diethylamino(difluoro)sulfanium;tetrafluoroborate

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:

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

Procedure: To a solution of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (3.4 g, 11.8 mmol; Intermediate 33, Step 1) in dry dichloromethane (100 mL), was added triethylamine.3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g, 34.9 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether), and then re-crystallized from petroleum ether to afford the title compound (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291 (M+H)+. The organic layer was dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether) re-crystallized from petroleum ether

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

Procedure: To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 20) in dry dichloromethane (25 mL), was added triethylamine.3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+. The organic layer was dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether)

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

Procedure: To a cooled (0° C.) solution of XtalFluor-E (4.50 g, 19.65 mmol) in dichloromethane (50 mL) was added a solution of 4-formyl-N-CBZ-piperidine (2.30 g, 9.30 mmol, Oakwood) in dichloromethane (7 mL) followed by triethylamine trihydrofluoride (3.00 mL, 18.40 mmol). The reaction was allowed to warm to room temperature overnight. Then the reaction mixture was cooled to 0° C. and quenched slowly with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco 40 g) eluting with (EtOAc):hexanes (0:1→1:1) to give benzyl 4-(difluoromethyl)piperidine-1-carboxylate as a light-yellow oil (1.16 g, 46% yield). Then the reaction mixture was cooled to 0° C. quenched slowly with saturated NaHCO3 solution The layers were separated the aqueous layer was extracted with dichloromethane (3×) The combined organic layers were evaporated onto silica gel purified by flash chromatography (Isco 40 g) eluting with (EtOAc)

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

Procedure: To a solution of 1-(2-bromophenyl)ethanol (1 g, 4.97 mmol) in DCM (12 mL) was added triethylamine trihydrofluoride (1.621 mL, 9.95 mmol) and XtalFluor-E® (1.708 g, 7.46 mmol) dropwise over 5 min. After addition the resulting mixture was stirred at room temperature for 1 h and then cooled to 0° C. and quenched by addition of sat. aq. NaHCO3. The layers were separated and the aqueous was extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 1-bromo-2-(1-fluoroethyl)benzene. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (dd, J=7.8, 1.8 Hz, 1H), 7.38 (td, J=7.6, 1.3 Hz, 1H), 7.19 (td, J=7.7, 1.7 Hz, 1H), 5.90 (dq, J=46.6, 6.4 Hz, 1H), 1.60 (dd, J=3-24.2, 6.5 Hz, 3H). After addition the resulting mixture cooled to 0° C. quenched by addition of sat. aq. NaHCO3 The layers were separated the aqueous was extracted with DCM (2×) The combined organic layers were dried over anhydrous MgSO4 filtered concentrated in vacuo

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

Procedure: To a solution of tert-butyl 4-(6-((1S,45)-4-(benzoyloxy)-3-oxocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (730 mg, 1.034 mmol) in DCM (7 mL) at RT was added XtalFlour-E (939 mg, 4.14 mmol) followed by triethylamine trihydrofluoride (0.674 mL, 4.14 mmol). The resultant mixture was stirred at RT for 5 hours. The mixture was filtered and the filtered solution was directly applied for ISCO separation: 24 g silica gel, 0 to 70% EtOAc in Heptane, 30 min. A light yellow solid (670 mg, 0.902 mmol, 87% yield) was obtained. LC-MS (m/z): (MH+) 728.0 at 0.95 min (non-polar MS method). 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 2H) 1.19-1.39 (m, 21H) 1.48-1.68 (m, 11H) 1.86-2.08 (m, 2H) 2.08-2.21 (m, 1H) 2.26-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.21-3.44 (m, 1H) 5.22-5.51 (m, 1H) 7.41-7.55 (m, 4H) 7.60 (s, 1H) 7.96 (d, J=7.82 Hz, 1H) 8.06-8.19 (m, 2H) 8.42 (s, 1H). The mixture was filtered the filtered solution was directly applied for ISCO separation 24 g silica gel, 0 to 70% EtOAc in Heptane, 30 min

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

Procedure: To a stirred solution of triethylamine trihydrofluoride (2.72 mL, 16.7 mmol) and triethylamine (1.17 mL, 8.41 mmol) in dichloromethane (30 mL) was added Xtalfluor-E (2.9 g, 12.6 mmol) at 0° C. To the solution was then added methyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-oxocyclohexyl)-D-alaninate (3 g, 8.37 mmol) slowly. An additional amount of Xtalfluor-E (2.9 g, 12.6 mmol) was added after 3 h, and resulting mixture was stirred at rt for 9 h. The reaction mixture was quenched with a 5% aqueous NaHCO3 solution. The resulting mixture was extracted with dichloromethane (40 mL×3). The organic phases were combined, dried over Na2SO4, evaporated to give the crude material, which was then purified by silica gel column chromatography to give the desired product (2.2 g). 1HNMR (300 MHz, CDCl3): δ 1.60-1.99 (m, 6H), 2.19-2.24 (m, 3H), 3.16-3.25 (m, 3H), 3.75 (s, 3H), 4.06 (q, J=6.9 Hz, 1H), 8.65 (s, 1H). resulting mixture The reaction mixture was quenched with a 5% aqueous NaHCO3 solution The resulting mixture was extracted with dichloromethane (40 mL×3) dried over Na2SO4 evaporated to give the crude material, which was then purified by silica gel column chromatography