(1-methylcyclopropyl)methanol

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

Procedure: 1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+. The resulting mixture then was stirred at room temperature overnight

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

Procedure: Treat a 0° C. solution of (1-methylcyclopropyl)methanol (1.0 g, 11.61 mmol) in DCM (50 mL) with TEA (1.29 g, 12.77 mmol), add methanesulfonyl chloride (1.46 g, 12.77 mmol) drop-wise and stir at 0° C. for 2 h. Warm the mixture to RT, wash with H2O, then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (1.85 g, 97%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (s, 2H), 3.20 (s, 3H), 1.17 (s, 3H), 0.59 (m, 2H), 0.47 (m, 2H). Warm the mixture to RT wash with H2O brine, dry over Na2SO4 concentrate to dryness

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

Procedure: Prepared as in Example 166d from (1-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.44-0.46 (m, 2H), 0.57-0.59 (m, 2H), 1.22 (s, 3H), 4.06 (s, 2H), 7.67 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.85-7.92 (m, 2H).

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

Procedure: 2.98 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.59 g of 2,5-dimethyl-4-nitrophenol, 0.81 g of (1-methylcyclopropyl)methanol, 2.98 g of triphenylphosphine and 50 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.77 g of 2,5-dimethyl-1-[(1-methylcyclopropyl)methoxy]-4-nitrobenzene. After cooling the mixture was extracted with ethyl acetate the organic layer was washed with water and saturated salt water dried over anhydrous magnesium sulfate

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

Procedure: 1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+. The resulting mixture then was stirred at room temperature overnight

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

Procedure: 1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+. The resulting mixture then was stirred at room temperature overnight

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

Procedure: Treat a cooled solution (0° C.) of 1-methylcyclopropanemethanol (2.0 g, 23.22 mmol) in DCM (75 mL) with TEA (2.58 g, 25.5 mmol) and add methanesulfonyl chloride (2.93 g, 25.5 mmol) dropwise. Stir the mixture at 0° C. for 2 h, wash with H2O then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (3.66 g, 96%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 3.60 (s, 3H), 2.10 (m, 2H), 0.72 (s, 3H), 0.14 (m, 2H), 0.01 (m, 2H). wash with H2O brine, dry over Na2SO4 concentrate to dryness

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

Procedure: Treat a cooled solution (0° C.) of 1-methylcyclopropanemethanol (2.0 g, 23.22 mmol) in DCM (75 mL) with TEA (2.58 g, 25.5 mmol) and add methanesulfonyl chloride (2.93 g, 25.5 mmol) dropwise. Stir the mixture at 0° C. for 2 h, wash with H2O then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (3.66 g, 96%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 3.60 (s, 3H), 2.10 (m, 2H), 0.72 (s, 3H), 0.14 (m, 2H), 0.01 (m, 2H). wash with H2O brine, dry over Na2SO4 concentrate to dryness

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

Procedure: To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-methylcyclopropyl)methanol (0.44 g) and tributylphosphine (1.9 mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 21%). cooling washed with 5% aqueous potassium hydrogensulfate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography

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

Procedure: To a solution of 6-methylpyridin-3-ol (0.5 g, 4.6 mmol) in toluene (6 mL) was added (1-methylcyclopropyl)methanol (0.59 g, 6.9 mmol) and stirred under nitrogen atmosphere. The solution was added cyanomethylenetri-n-butylphosphorane (CMBP, 2.5 ml, 9.53 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 820 mg (quantitative yield) of the title compound as a brown oil: stirred at 100° C. for 3 hours The reaction mixture was evaporated The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v))

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

Procedure: 1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+. The resulting mixture then was stirred at room temperature overnight

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

Procedure: 1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+. The resulting mixture then was stirred at room temperature overnight