but-1-ynyl(trimethyl)silane

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

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

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

Procedure: The title compound was prepared from 7-methoxybenzofuran-3-yl trifluoromethanesulfonate and Intermediate 39 following General Procedure B. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 7.26 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 2.52-2.47 (m, 2H), 1.21 (t, 3H). LCMS: 201 (M+H)+.

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

Procedure: The title compound was prepared from 7-methoxybenzofuran-3-yl trifluoromethanesulfonate and Intermediate 39 following General Procedure B. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 7.26 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 2.52-2.47 (m, 2H), 1.21 (t, 3H). LCMS: 201 (M+H)+.

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-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.2 g, 20.7 mmol; Intermediate 45), DMA (20 mL), CuI (393.3 mg, 2.07 mmol), Pd(OAc)2 (465.0 mg, 2.07 mmol), dppf (1.1 g, 2.07 mmol), Cs2CO3 (10.8 g, 33.1 mmol), and but-1-yn-1-yltrimethylsilane (3.4 g, 26.9 mmol; Intermediate 39) sequentially while N2 was bubbled through the solution. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (350 mL) and H2O (300 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with 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 EtOAc in petroleum ether (1:30) to afford the title compound as a yellow solid (3.9 g, yield 69.1%). 1H NMR (DMSO-d6, 400 MHz): δ 7.76-7.71 (m, 2H), 7.49 (d, 1H), 5.79 (dd, 1H), 3.88-3.85 (m, 1H), 3.74-3.71 (m, 1H), 2.44 (q, 2H), 2.24-2.21 (m, 1H), 2.01-1.91 (m, 2H), 1.70-1.65 (m, 1H), 1.57-1.54 (m, 2H), 1.18 (t, 3H); LCMS: 273 (M+H)+. was bubbled through the solution The reaction mixture was diluted with EtOAc (350 mL) and H2O (300 mL) filtered The organic layer of the filtrate was separated the aqueous layer was extracted with 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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed (3× vacuum/nitrogen cycles) solution of TBAF (4.0 mL, 0.5 M THF, 2.00 mmol), but-1-yn-1-yltrimethylsilane (267 mg, 2.11 mmol; Intermediate 39) was added. The solution was stirred at room temperature for a few minutes before transferring into a reaction vessel containing tert-butyl 7-fluoro-5-iodo-1H-indole-1-carboxylate (360 mg, 1.00 mmol), Pd(PPh3)4 (232 mg, 0.20 mmol), and CuI (76 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (100 mL), washed (50 mL water then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as brown oil (260 mg, 91%). 1H NMR (300 MHz, DMSO-d6): δ 7.85 (d, 1H), 7.58 (d, 1H), 7.21 (dd, 1H), 6.83 (dd, 1H), 2.51 (q, 2H), 1.68 (s, 9H), 1.26 (t, 3H). was added before transferring into a reaction vessel The reaction mixture was stirred at room temperature overnight washed (50 mL water 50 mL brine), dried over Na2SO4 concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: To a degassed (3× vacuum/nitrogen cycles) solution of TBAF (4.0 mL, 0.5 M THF, 2.00 mmol), but-1-yn-1-yltrimethylsilane (267 mg, 2.11 mmol; Intermediate 39) was added. The solution was stirred at room temperature for a few minutes before transferring into a reaction vessel containing tert-butyl 7-fluoro-5-iodo-1H-indole-1-carboxylate (360 mg, 1.00 mmol), Pd(PPh3)4 (232 mg, 0.20 mmol), and CuI (76 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (100 mL), washed (50 mL water then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as brown oil (260 mg, 91%). 1H NMR (300 MHz, DMSO-d6): δ 7.85 (d, 1H), 7.58 (d, 1H), 7.21 (dd, 1H), 6.83 (dd, 1H), 2.51 (q, 2H), 1.68 (s, 9H), 1.26 (t, 3H). was added before transferring into a reaction vessel The reaction mixture was stirred at room temperature overnight washed (50 mL water 50 mL brine), dried over Na2SO4 concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: Nitrogen was bubbled into a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.5 g, 25.33 mmol) and DMA (100 mL). After 5 min, CuI (241 mg, 1.27 mmol), Pd(OAc)2 (284 mg, 1.27 mmol), dppf (704 mg, 1.27 mmol), K2CO3 (4.89 g, 35.46 mmol), and but-1-yn-1-yltrimethylsilane (4.46 g, 35.46 mmol; Intermediate 39) were added sequentially with continued N2 bubbling. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (250 mL) and H2O (200 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (1:30 EtOAc/petroleum ether) to give the pure product as a yellow solid (3.6 g) and an impure product (2 g; further purified to give additional 1.47 g). 1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H), 7.68 (d, 1H), 7.26 (dd, 1H), 5.79 (dd, 1H), 3.92-3.87 (m, 1H), 3.69-3.60 (m, 1H), 2.47-2.34 (m, 1H), 2.43 (q, 2H), 2.07-2.02 (m, 2H), 1.76-1.69 (m, 1H), 1.57-1.50 (m, 2H), 1.17 (t, 3H); LCMS: 273 (M+H)+. filtered The organic layer of the filtrate was separated the aqueous layer was extracted with EtOAc (2×100 mL) The combined organic layers were washed with brine (3×50 mL) dried over anhydrous Na2SO4 concentrated purified by silica gel chromatography (1:30 EtOAc/petroleum ether)

