methyl 2-(bromomethyl)-5-chlorobenzoate

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

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

Procedure: Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. Aqueous was extracted with ethyl acetate (3×30 mL) and combined organics were washed with water (2×40 mL) and 50 mL of brine. Organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate which was used in the next step without further purification. reaction mixture was quenched with 25 mL of water Aqueous was extracted with ethyl acetate (3×30 mL) combined organics were washed with water (2×40 mL) and 50 mL of brine Organics were dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. Aqueous was extracted with ethyl acetate (3×30 mL) and combined organics were washed with water (2×40 mL) and 50 mL of brine. Organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate which was used in the next step without further purification. reaction mixture was quenched with 25 mL of water Aqueous was extracted with ethyl acetate (3×30 mL) combined organics were washed with water (2×40 mL) and 50 mL of brine Organics were dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. The aqueous was extracted with ethyl acetate (3×30 mL) and the combined organics were washed with water (2×40 mL) and 50 mL of brine. The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate (429 mg, 97%) as an off-white solid, which was used in the next step without further purification. reaction mixture was quenched with 25 mL of water The aqueous was extracted with ethyl acetate (3×30 mL) the combined organics were washed with water (2×40 mL) and 50 mL of brine The organics were dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: To a solution of potassium tert-butoxide (533 mg, 4.75 mmol) in tetrahydrofuran (10 ml) was added cyclohexylmethanol (594 mg, 5.20 mmol) in tetrahydrofuran (2.5 ml), methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (2.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 2 N hydrochloric acid solution (pH ca. 2) at 0° C. It was extracted with dichloromethane, the organic extracts were dried over sodium sulfate and concentrated to afford 302 mg of crude 5-chloro-2-[(cyclohexylmethoxy)methyl]benzoic acid. This carboxylic acid was converted into 132 mg (31%) of the title compound according to the procedure described in step 6 of Example 1: It was extracted with dichloromethane the organic extracts were dried over sodium sulfate concentrated

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

Procedure: To a suspension of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.1 mmol) in tetrahydrofuran (4 ml) was added 5-chloro-N-methylpyridin-2-amine (128 mg, 1.14 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred for 30 min. The mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred at 80° C. for 8 hr. After cooling to room temperature, the mixture was added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 102 mg (33%) of the title compound: stirred at 80° C. for 8 hr extracted with ethyl acetate The organic layer was dried over sodium sulfate evaporated The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1)

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

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 16 from methyl 2-(bromomethyl)-5-chlorobenzoate and 2-methylpropan-1-ol:

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

Procedure: A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (200 mg, 0.80 mmol), cyclopentanol (379 mg 4.4 mmol), and potassium tert-butoxide (448 mg, 4.0 mmol) in tetrahydrofuran (8 mL) was stirred at room temperature for 3 hours. The mixture was acidified with 2 N hydrochloric acid and the acidic aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 100 mg (49%) of the title compound: the acidic aqueous mixture was extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate evaporated The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1)

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

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromomethyl)-5-chlorobenzoate and 3-chloro-5-hydroxypyridine:

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

Procedure: To a solution of 3-fluoro-5-hydroxypyridine (34 mg, 0.30 mmol) in dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 12 mg, 0.30 mmol) at 0° C. and the mixture was stirred at room temperature for 15 minutes. To the mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (100 mg, 0.4 mmol) in dimethylformamide and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel to afford 47 mg (53%) of the title compound: the mixture was stirred at room temperature overnight The mixture was quenched with water extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate evaporated The residue was purified by flash column chromatography on silica gel

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

Procedure: To a solution of potassium tert-butoxide (533 mg, 4.75 mmol) in tetrahydrofuran (10 ml) was added cyclohexylmethanol (594 mg, 5.20 mmol) in tetrahydrofuran (2.5 ml), methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetarahydrofuran (2.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 2 N hydrochloric acid solution (pH ca. 2) at 0° C. It was extracted with dichloromethane, the organic extracts were dried over sodium sulfate and concentrated to afford 302 mg of crude 5-chloro-2-[(cyclohexylmethoxy)methyl]benzoic acid. This carboxylic acid was converted into 132 mg (31%) of the title compound according to the procedure described in step 6 of Example 1: It was extracted with dichloromethane the organic extracts were dried over sodium sulfate concentrated

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

Procedure: To s suspension of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.1 mmol) in terahydorofuran (4 ml) was added 5-chloro-N-methylpyridin-2-amine (128 mg, 1.14 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred for 30 min. The mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred at 80° C. for 8 hr. After cooling to room temperature, the mixture was added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 102 mg (33%) of the title compound: stirred at 80° C. for 8 hr extracted with ethyl acetate The organic layer was dried over sodium sulfate evaporated The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1)