Scheme 3.

Optimized synthetic route to hit and final compounds

Reagents and conditions: a) R¹SO₂NH₂, TiCl₄·2THF or 1M TiCL₄ in DCM, Et₃N, THF, microwave, 60 °C, 15–30 min., 30~86%; b) EtOH :DCM (1:1) for tetrazole-5-thiol, r.t., 2 h, THF for 1-methyl-tetrazole-5-thiol or 3-mercapto-1,2,4-triazole, r.t., 2 h; THF, 1 eq. pyridine for thioglycolic acid, r.t., 10–30 min.; c) Na₂S₂O₄, EtOAc and H₂O (mixing in a separating funnel), 54~100 %; d). NaN₃, water, reflux 2 h, 67%; e) TFA/anisole (5:1, 2 mL/mmole), microwave 100 °C, 2 h, 93%.