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

Procedure: To a degassed (3× vacuum/nitrogen cycles) solution of TBAF (3.56 mL, 0.5 M THF, 1.78 mmol), but-1-yn-1-yltrimethylsilane (250 mg, 1.98 mmol; Intermediate 39) was added. The solution was stirred at rt for a few minutes before transferring into a reaction vessel containing 1-(5-iodo-1H-indol-1-yl)ethanone (254 mg, 089 mmol), Pd(PPh3)4 (203 mg, 0.18 mmol), and CuI (69 mg, 0.36 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed (50 mL saturated NaHCO3 then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as orange oil (180 mg, 96%). 1H NMR (300 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.89 (d, 1H), 7.64 (d, 1H), 7.32 (dd, 1H), 6.71 (d, 1H), 2.64 (s, 3H), 2.40 (q, 2H), 1.18 (t, 3H). was added before transferring into a reaction vessel The reaction mixture was stirred at room temperature overnight washed (50 mL saturated NaHCO3 50 mL brine), dried over Na2SO4 concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: Nitrogen was bubbled into a solution of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (19.7 g, 65.9 mmol; Intermediate 21) and DMA (60 mL). After 5 min, CuI (1.25 g, 6.6 mmol), Pd(OAc)2 (1.48 g, 6.6 mmol), dppf (3.66 g, 6.6 mmol), Cs2CO3 (34.3 g, 105.4 mmol), and but-1-yn-1-yltrimethylsilane (11.6 g, 92.3 mmol; Intermediate 39) were added sequentially with continued N2 bubbling. The resulting mixture was heated at 80° C. for 18 h under N2. The reaction mixture was diluted with EtOAc (900 mL) and H2O (500 mL) and then filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (1:30 EtOAc/petroleum ether) to give the title compound (15.2 g) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.26 (s, 1H), 7.57 (d, 1H), 7.42 (dd, 1H), 5.87 (dd, 1H), 3.90-3.86 (m, 1H), 3.78-3.71 (m, 1H), 2.48 (q, 2H), 2.40-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.71 (m, 1H), 1.59-1.57 (m, 2H), 1.19 (t, 3H); LCMS: 273 (M+H)+. filtered The organic layer of the filtrate was separated the aqueous layer was extracted with EtOAc (2×100 mL) The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na2SO4 concentrated purified by silica gel chromatography (1:30 EtOAc/petroleum ether)

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

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