tert-butyl (2R)-2-(hydroxymethyl)piperidine-1-carboxylate

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

Procedure: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

Procedure: To a solution of (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate (Example 15f, 7.10 g, 33.0 mmol) and 2,6-dinitrobenzonitrile (6.37 g, 33.0 mmol) in THF (142 mL) cooled to -78° C., was added NaH (60% dispersion in oil, 1.45 g, 36.3 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 18 hours. Upon completion, the reaction was cooled to 0° C. and quenched with water. The mixture was extracted with ethyl acetate, and the organic extracts were combined and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate/hexanes to afford (R)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (10.8 g, 91%) as a yellow solid. MS 282 (MH+-boc). Upon completion, the reaction was cooled to 0° C. quenched with water The mixture was extracted with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated The residue was recrystallized from ethyl acetate/hexanes

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

Procedure: A 4M HCl solution in dioxane (30 mL) was added to (R)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (4.65 g, 21.6 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.47 g). The solvent was removed in vacuo

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

Procedure: A 4M HCl solution in dioxane (30 mL) was added to (R)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (4.65 g, 21.6 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.47 g). The solvent was removed in vacuo

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.65 g., 99%). at rt for 2 h extracted with EtOAc (300 mL) The aqueous layer was re-extracted with EtOAc (2×150 mL) dried over anhydrous Na2SO4 concentrated

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

Procedure: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

Procedure: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

Procedure: To a solution of (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate (Example 15f, 7.10 g, 33.0 mmol) and 2,6-dinitrobenzonitrile (6.37 g, 33.0 mmol) in THF (142 mL) cooled to -78° C., was added NaH (60% dispersion in oil, 1.45 g, 36.3 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 18 hours. Upon completion, the reaction was cooled to 0° C. and quenched with water. The mixture was extracted with ethyl acetate, and the organic extracts were combined and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate/hexanes to afford (R)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (10.8 g, 91%) as a yellow solid. MS 282 (MH+-boc). Upon completion, the reaction was cooled to 0° C. quenched with water The mixture was extracted with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated The residue was recrystallized from ethyl acetate/hexanes

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

Procedure: A mixture of (R)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (840 mg, 3.9 mmol) in 1,4-dioxane (15 mL) was treated with hydrogen chloride (4.0N solution in dioxane, 9.8 mL, 39 mmol), and stirred at ambient temperature for 3 hours. The solvent was evaporated in vacuo to afford the title compound as a white solid (594 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 4.72 (t, J=5.3, 1H), 3.35 (m, 1H), 3.28-3.15 (m, 3H), 2.72 (m, 1H), 2.59-2.52 (m, 1H), 1.88-1.72 (m, 2H), 1.72-1.53 (m, 2H), 1.16 (m, 1H). The solvent was evaporated in vacuo

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

Procedure: A mixture of (R)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (840 mg, 3.9 mmol) in 1,4-dioxane (15 mL) was treated with hydrogen chloride (4.0N solution in dioxane, 9.8 mL, 39 mmol), and stirred at ambient temperature for 3 hours. The solvent was evaporated in vacuo to afford the title compound as a white solid (594 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 4.72 (t, J=5.3, 1H), 3.35 (m, 1H), 3.28-3.15 (m, 3H), 2.72 (m, 1H), 2.59-2.52 (m, 1H), 1.88-1.72 (m, 2H), 1.72-1.53 (m, 2H), 1.16 (m, 1H). The solvent was evaporated in vacuo

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

Procedure: 1,1-Dimethylethyl (2R)-2-[{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]-methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidine-1-carboxylate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1,1-dimethylethyl (2R)-2-(hydroxymethyl)piperidine-1-carboxylate following General Procedure J.

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

Procedure: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g. 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS116 (MH+-boc) was cooled to 0° C BH3Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)