methyl-methanesulfonamide (1.0 g, 3.8 mmol) and copper cyanide (0.78 g, 8.7 mmol) in N,N-dimethylformamide (5 mL) was heated at 150° C. for 18 hours. The mixture was cooled to room temperature. A solution of potassium cyanide (5 g) and water (50 mL) was added to the vigorously stirred dark mixture and was stirred for 1 hour. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL) then saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to a yellow oil (1.0 g). The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane). N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a tan solid (0.184 g, 23%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69-7.64 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.54-7.49 (m, 1H), 3.36 (s, 3H), 2.88 (s, 3H). MS=211 (MH)+. 169 c) -(3-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide (0.184 g, 0.875 mmol) in a manner analogous to Example 156b. Product isolated as a tan viscous oil (0.184 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.39-7.33 (m, 2H), 7.28-7.23 (m, 2H), 3.90 (s, 2H), 3.33 (s, 3H), 2.86 (s, 3H). MS=215 (MH)+. 169 d) N-{3-[(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 (184.0 mg, 0.7915 mmol) and N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide (188.0 mg, 0.8773 mmol) in a manner analogous to Example 2d. Product isolated as a yellow resin (0.082 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.89 (d, J=6.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.33-7.29 (m, 2H), 6.85 (t, J=7.4 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 5.43-5.38 (m, 1H), 4.49 (d, J=5.7 Hz, 2H), 3.32 (s, 3H), 2.83 (s, 3H). MS=366, 368 (MH)+. 169 e) N-Methyl-N-[3-({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-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (82.0 mg, 0.224 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (48.0 mg, 0.251 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.024 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.82 (d, J=6.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.42-7.28 (m, 4H), 6.96 (d, J=8.8 Hz, 2H), 6.65 (t, J=7.2 Hz, 1H), 6.54 (s, 1H), 6.29 (d, J=7.6 Hz, 1H), 5.19 (t, J=5.6 Hz, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.30 (s, 3H), 3.17-3.13 (m, 4H), 2.81 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+. filtered through a plug of diatomaceous earth evaporated under reduced pressure

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

Procedure: 169 b) A suspension of N-(3-bromo-phenyl)-N-methyl-methanesulfonamide (1.0 g, 3.8 mmol) and copper cyanide (0.78 g, 8.7 mmol) in N,N-dimethylformamide (5 mL) was heated at 150° C. for 18 hours. The mixture was cooled to room temperature. A solution of potassium cyanide (5 g) and water (50 mL) was added to the vigorously stirred dark mixture and was stirred for 1 hour. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL) then saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to a yellow oil (1.0 g). The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane). N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a tan solid (0.184 g, 23%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69-7.64 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.54-7.49 (m, 1H), 3.36 (s, 3H), 2.88 (s, 3H). MS=211 (MH)+. The mixture was cooled to room temperature The mixture was extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with water (2×30 mL) saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate filtered The filtrate was evaporated to a yellow oil (1.0 g) The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane)

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

Procedure: To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+. filtered through a plug of diatomaceous earth evaporated under reduced pressure

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

Procedure: A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m). was added dropwise over 5 minutes stirring The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml) The organic layer was dried over sodium sulphate the solvent removed under reduced pressure