Scheme 3. Head-to-tail synthesis of analogues varying hinge-binding group^a.

^aReagents and conditions: (a) ArCl, o-xylene, 135°C, [14–60 h], 18–76%; (b) (for 96) 4-chloro-1H-pyrrolo[2,3-b]pyridine, neat, μW, 150°C, 20 min, 12%; (c) (for 97) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 2,6-lutidine, NMP, 130°C, 22 h, 28%; (d) (for 98 and 99) 4,6-dichloropyrimidine or 2,4-dichloropyrimidine, K₂CO₃, DMF, 70°C, 16 h, 54–61%; (e) Fe, NH₄Cl, EtOH/H₂O (3:1), [31–78°C], [2–6 h], 58–95%; (f) ArCl, KO^tBu, DMF or DMA, [0–110°C or rt-80°C], [4–16 h], 11–58%; (g) 2,4-difluoro-1-isocyanatobenzene, EtOH, 0°C-rt, [0.5–24 h], 5–58%; (h) 2,4-difluoroaniline, CDI, DCM or DMSO, 0°C or rt, [0.5–2 h], then [35–40°C], [2.5–4 h], 4–67%; (i) benzylamine, Et₃N, THF, 66°C, 10 h, 52%.