oxetan-3-ylmethyl methanesulfonate

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 from Example 242, step 1 was reacted in a manner similar to Example 245 except that 1,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)+

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

Procedure: Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring 1 h, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18 h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 404.1 (M+1)+ stirring continued for 18 h EA extractive work up from 1 M HCl and preparative HPLC purification

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

Procedure: The title compound from Example 242, step 1 was reacted in a manner similar to Example 245 except that 1,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)+

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

Procedure: Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring 1 h, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18 h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 404.1 (M+1)+ stirring continued for 18 h EA extractive work up from 1 M HCl and preparative HPLC purification

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

Procedure: Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring 1 h, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18 h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 404.1 (M+1)+ stirring continued for 18 h EA extractive work up from 1 M HCl and preparative HPLC purification

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-nitropyrazole (1000 mg, 8.80 mmol), oxetan-3-ylmethyl methanesulfonate (1.90 g, 11.0 mmol), cesium carbonate (8.70 g, 27.0 mmol) and acetonitrile (13 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature, saturated ammonium chloride was added. The mixture was extracted with methylene chloride 3×. Combined organics were dried (Na2SO4) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography eluting with 0 to 70% ethyl acetate in heptane to give 4-nitro-1-(oxetan-3-ylmethyl)pyrazole (1.60 g, 99%). The mixture was cooled to room temperature The mixture was extracted with methylene chloride 3× Combined organics were dried (Na2SO4) the solvent removed under reduced pressure The crude product was purified by flash chromatography eluting with 0 to 70% ethyl acetate in heptane

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

Procedure: Oxetan-3-ylmethanol (1.85 g, 21.0 mmol) was dissolved in methylene chloride and cooled to 0° C. Triethylamine (5.31 g, 52.2 mmol) was added followed by slow addition of methanesulfonyl chloride (2.89 g, 25.2 mmol). The mixture was allowed to warm to ambient temperature for 2 h and quenched with sat. sodium bicarbonate (14 mL). The aqueous solution was extracted with methylene chloride 3×. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude oxetan-3-ylmethyl methanesulfonate (quant.). to warm to ambient temperature for 2 h quenched with sat. sodium bicarbonate (14 mL) The aqueous solution was extracted with methylene chloride 3× The combined organic layers were dried over sodium sulfate filtered concentrated

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

Procedure: The title compound from Example 242, step 1 was reacted in a manner similar to Example 245 except that 1,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)+