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. Author manuscript; available in PMC: 2016 Jun 10.
Published in final edited form as: J Med Chem. 2015 Aug 4;58(15):5863–5888. doi: 10.1021/acs.jmedchem.5b00423

Scheme 8a.

Scheme 8a

aReagents and conditions: (a) (i) methyl 6-chloro-4-methylpicolinate, Pd(OAc)2, XantPhos, Cs2CO3, toluene, 110 °C, 16 h; (ii) 2 N aq NaOH, THF, CH3OH, rt, 16 h; (iii) 2 N aq HCl; (b) (i) methyl 2-chloro-6-methylisonicotinate, Pd(OAc)2, XantPhos, Cs2CO3, toluene, 110 °C, 16 h; (ii) 2 N aq NaOH, THF, CH3OH, rt, 16 h; (iii) 2 N aq HCl; (c) (i) methyl 6-chloro-3-methylpicolinate, Pd(OAc)2, JohnPhos, Cs2CO3, toluene, reflux, 14 h; (ii) LiOH·H2O, THF, CH3OH, H2O, rt, 72 h; (iii) 2 N aq HCl; (d) (i) methyl 5-bromonicotinate, Pd2(dba)3, XantPhos, Cs2CO3, 1,4-dioxane, reflux, 16 h; (ii) LiOH·H2O, THF, CH3OH, H2O, rt, 4 h; (iii) 2 N aq HCl; (e) methyl 3-bromobenzoate, Pd(OAc)2, BINAP, NaOt-Bu, toluene, 110 °C, 16 h; (ii) LiOH·H2O, THF, CH3OH, H2O, rt, 16 h; (iii) 2 N aq HCl; (f) (i) methyl 2-chloro-6-methylnicotinate, Pd2(dba)3, XantPhos, Cs2CO3, toluene, 100 °C, 16 h; (ii) LiOH·H2O, THF, CH3OH, H2O, 50 °C, 30 min; (iii) 2 N aq HCl; (g) (i) methyl 2-chloronicotinate, Pd(OAc)2, XantPhos, Cs2CO3, 1,4-dioxane, 110 °C, 16 h; (ii) LiOH·H2O, THF, CH3OH, H2O, rt, 16 h; (iii) 2 N aq HCl.