Scheme 3. Synthesis of front-pocket derivatives.

(A) Synthesis of inhibitors 73–75.^a (B) Synthesis of inhibitor 76.^b (C) Synthesis of inhibitors 79-82.^c

^aReagents and conditions: (a) 2-R-5-nitrobenzenesulfonyl chloride, triethylamine, acetone / water (3:1), rt, 5 h; (b) iron, ammonium chloride, methanol/water (9:1), reflux, 3 h; (c) 4 N HCl in 1,4-dioxane, acetonitrile, water, 2-butanol, reflux, 6 h; (d) potassium carbonate, [1,1’-Bis(diphenyl-phosphino)ferrocene]palladium(II) dichloride, 4-fluoro-3methoxyphenylboronic acid, 1,4-dioxane / dimethylformamide (1:1), 100 °C, μW, 2 h. ^bReagents and conditions: (a) potassium carbonate, XPhos Pd G2, 4-hydroxyphenylboronic acid, 1,4-dioxane/dimethylformamide (1:1), 100 °C, μW, 2 h. ^cReagents and conditions: (a) sodium ethanethiolate, dimethylformamide, 100 °C, μW, 10 h; (b) potassium carbonate, [1,1’-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 4-fluoro-3-methoxyphenylboronic acid, 1,4-dioxane/dimethylformamide (1:1), 100 °C, μW, 2 h; (c) potassium carbonate, R-Br, dimethylformamide, rt, 2–10 h.