Scheme 2. Synthesis of Amine-Based P2–P4 Macrocyclic NS3/4a Protease Inhibitors.

Reagents and conditions: (a) LiOH·H₂O, THF-MeOH; (b) 10, HATU, DIPEA, DMF; (c) 1,3-dibromopropane, Cs₂CO₃, DMF, 50 °C; (d) DIPEA/Et₃N, KI, HNR₁R₂; (e) DIAD, Ph₃P, 4-hydroxy-1-methylpiperidine or N-Boc-4-hydroxypiperidine, THF, 40 °C (f) TFA, CH₂Cl₂; (g) RX, DIPEA/Et₃N, KI, MeCN or DMF, 100 °C or (methylsulfonyl)ethene, DIPEA, CH₂Cl₂ for synthesis of 28.