2-bromo-6-methylaniline

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

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-6-methylaniline (1.080 mL, 8.58 mmol), 4-chloro-3-methyl-1H-pyrazole (1.0 g, 8.58 mmol), potassium carbonate (2.49 g, 18.02 mmol), and copper(I) iodide (0.082 g, 0.429 mmol) were added to a RBF which was evacuated and flushed with N2 3×. Toluene (9 mL) (degassed by bubbling N2 through solution for 10 minutes) and N1,N2-dimethylethane-1,2-diamine (0.185 mL, 1.716 mmol) were added and the mixture was heated in an oil bath at 110° C. After 18 h, the reaction was allowed to cool, diluted with EtOAc, and 10:1 saturated ammonium chloride/ammonium hydroxide. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes to provide 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylaniline. was evacuated flushed with N2 3× to cool The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo to give the crude material The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-6-methylaniline (1.080 mL, 8.58 mmol), 4-chloro-3-methyl-1H-pyrazole (1.0 g, 8.58 mmol), potassium carbonate (2.49 g, 18.02 mmol), and copper(I) iodide (0.082 g, 0.429 mmol) were added to a RBF which was evacuated and flushed with N2 3×. Toluene (9 mL) (degassed by bubbling N2 through solution for 10 minutes) and N1,N2-dimethylethane-1,2-diamine (0.185 mL, 1.716 mmol) were added and the mixture was heated in an oil bath at 110° C. After 18 h, the reaction was allowed to cool, diluted with EtOAc, and 10:1 saturated ammonium chloride/ammonium hydroxide. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes to provide 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylaniline. was evacuated flushed with N2 3× to cool The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo to give the crude material The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes

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

Procedure: To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+). The mixture was irradiated in a microwave at 220° C. for 40 minutes the product was extracted with dichloromethane (3×20 mL) washed with water and brine dried over MgSO4 concentrated The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized

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

Procedure: To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+). The mixture was irradiated in a microwave at 220° C. for 40 minutes the product was extracted with dichloromethane (3×20 mL) washed with water and brine dried over MgSO4 concentrated The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized

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

Procedure: To a solution of 2-bromo-6-methylaniline (0.5 g, 2.69 mmol) in acetonitrile (30.0 mL) at ambient temperature was added a 37% aqueous solution of formaldehyde (4.0 mL, 53.6 mmol), followed by NaBH3CN (1.40 g, 22.1 mmol). The pH of the reaction was adjusted to pH 5-6 with glacial acetic acid, and the reaction was stirred for 4 h, then the solvent was removed. The residue was dissolved in EtOAc, and basified with NaOH 2N, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent to produce Compound 150 as a clear oil. the solvent was removed The residue was dissolved in EtOAc dried over MgSO4 filtered The solvent was removed the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent

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

Procedure: To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+). The mixture was irradiated in a microwave at 220° C. for 40 minutes the product was extracted with dichloromethane (3×20 mL) washed with water and brine dried over MgSO4 concentrated The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized

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

Procedure: To a solution of 2-bromo-6-methylaniline (0.5 g, 2.69 mmol) in acetonitrile (30.0 mL) at ambient temperature was added a 37% aqueous solution of formaldehyde (4.0 mL, 53.6 mmol), followed by NaBH3CN (1.40 g, 22.1 mmol). The pH of the reaction was adjusted to pH 5-6 with glacial acetic acid, and the reaction was stirred for 4 h, then the solvent was removed. The residue was dissolved in EtOAc, and basified with NaOH 2N, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent to produce Compound 150 as a clear oil. the solvent was removed The residue was dissolved in EtOAc dried over MgSO4 filtered The solvent was removed the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent

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

Procedure: To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+). The mixture was irradiated in a microwave at 220° C. for 40 minutes the product was extracted with dichloromethane (3×20 mL) washed with water and brine dried over MgSO4 concentrated The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized

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

Procedure: To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+). The mixture was irradiated in a microwave at 220° C. for 40 minutes the product was extracted with dichloromethane (3×20 mL) washed with water and brine dried over MgSO4 concentrated The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-6-methylaniline (1.080 mL, 8.58 mmol), 4-chloro-3-methyl-1H-pyrazole (1.0 g, 8.58 mmol), potassium carbonate (2.49 g, 18.02 mmol), and copper(I) iodide (0.082 g, 0.429 mmol) were added to a RBF which was evacuated and flushed with N2 3×. Toluene (9 mL) (degassed by bubbling N2 through solution for 10 minutes) and N1,N2-dimethylethane-1,2-diamine (0.185 mL, 1.716 mmol) were added and the mixture was heated in an oil bath at 110° C. After 18 h, the reaction was allowed to cool, diluted with EtOAc, and 10:1 saturated ammonium chloride/ammonium hydroxide. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes to provide 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylaniline. was evacuated flushed with N2 3× to cool The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo to give the crude material The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes