3-cyclopropylprop-1-ynyl(trimethyl)silane

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

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

Procedure: To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.0 g, 14.3 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.0 g, 1.43 mmol), CuI (271 mg, 1.43 mmol), TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF (20 mL), was added (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (7.9 g, 42.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound as yellow solid (3.4 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H), 2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H), 1.60-1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m, 2H); LCMS: 281 (M+H)+. filtered The filtrate was washed with water (3×10 mL) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75˜110° C. then distillation at 138˜142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). re-cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to warm to room temperature stirred overnight Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially The organic layer was dried over anhydrous sodium sulfate Hexane and THF was distilled off at 75˜110° C. distillation at 138˜142° C.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75˜110° C. then distillation at 138˜142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). re-cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to warm to room temperature stirred overnight Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially The organic layer was dried over anhydrous sodium sulfate Hexane and THF was distilled off at 75˜110° C. distillation at 138˜142° C.

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75˜110° C. then distillation at 138˜142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). re-cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to warm to room temperature stirred overnight Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially The organic layer was dried over anhydrous sodium sulfate Hexane and THF was distilled off at 75˜110° C. distillation at 138˜142° C.

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

Procedure: To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.0 g, 14.3 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.0 g, 1.43 mmol), CuI (271 mg, 1.43 mmol), TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF (20 mL), was added (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (7.9 g, 42.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound as yellow solid (3.4 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H), 2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H), 1.60-1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m, 2H); LCMS: 281 (M+H)+. filtered The filtrate was washed with water (3×10 mL) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75110° C. then distillation at 138142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). re-cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to warm to room temperature stirred overnight Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially The organic layer was dried over anhydrous sodium sulfate Hexane and THF was distilled off at 75110° C. distillation at 138142° C.

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

Procedure: To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.0 g, 14.3 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.0 g, 1.43 mmol), CuI (271 mg, 1.43 mmol), TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF (20 mL), was added (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (7.9 g, 42.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound as yellow solid (3.4 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H), 2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H), 1.60-1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m, 2H); LCMS: 281 (M+H)+. filtered The filtrate was washed with water (3×10 mL) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75˜110° C. then distillation at 138˜142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). re-cooled to −78° C the mixture was stirred at −78° C. for 30 minutes to warm to room temperature stirred overnight Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially The organic layer was dried over anhydrous sodium sulfate Hexane and THF was distilled off at 75˜110° C. distillation at 138˜142° C.

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