(1-methylpiperidin-2-yl)methanol

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

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

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

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

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

Procedure: The procedures of Reference Example 3 were repeated using 2.58 g of 1-methyl-2-piperidinemethanol and 3.72 g of methyl p-toluenesulfonate to give 4.95 g of the desired compound.

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

Procedure: The procedures of Reference Example 3 were repeated using 2.58 g of 1-methyl-2-piperidinemethanol and 3.72 g of methyl p-toluenesulfonate to give 4.95 g of the desired compound.

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

Procedure: 6-Bromo-1-(N-methylpiperidin-2-yl)methyl)-1H-indole (220 mg, 57.2%) and 6-bromo-1-(N-methyl-azepan-3-yl)-1H-indole (94 mg, 24.4%); from 6-bromo-1-methanesulfonyl-1H-indole (344 mg, 1.25 mmol) and N-methylpiperidine-2-methanol (395 mg, 2.5 mmol) with NaH (53 mg, 2.2 mmol) and potassium carbonate (325 mg, 2.35 mmol) in toluene (10 mL) at 100° C. overnight. at 100° C. overnight

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

Procedure: 6-Bromo-1-(N-methylpiperidin-2-yl)methyl)-1H-indole (220 mg, 57.2%) and 6-bromo-1-(N-methyl-azepan-3-yl)-1H-indole (94 mg, 24.4%); from 6-bromo-1-methanesulfonyl-1H-indole (344 mg, 1.25 mmol) and N-methylpiperidine-2-methanol (395 mg, 2.5 mmol) with NaH (53 mg, 2.2 mmol) and potassium carbonate (325 mg, 2.35 mmol) in toluene (10 mL) at 100° C. overnight. at 100° C. overnight

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

Procedure: 1-Methyl-2-piperidinemethanol (0.459 g, 3.580 mmol, 1 eq) was suspended in dry CH2Cl2 (5 mL). p-Toluenesulfonyl chloride (0.684 g, 3.580 mmol, 1 eq) and triethyl amine (1.00 mL, 7.160 mmol, 2 eq) were added. The reaction mixture was stirred at room temperature for 8 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was dissolved in dry acetonitrile (20 mL). 2-Methyl-3-benzyloxycarbonyl-5-hydroxyindole (1.005 g, 3.580 mmol, 1 eq) and Cs2CO3 (1.159 g, 3.580 mmol, 1 eq) were added. The reaction mixture was stirred and heated to reflux for 16 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (15%) of the indole-piperidine ether was obtained as a brown solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.HCl.0.8H2O: C, 65.02; H, 6.96; N, 6.32; Found: C, 65.36; H, 7.02; N, 5.96. Then the reaction was quenched with saturated sodium bicarbonate extracted with ethyl acetate (3×) The combined organic phases were washed with brine dried over Na2SO4 After removing the solvent the residue was dissolved in dry acetonitrile (20 mL) The reaction mixture was stirred heated to reflux for 16 hours Then the reaction was quenched with saturated sodium bicarbonate extracted with ethyl acetate (3×) The combined organic phases were washed with brine dried over Na2SO4 After removing the solvent chromatographed eluting with ethyl acetate/methanol/triethyl amine (100/10/1)

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

Procedure: To a THF solution (17 ml) of 1-methyl-2-piperidinemethanol (1.70 g, 13.2 mmol) cooled in an ice-sodium chloride bath to -5° C. was dropwise added a 1.5M hexane solution of n-BuLi (8.7 ml, 13.0 mmol) over a period of 5 min. Stirring was continued under ice-cooling for 30 min. To a mixture was then dropwise added a THF solution (5 ml) of indolecarboxylic acid chloride (1.50 g, 8.35 mmol) over a period of 5 min. After stirring at room temperature for 5 hours, a reaction solution was poured onto diluted hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were then adjusted with saturated aqueous NaCO3 to a pH of >10 and again extracted with EtOAc. The basic extract was washed successively with water and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The pale yellow crystals thus produced were recrystallized from a chloroform-methanol mixture to give 1.20 g of the title compound as prisms. m.p. 168°-170° C.; cooling for 30 min After stirring at room temperature for 5 hours The organic layer was separated the aqueous layer was extracted with EtOAc again extracted with EtOAc The basic extract was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure The pale yellow crystals thus produced were recrystallized from a chloroform-methanol mixture

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

Procedure: 6-Bromo-1-(N-methylpiperidin-2-yl)methyl)-1H-indole (220 mg, 57.2%) and 6-bromo-1-(N-methyl-azepan-3-yl)-1H-indole (94 mg, 24.4%); from 6-bromo-1-methanesulfonyl-1H-indole (344 mg, 1.25 mmol) and N-methylpiperidine-2-methanol (395 mg, 2.5 mmol) with NaH (53 mg, 2.2 mmol) and potassium carbonate (325 mg, 2.35 mmol) in toluene (10 mL) at 100° C. overnight. at 100° C. overnight

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A cooled (0° C.) solution of 1-methylpiperidine-2-methanol (97 mg, 0.75 mmol) and diisopropylethylamine (0.31 mL, 1.75 mmol) in anhydrous acetonitrile (12 mL) under nitrogen was treated with methanesulfonyl chloride (86 mg, 0.75 mmol), stirred 3 h, and treated with (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and heated to 60° C. for 15 h. The reaction mixture was concentrated, deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-((1-methylpiperidin-2-yl)methyl)pyrrolidine-3-carboxylic acid (121 mg, 55%) as a white foam. NMR (D2O) δ 3.60-4.00 (m, 4 H), 3.15-3.55 (m, 3 H), 2.90 (m, 2 H), 2.67 (s, 3 H), 2.50-2.80 (m, 2 H), 2.00-2.30 (m, 1 H), 1.45-1.95 (m, 5 H), 1.10-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 328.1; MS (m−H2O+1): 310.1. The reaction mixture was concentrated isolated