N-(3-bromophenyl)methanesulfonamide

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

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

Procedure: The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylsulfonylamino-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours. The product was obtained in 35% yield. A sample was obtained by recrystallization from ethyl acetate for analysis: mp 100°-101 ° C. Analysis calculated for C22H25N3O2S·1.5 H2O: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89. with a heating time of 1.5 hours The product was obtained in 35% yield

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

Procedure: To a stirred solution of 3-bromo aniline (6 g, 34.87 mmol) in dry DCM (200 ml) at 10° C. was added pyridine (4.13 mg, 52.31 mmol) followed by methane sulfonyl chloride (5.194 g, 45.34 mmol) and stirred at RT for 15 h. The reaction was monitored by TLC (35% Ethyl acetate in hexane). The reaction mixture was diluted with DCM (50 ml) and washed with 1N HCl (25 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 8.45 g (96.3% yield) of N-(3-bromophenyl) methanesulfonamide. 1H NMR (DMSO-d6, 300 MHz): δ 10.01 (s, 1H), 7.368 (s, 1H), 7.365-7.19 (m, 3H), 3.03 (s, 1H). MS: m/z=251.8 (M+1). washed with 1N HCl (25 ml) The organic layer was dried over Na2SO4 concentrated 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: 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: The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylsulfonylamino-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours. The product was obtained in 35% yield. A sample was obtained by recrystallization from ethyl acetate for analysis: mp 100°-101 ° C. Analysis calculated for C22H25N3O2S·1.5 H2O: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89. with a heating time of 1.5 hours The product was obtained in 35% yield

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:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(3-Bromophenyl)methanesulfonamide 0.36 g, N,N-dicyclohexylmethylamine 0.41 mL and palladium acetate 5.4 mg were added to N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g at room temperature, and it was stirred at 130° C. for 4 hours. N-(3-bromophenyl)methanesulfonamide 0.12 g, N,N-dicyclohexylmethylamine 0.10 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 5.4 mg were added to it, and it was stirred at 130° C. for 2 hours. (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 11 mg and tri-tert-butylphosphine tetrafluoroborate 6.9 mg were added to it, and it was stirred at 130° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=1:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-(methanesulfonamido)phenyl)vinyl)benzoate. was stirred at 130° C. for 2 hours was stirred at 130° C. for 8 hours After the reaction mixture was cooled to room temperature The organic layer was separated collected the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution

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

Procedure: The m-bromo aniline was dissolved in 40 mL of pyridine and cooled to 0° C. followed by addition of methansulfonyl chloride dropwise via syringe. After 10 minutes, the solution was warmed to room temperature and stirred for 4 hours. Upon concentration the residue was partitioned between 350 mL of H2O and 500 mL of dichloromethane in a separatory funnel. The organics were separated and washed with 100 mL of 3N HCl, 200 mL of sat'd NaHCO3 and dried over MgSO4. Upon filtration and concentration in vacuo an off-white solid was obtained. This product was recrystallized from dichloromethane/hexanes to afford 6.7 g (90%) of the desired product as white needles. the solution was warmed to room temperature Upon concentration the residue was partitioned between 350 mL of H2O and 500 mL of dichloromethane in a separatory funnel The organics were separated washed with 100 mL of 3N HCl, 200 mL of sat'd NaHCO3 dried over MgSO4 Upon filtration and concentration in vacuo an off-white solid was obtained This product was recrystallized from dichloromethane/hexanes

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