Scheme 4. Synthesis of BI-0474 (23).

Reagents and conditions: (a) BOC-piperazine, DIPEA, DMSO, 1 h, 60 °C, 69%; (b) (S)-1,3-dimethylpiperazine, Pd₂dba₃, xantphos, Cs₂CO₃, dioxane, 16 h, 110 °C, 19%; (c) NH₂OH·HCl, Na₂CO₃, EtOH, 1 h, 85 °C, 99%; (d) 18a, HATU, DIPEA, DMF, 16 h, 25 °C, 29%; (e) DBU, 16 h, 90 °C, 56%; (f) HCl, dioxane, 1 h, 40 °C, 67%; and (g) acryloyl chloride, K₂CO₃, acetone/water, 15 min, RT, 47%.