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An efficient synthesis of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) is described. Our route features the construction of a crystalline lactone intermediate via a selective palladium-catalyzed 4-methylimidazole N 1 -arylation using the Buchwald Xantphos Pd G4 precatalyst, which does not require a preactivation step. The weak inorganic base KHCO 3 was employed to minimize saponification of a particularly sensitive lactone substrate. Additional key transformations include DABAL-Me 3 -mediated lactone aminolysis and a mild TBD/ethyl trifluoroacetate mediated lactam ring closure to afford a representative GSM in high yield.