Scheme 2. Synthesis of ponatinib-SH (2a) and GZD824-SH (3a) via NCL-type reaction. Reagents and conditions: (a) NBS, AIBN, AcOH, 80 °C, 26 h, 72%; (b) 1-methylpiperazine, DIPEA, DMF, rt, 1 h, 91%; (c) tBuSH, Cs₂CO₃, DMF, rt, 1 h, 83%; (d) (i) Na₂S₂O₄, MeOH, H₂O, rt, 1 h; (ii) conc. HCl, rt, 3 h, 86%; (e) TFMSA, TFA, thioanisole, rt, 30 min, 100%; (f) (i) ethynyltrimethylsilane, Pd(PPh₃)₂Cl₂, CuI, NEt₃, THF, rt, 17 h, Ar; (ii) K₂CO₃, MeOH, rt, 30 min, 88%; (g) 3-bromoimidazo[1,2-b]pyridazine or 5-bromo-1H-pyrazolo[3,4-b]pyridine, Pd(PPh₃)₂Cl₂, CuI, DIPEA, DMF, 80 °C, 5 h, Ar, 99% 15/75% 16; (h) NaOH, MeOH, H₂O, 60 °C, 3 h, 67% 17/90% 18; (i) thiophenol, HATU, DIPEA, DMF, 45 °C, 3 h, 100% 19/56% 20; (j) transfer buffer (4 M GnHCl, 100 mM NaH₂PO₄/Na₂HPO₄, 12.5 mM TCEP, pH 7.2), MeCN, 40 °C, 24 h, Ar.