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A solution of 4-carboxymethoxy)piperidine-1-carboxylic acid tert-butyl ester (14.13 g, 54.7 mmol) and NEt3 (7.7 mL, 65.6 mmol) in anhydrous THF (250 mL) was cooled to 0° C., before being treated dropwise with isobutyl chloroformate (8.5 mL, 65.6 mmol). After stirring at 0° C. for 30 min, the reaction mixture was cooled to −20° C., before being added rapidly, via cannula, to a solution of NH3 in anhydrous CH2Cl2 (0.7 M, 250 mL, 175 mmol) at −70° C. The reaction was allowed to warm to 20° C., before being stirred for 1 h. The mixture was diluted with CH2Cl2 (250 mL), before being washed with saturated aqueous NaHCO3 (200 mL), 0.5 M HCl (200 mL), and brine (200 mL). After drying (MgSO4), the solution was filtered and the solvent evaporated to give a residue that was purified by flash chromatography (IH-THF, 3:7) to afford 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester: δH(CDCl3): 1.49 (s, 9H), 1.53-1.60 (m, 2H), 1.85-1.92 (m, 2H), 3.11 (m, 2H), 3.58 (m, 1H), 3.76-3.83 (m, 2H), 3.98 (s, 2H), 6.19 (brs, 1H), 6.56 (brs, 1H). A solution of this compound (235 mg, 0.91 mmol) and NEt3 (140 μL, 1.00 mmol) in anhydrous CH2Cl2 (5 mL) was cooled to 0° C., then a solution of trichloroacetyl chloride (174 mg, 0.96 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise. The reaction mixture was stirred at 20° C. for 1 h, then the solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 1:1) to furnish 4-cyanomethoxypiperidine-1-carboxylic acid tert-butyl ester: δH (CDCl3): 1.50 (s, 9H), 1.58-1.65 (m, 2H), 1.89-1.95 (m, 2H), 3.20 (m, 2H), 3.74-3.79 (m, 3H), 4.33 (s, 2H). A solution of K2CO3 (119 mg, 0.86 mmol) and NH2OH.HCl (119 mg, 1.71 mmol) in H2O (0.5 mL) was added to the above nitrile (206 mg, 0.86 mmol) in EtOH (2 mL). The mixture was heated at 75° C. for 45 min, before being cooled to ambient temperature. The solvents were evaporated, then the residue was diluted with EtOAc (50 mL), before being washed with H2O (2×10 mL) and brine (10 mL). The EtOAc solution was dried MgSO4), filtered, and concentrated to afford the title compound: m/z (ES+)=274.0 [M+H]+.

1. temperaturethe reaction mixture was cooled to −20° C.
2. temperatureto warm to 20° C.
3. stirringbefore being stirred for 1 h
4. washbefore being washed with saturated aqueous NaHCO3 (200 mL), 0.5 M HCl (200 mL), and brine (200 mL)
5. dry with materialAfter drying (MgSO4)
6. filtrationthe solution was filtered
7. customthe solvent evaporated
8. customto give a residue that
9. customwas purified by flash chromatography (IH-THF, 3:7)