4-(iodomethyl)oxan-4-ol

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

Procedure: To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL) was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) at ambient temperature. After being stirred at room temperature for 1 h, 4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77 Step 1) was added to the mixture. The mixture was heated at 70° C. and stirred for 3 days. After cooling to room temperature, aq. citric acid was added to the mixture. The mixture was extracted with ethyl acetate twice and washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford 72 mg of crude oil. The residual oil was purified by preparative HPLC purification. The mixture was heated at 70° C. stirred for 3 days After cooling to room temperature The mixture was extracted with ethyl acetate twice washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine dried over sodium sulfate concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile

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

Procedure: To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL) was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) at ambient temperature. After being stirred at room temperature for 1 h, 4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77 Step 1) was added to the mixture. The mixture was heated at 70° C. and stirred for 3 days. After cooling to room temperature, aq. citric acid was added to the mixture. The mixture was extracted with ethyl acetate twice and washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford 72 mg of crude oil. The residual oil was purified by preparative HPLC purification. The mixture was heated at 70° C. stirred for 3 days After cooling to room temperature The mixture was extracted with ethyl acetate twice washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine dried over sodium sulfate concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile

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

Procedure: To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL) was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) at ambient temperature. After being stirred at room temperature for 1 h, 4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77 Step 1) was added to the mixture. The mixture was heated at 70° C. and stirred for 3 days. After cooling to room temperature, aq. citric acid was added to the mixture. The mixture was extracted with ethyl acetate twice and washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford 72 mg of crude oil. The residual oil was purified by preparative HPLC purification. The mixture was heated at 70° C. stirred for 3 days After cooling to room temperature The mixture was extracted with ethyl acetate twice washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine dried over sodium sulfate concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 N aq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL) was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) of tetrahydro-4H-pyran-4-one was added to the mixture and the mixture was stirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g (23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57 mmol) were added to the mixture. After being stirred at room temperature for 19 h, ethyl acetate was added to the mixture. The mixture was extracted with ethyl acetate three times and the extracts were combined. The extracts were dried over sodium sulfate and concentrated in vacuo to afford a beige solid. The residual solid was recrystallized from acetonitrile to afford 3.13 g (55%) of the title compound. After cooling to room temperature After being stirred at room temperature for 19 h The mixture was extracted with ethyl acetate three times The extracts were dried over sodium sulfate concentrated in vacuo to afford a beige solid The residual solid was recrystallized from acetonitrile