(1-methylcyclohexyl)methanol

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

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

Procedure: General Procedure C for compounds 7a-m: A mixture of compound 3 (0.5 mmol), compounds 6a-m (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in 3 mL DMF. The solution was heated to 80° C. for 4 hr. the solution was poured into water, extracted with ethyl acetate (10 ml * 3), and concentrated. The residue was purified by chromatography. extracted with ethyl acetate (10 ml * 3) concentrated The residue was purified by chromatography

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

Procedure: General Procedure C for compounds 7a-m: A mixture of compound 3 (0.5 mmol), compounds 6a-m (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in 3 mL DMF. The solution was heated to 80° C. for 4 hr. the solution was poured into water, extracted with ethyl acetate (10 ml * 3), and concentrated. The residue was purified by chromatography. extracted with ethyl acetate (10 ml * 3) concentrated The residue was purified by chromatography

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of LiAlH4 (20 mmol) in anhydrous THF (10 mL) at 4° C. was added 1-methyl-cyclohexanecarboxylic acid (i, 7.0 mmol) in 50 mL of THF dropwise over a period of 1 hour. The solution was stirred at refluxing temperature under N2 for 6 hours. The solution was cooled to 4° C. by ice bath, and 1 mL of 1 N NaOH (1 mL) followed by H2O (2 mL) was slowly added to the solution to quench the reaction. The solution was stirred at 23° C. for 1 hour and then filtered to remove solid material. The solution was concentrated. Purification by flash silica gel chromatography (ethyl acetate/hexanes, 1:2) gave the product, (1-methyl-cyclohexyl)-methanol (ii), in 82% yield. at refluxing temperature under N2 for 6 hours was slowly added to the solution to quench the reaction The solution was stirred at 23° C. for 1 hour filtered to remove solid material The solution was concentrated Purification by flash silica gel chromatography (ethyl acetate/hexanes, 1:2)

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

Procedure: To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran (300 mL) at 0° C. was added 1 M diborane in tetrahydrofuran (200 mL, 200 mmol) over 90 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for two days. The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling. Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed. The organic layer washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue was purified by flash chromatography using 20% diethylether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%). The cooling bath was removed The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed The organic layer washed with water and saturated sodium chloride dried filtered concentrated The residue was purified by flash chromatography

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

Procedure: To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran (300 mL) at 0° C. was added 1 M diborane in tetrahydrofuran (200 mL, 200 mmol) over 90 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for two days. The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling. Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed. The organic layer washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue was purified by flash chromatography using 20% diethylether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%). The cooling bath was removed The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed The organic layer washed with water and saturated sodium chloride dried filtered concentrated The residue was purified by flash chromatography

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

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

Procedure: Under ice cooling and stirring, hydrogen chloride was blown into a mixture of 128 g of (1-methylcyclohexyl)methanol, 400 g of hexane, and 36 g of paraformaldehyde, until the is reactant alcohol disappeared on gas chromatography analysis. The excess hydrogen chloride was purged by feeding nitrogen into the reactor, after which the water layer was removed by separatory operation. The solution was dried over magnesium sulfate and the solids filtered off, yielding a hexane solution of chloromethyl[(1-methylcyclohexyl)methyl] ether. The excess hydrogen chloride was purged after which the water layer was removed by separatory operation The solution was dried over magnesium sulfate the solids filtered off

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

Procedure: Under ice cooling and stirring, hydrogen chloride was blown into a mixture of 128 g of (1-methylcyclohexyl)methanol, 400 g of hexane, and 36 g of paraformaldehyde, until the is reactant alcohol disappeared on gas chromatography analysis. The excess hydrogen chloride was purged by feeding nitrogen into the reactor, after which the water layer was removed by separatory operation. The solution was dried over magnesium sulfate and the solids filtered off, yielding a hexane solution of chloromethyl[(1-methylcyclohexyl)methyl] ether. The excess hydrogen chloride was purged after which the water layer was removed by separatory operation The solution was dried over magnesium sulfate the solids filtered off

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

Procedure: Under ice cooling and stirring, hydrogen chloride was blown into a mixture of 128 g of (1-methylcyclohexyl)methanol, 400 g of hexane, and 36 g of paraformaldehyde, until the is reactant alcohol disappeared on gas chromatography analysis. The excess hydrogen chloride was purged by feeding nitrogen into the reactor, after which the water layer was removed by separatory operation. The solution was dried over magnesium sulfate and the solids filtered off, yielding a hexane solution of chloromethyl[(1-methylcyclohexyl)methyl] ether. The excess hydrogen chloride was purged after which the water layer was removed by separatory operation The solution was dried over magnesium sulfate the solids filtered off

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

Procedure: To a cold solution (-4° C.) of (1-methylcyclohexyl)methanol (6.2 g, 0.048 mol) in DMF (90 ml) was added 50% oily sodium hydride (2.81 g, 0.059 mol as NaH). After stirring for 1 hr, sulfamoyl chloride (7.82 g, 0.062 mol) was added and the stirring was continued for an additional 30 min at -4° C. The reaction mixture was poured into cold water and extracted with toluene. The organic layer was dried (Na2SO4) and the solvents were removed under vacuum to give a syrup which crystallized upon cooling. Recrystallization from chloroform/hexane gave pure (1-methylcyclohexyl)methane sulfamate, mp 40°-42° C. the stirring was continued for an additional 30 min at -4° C extracted with toluene The organic layer was dried (Na2SO4) the solvents were removed under vacuum to give a syrup which crystallized upon cooling Recrystallization from chloroform/hexane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1-methylcyclohexyl)methanol (4.98 g, 38.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (20.67 g, 83.10 mmol) in anhydrous dimethylsulfoxide (80 mL) was added cesium carbonate (25.14 g, 77.20 mmol). The mixture was heated to 70° C. and stirred for 16 hours. The mixture was then cooled to ambient temperature, filtered through a pad of diatomaceous earth and the solid was washed with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (6.26 g, 44%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.2 Hz, 1H), 3.70 (s, 2H), 1.57 (s, 9 H), 1.52-1.31 (m, 10H), 1.08 (s, 3H). The mixture was then cooled to ambient temperature filtered through a pad of diatomaceous earth the solid was washed with ethyl acetate The combined organic layers were washed with water and brine dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes)