tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate

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 crude tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate. Concentration

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h The mixture was then extracted with ethyl acetate (×2) The combined organic layers were washed with brine dried with Na2SO4 Evaporation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to n-BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (Int-12a, 3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl-4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate (Int-12b) which was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12c) which was treated with SEMCl (72.05 mmoL, 12.71 mL) and DIEA (144.4 mmoL, 25.05 mL) in DCE (100 mL) at 50° C. for 1 h. The mixture was diluted with H2O and then extracted with CH2Cl2 (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12d): LCMS tR=3.05 Min (5 min run, UV254nm). Mass calculated for, M+591.3, observed m/z 592.3 (M+H). The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h The mixture was then extracted with ethyl acetate (x2) The combined organic layers were washed with brine dried with Na2SO4 Evaporation