2-propan-2-ylpyrrolidine;hydrochloride

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

Procedure: To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H). Upon completion of the addition the reaction mixture was cooled back to 0° C. quenched with dimethyl sulfide ( 0.54 mL, 7.34 mmol, dropwise addition) to warm to room temperature The mixture was cooled to 0° C. diluted with Et2O (5 mL) Et2O and hexane (15 mL) The resulting orange precipitate was filtered transferred to a 25 mL sealable tube under nitrogen the tube was sealed the reaction mixture was stirred overnight at 95° C was added the reaction mixture was stirred overnight at 95° C The reaction was cooled to room temperature decanted The solution was concentrated the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O The resulting mixture was filtered through a 0.45μ frit purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA)

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

Procedure: To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H). Upon completion of the addition the reaction mixture was cooled back to 0° C. quenched with dimethyl sulfide ( 0.54 mL, 7.34 mmol, dropwise addition) to warm to room temperature The mixture was cooled to 0° C. diluted with Et2O (5 mL) Et2O and hexane (15 mL) The resulting orange precipitate was filtered transferred to a 25 mL sealable tube under nitrogen the tube was sealed the reaction mixture was stirred overnight at 95° C was added the reaction mixture was stirred overnight at 95° C The reaction was cooled to room temperature decanted The solution was concentrated the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O The resulting mixture was filtered through a 0.45μ frit purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA)

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

Procedure: To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H). Upon completion of the addition the reaction mixture was cooled back to 0° C. quenched with dimethyl sulfide ( 0.54 mL, 7.34 mmol, dropwise addition) to warm to room temperature The mixture was cooled to 0° C. diluted with Et2O (5 mL) Et2O and hexane (15 mL) The resulting orange precipitate was filtered transferred to a 25 mL sealable tube under nitrogen the tube was sealed the reaction mixture was stirred overnight at 95° C was added the reaction mixture was stirred overnight at 95° C The reaction was cooled to room temperature decanted The solution was concentrated the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O The resulting mixture was filtered through a 0.45μ frit purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA)