2-cyclobutylethynyl(trimethyl)silane

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

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

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

Procedure: A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 48) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+. was bubbled through the mixture The reaction mixture was cooled to room temperature diluted with EtOAc (100 mL) and H2O (100 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with additional EtOAc (2×50 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified on a silica gel column

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

Procedure: A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 48) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+. was bubbled through the mixture The reaction mixture was cooled to room temperature diluted with EtOAc (100 mL) and H2O (100 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with additional EtOAc (2×50 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified on a silica gel column

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

Procedure: To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H). cooled to −78° C to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL) extracted with pentane (2×200 mL) The combined organic layers were washed with brine (500 mL) dried over anhydrous Na2SO4 The solvent was evaporated on a rotary evaporator The residue was distilled at 160-162° C./760 Torr

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

Procedure: A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 42) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+. was bubbled through the mixture The reaction mixture was cooled to room temperature diluted with EtOAc (100 mL) and H2O (100 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with additional EtOAc (2×50 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified on a silica gel column

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

Procedure: To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H). cooled to −78° C to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL) extracted with pentane (2×200 mL) The combined organic layers were washed with brine (500 mL) dried over anhydrous Na2SO4 The solvent was evaporated on a rotary evaporator The residue was distilled at 160-162° C./760 Torr

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

Procedure: A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 42) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0˜10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+. was bubbled through the mixture The reaction mixture was cooled to room temperature diluted with EtOAc (100 mL) and H2O (100 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with additional EtOAc (2×50 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified on a silica gel column

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

Procedure: To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H). cooled to −78° C to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL) extracted with pentane (2×200 mL) The combined organic layers were washed with brine (500 mL) dried over anhydrous Na2SO4 The solvent was evaporated on a rotary evaporator The residue was distilled at 160-162° C./760 Torr

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

Procedure: A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 48) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+. was bubbled through the mixture The reaction mixture was cooled to room temperature diluted with EtOAc (100 mL) and H2O (100 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with additional EtOAc (2×50 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified on a silica gel column

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

Procedure: To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H). cooled to −78° C to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL) extracted with pentane (2×200 mL) The combined organic layers were washed with brine (500 mL) dried over anhydrous Na2SO4 The solvent was evaporated on a rotary evaporator The residue was distilled at 160-162° C./760 Torr