ethyl 3-hydroxycyclopentane-1-carboxylate

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

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.650 g, 1.24 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.784 g, 4.96 mmol) in 4 mL of DMF was added DBU (0.747 mL, 4.96 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes) afforded the desired product. LCMS: calculated for C28H25F2IN2O3 602.41, observed m/e 602.9 (M+H)+ (Rt 2.57/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes)

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

Procedure: To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min). washed with H2O and brine The aqueous layer was further extracted with EtOAc the combined organic layers were dried over Na2SO4 filtered concentrated Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes)

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

Procedure: To a 0° C. solution of ethyl-3-oxo-cyclopentane-1-carboxylate (2.0 g) in THF (50 mL) was added NaBH4 (970 mg). The reaction mixture was maintained at 0° C. for 30 min, and then overnight at ambient temperature. The reaction was then treated with H2O and diluted with Et2O. The resulting layers were separated, and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification. overnight at ambient temperature The resulting layers were separated the aqueous layer was further extracted with Et2O The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification

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

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.650 g, 1.24 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.784 g, 4.96 mmol) in 4 mL of DMF was added DBU (0.747 mL, 4.96 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes) afforded the desired product. LCMS: calculated for C28H25F2IN2O3 602.41, observed m/e 602.9 (M+H)+ (Rt 2.57/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes)

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

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.650 g, 1.24 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.784 g, 4.96 mmol) in 4 mL of DMF was added DBU (0.747 mL, 4.96 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes) afforded the desired product. LCMS: calculated for C28H25F2IN2O3 602.41, observed m/e 602.9 (M+H)+ (Rt 2.57/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes)

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

Procedure: To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min). washed with H2O and brine The aqueous layer was further extracted with EtOAc the combined organic layers were dried over Na2SO4 filtered concentrated Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes)

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

Procedure: To a 0° C. solution of ethyl-3-oxo-cyclopentane-1-carboxylate (2.0 g) in THF (50 mL) was added NaBH4 (970 mg). The reaction mixture was maintained at 0° C. for 30 min, and then overnight at ambient temperature. The reaction was then treated with H2O and diluted with Et2O. The resulting layers were separated, and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification. overnight at ambient temperature The resulting layers were separated the aqueous layer was further extracted with Et2O The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification

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

Procedure: To a 0° C. solution of ethyl-3-oxo-cyclopentane-1-carboxylate (2.0 g) in THF (50 mL) was added NaBH4 (970 mg). The reaction mixture was maintained at 0° C. for 30 min, and then overnight at ambient temperature. The reaction was then treated with H2O and diluted with Et2O. The resulting layers were separated, and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification. overnight at ambient temperature The resulting layers were separated the aqueous layer was further extracted with Et2O The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification

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

Procedure: A solution of 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (prepared as described in PCT Int. Appl. 2008131946, 3.180 g, 20.1 mmol) in dichloromethane (100 mL) was subsequently treated with 2,6-lutidine (4.7 mL, 40.2 mmol) and triisopropylsilyl trifluoromethanesulfonate (8.1 mL, 30.15 mmol). After stirring for 3.5 h, the reaction was quenched with pH 4 buffer. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (6.15 g, 97%) as a light yellow oil and as a 3.5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3): δ 1.04-1.08 (m, 27H), 1.27 (t, J=7.1 Hz, 4H), 1.70-2.00 (m, 5.2H), 2.04-2.21 (m, 2.6H), 2.66-2.79 (m, 1H), 2.97-3.10 (m, 0.3H), 4.14 (q, J=7.1 Hz, 2.6H), 4.29-4.39 (m, 1H), 4.43-4.50 (m, 0.3H). the reaction was quenched with pH 4 buffer The aqueous layer was extracted with dichloromethane filtered through a phase separator the volatiles were removed in vacuo The residue was purified by silica gel chromatography eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1

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

Procedure: A mixture of 1,4-dichloro-2-nitro-benzene (190 mg, 1.1 mmol), 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (180 mg, 1.14 mmol), triphenylphosphine (448 mg) and DIAD (345 mg) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography to afford 280 mg of 3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl ester. The reaction mixture was then evaporated under reduced pressure the crude residue was purified by flash chromatography

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

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.650 g, 1.24 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.784 g, 4.96 mmol) in 4 mL of DMF was added DBU (0.747 mL, 4.96 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes) afforded the desired product. LCMS: calculated for C28H25F2IN2O3 602.41, observed m/e 602.9 (M+H)+ (Rt 2.57/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes)

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

Procedure: To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min). washed with H2O and brine The aqueous layer was further extracted with EtOAc the combined organic layers were dried over Na2SO4 filtered concentrated Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes)