(2-methylcyclopropyl)methanol

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

Procedure: 37 mg (0.431 mmol) of (2-methylcyclopropyl)methanol and 17 mg (0.431 mmol) of sodium hydride (60% strength dispersion in mineral oil) were initially charged in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 60 minutes. 100 mg (0.288 mol) of methyl 2-chloro-6-(3-fluoro-4-methylphenyl)-4-(trifluoromethyl)nicotinate (Example 2A) in 2 ml of tetrahydrofuran were then added. The mixture was stirred at reflux temperature for 3 h and then at room temperature overnight. For work-up, the reaction mixture was adjusted to pH 1 using 1N hydrochloric acid. After removal of the volatile components on a rotary evaporator, the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 20 mg (18% of theory) of the target compound. The mixture was stirred at reflux temperature for 3 h at room temperature overnight After removal of the volatile components on a rotary evaporator the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10)

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

Procedure: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).

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

Procedure: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).

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

Procedure: 2.55 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.40 g of 2,5-dimethyl-4-nitrophenol, 0.72 g of (2-methylcyclopropyl)methanol, 2.64 g of triphenylphosphine and 100 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 1.64 g of 2,5-dimethyl-1-[(2-methylcyclopropyl)methoxy]-4-nitrobenzen e. 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: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).

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

Procedure: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).

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

Procedure: 50 mg (0.15 mmol) (S)—N-{1-(4-[1-(4-Hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48), 14 mg (0.16 mmol) 2-methylcyclopropanemethanol and 38.8 mg (0.15 mmol) triphenylphosphine are added to 2 mL 2-methyl-tetrahydrofurane at 0° C. 30.5 μl (0.15 mmol) di-iso-propyl azodicarboxylate are added and the mixture is allowed to warm to rt. Stirring is continued over night followed by addition of 0.5 equivalents of triphenylphosphine and 0.5 equivalents of di-iso-propyl azodicarboxylate. Stirring is continued for one day and again additional triphenylphosphine and di-iso-propyl azodicarboxylate are added and stirring is continued for 16 h at 50° C. Then the mixture is filtered and purified using reversed phase HPLC (water/MeOH, 0.1% FA) to yield the desired product. is continued over night Stirring stirring is continued for 16 h at 50° C Then the mixture is filtered purified

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

Procedure: 37 mg (0.431 mmol) of (2-methylcyclopropyl)methanol and 17 mg (0.431 mmol) of sodium hydride (60% strength dispersion in mineral oil) were initially charged in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 60 minutes. 100 mg (0.288 mol) of methyl 2-chloro-6-(3-fluoro-4-methylphenyl)-4-(trifluoromethyl)nicotinate (Example 2A) in 2 ml of tetrahydrofuran were then added. The mixture was stirred at reflux temperature for 3 h and then at room temperature overnight. For work-up, the reaction mixture was adjusted to pH 1 using 1N hydrochloric acid. After removal of the volatile components on a rotary evaporator, the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 20 mg (18% of theory) of the target compound. The mixture was stirred at reflux temperature for 3 h at room temperature overnight After removal of the volatile components on a rotary evaporator the product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10)

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

Procedure: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).

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

Procedure: 2.55 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.40 g of 2,5-dimethyl-4-nitrophenol, 0.72 g of (2-methylcyclopropyl)methanol, 2.64 g of triphenylphosphine and 100 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 1.64 g of 2,5-dimethyl-1-[(2-methylcyclopropyl)methoxy]-4-nitrobenzen e. 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: Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).