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. 2021 Mar 5;64(6):3299–3319. doi: 10.1021/acs.jmedchem.0c02191

Scheme 4. Synthesis of 5, 6, 9–14, 16–21, 24, 25, and 29.

Scheme 4

(a) Ethyl bromoacetate, SIPEA, DMF, rt or benzyl bromoacetate, Et3N, THF, rt (from amine) or glycine ethyl ester hydrochloride, NaBH3CN, MeOH, rt (fromaldehyde or ketone); (b) (i) PivCl, DIPEA, DCM, rt; (ii) 2.5 N NaOH, MeOH, rt; (c) D, HATU, NMM, DMF, rt or D, EDCl, HOAt, DIPEA, DMF, rt; (d) H2, Pd/C, NH4COOH, MeOH, reflux; (e) TFA, DCM, rt or TsOH, MeOH, rt; (f) (i) pTsOH, acetone, rt; (ii) MeNH2, HCl, DIPEA, Na2SO4, DCM, rt then NaBH(OAc)3, rt; (g) 20% Pd(PPh3)4, 1,3-dimethylbarbituric acid, DCM, 35 °C; (h) Zn(CN)2, Pd(PPh3)4, DMF, 130 °C, MW; (j) H2, Raney-Ni, 2M NH3 in MeOH, 55 °C; (k) 4-benzyl-3,5-dimethyl-1H-pyrazole-1-carboximidamide hydrochloride, 5 equiv, Et3N, MeCN/THF, MW, 90 °C; (m) (i) pTsOH, acetone, rt; (ii) NH4OAc, MeOH, reflux; then NaBH3CN, rt; (n) H2O2, H2O, NaOH, DMSO, rt.