1-(hydroxymethyl)cyclopentane-1-carbonitrile

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

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

Procedure: At 0° C., to a solution of 1-hydroxymethyl-cyclopentanecarbonitrile (10 g, 79.9 mmol) in CH2Cl2 (100 mL) was added pyridine (6.3 g, 79.9 mmol) and p-toluenesulfonyl chloride (12.18 g, 63.9 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification. the solution was concentrated the residue was used for next step reaction without further purification

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

Procedure: To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). The reaction was stirred at ambient temperature for 64 hours the reaction was stirred for an additional 30 minutes the aqueous layer was extracted with ethyl acetate dried over sodium sulfate the solvent was then removed in vacuo To the resulting residue was added water The product was isolated by extraction with diethyl ether The ethereal extracts were dried over sodium sulfate the solvent was evaporated Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes)

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

Procedure: A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ3.62 (s, 2H), 2.39-1.60 (m, 8H). The resulting solution was heated to reflux for 3 hours The mixture was quenched by the addition of water was extracted with ethyl acetate The combined organic extracts were dried over Na2SO4 filtered the solvent was removed in vacuo

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

Procedure: To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). The reaction was stirred at ambient temperature for 64 hours the reaction was stirred for an additional 30 minutes the aqueous layer was extracted with ethyl acetate dried over sodium sulfate the solvent was then removed in vacuo To the resulting residue was added water The product was isolated by extraction with diethyl ether The ethereal extracts were dried over sodium sulfate the solvent was evaporated Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes)

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

Procedure: A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ□3.62 (s, 2H), 2.39-1.60 (m, 8H). The resulting solution was heated to reflux for 3 hours The mixture was quenched by the addition of water was extracted with ethyl acetate The combined organic extracts were dried over Na2SO4 filtered the solvent was removed in vacuo

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

Procedure: To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). The reaction was stirred at ambient temperature for 64 hours the reaction was stirred for an additional 30 minutes the aqueous layer was extracted with ethyl acetate dried over sodium sulfate the solvent was then removed in vacuo To the resulting residue was added water The product was isolated by extraction with diethyl ether The ethereal extracts were dried over sodium sulfate the solvent was evaporated Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes)

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

Procedure: A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ3.62 (s, 2H), 2.39-1.60 (m, 8H). The resulting solution was heated to reflux for 3 hours The mixture was quenched by the addition of water was extracted with ethyl acetate The combined organic extracts were dried over Na2SO4 filtered the solvent was removed in vacuo

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

Procedure: To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). The reaction was stirred at ambient temperature for 64 hours the reaction was stirred for an additional 30 minutes the aqueous layer was extracted with ethyl acetate dried over sodium sulfate the solvent was then removed in vacuo To the resulting residue was added water The product was isolated by extraction with diethyl ether The ethereal extracts were dried over sodium sulfate the solvent was evaporated Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes)

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

Procedure: A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ□3.62 (s, 2H), 2.39-1.60 (m, 8H). The resulting solution was heated to reflux for 3 hours The mixture was quenched by the addition of water was extracted with ethyl acetate The combined organic extracts were dried over Na2SO4 filtered the solvent was removed in vacuo

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

Procedure: 5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (200 mg, 0.56 mmol), 1-hydroxymethyl-cyclopentanecarbonitrile (145 mg, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (117 mg, 0.61 mmol) and 1-hydroxybenzotriazole hydrate (83 mg, 0.61 mmol) were stirred in DCM (20 ml) for 66 h at room temperature. The reaction was poured into water (25 ml) and diluted with DCM (25 ml). The organic layer was isolated using a hydrophobic filter tube and the DCM removed under reduced pressure and purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid. The organic layer was isolated the DCM removed under reduced pressure purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid

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

Procedure: 5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (200 mg, 0.56 mmol), 1-hydroxymethyl-cyclopentanecarbonitrile (145 mg, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (117 mg, 0.61 mmol) and 1-hydroxybenzotriazole hydrate (83 mg, 0.61 mmol) were stirred in DCM (20 ml) for 66 h at room temperature. The reaction was poured into water (25 ml) and diluted with DCM (25 ml). The organic layer was isolated using a hydrophobic filter tube and the DCM removed under reduced pressure and purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid. The organic layer was isolated the DCM removed under reduced pressure purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid