An efficient large-scale synthesis of a novel DPP-4 inhibitor 1, an isoquinolone derivative bearing an aminomethyl group at the 3-position and carbamoylmethoxy group at the 6-position, is described. We have developed an effective and convenient synthetic method utilizing a key intermediate possessing a cyano group at the 3-position and a halogen atom at the 6-position. The key reaction, the insertion of an oxygen atom at the 6-position of isoquinolone was achieved by a cross-coupling reaction using 6-bromoisoquinolone and sodium tert-butoxide ( t BuONa) in the presence of Pd(OAc)2 and rac-BINAP as a catalyst to afford 6-tert-butoxyisoquinolone in good yield. The cyano group at the 3-position was hydrogenated in the presence of Raney nickel to give the aminomethyl moiety of compound 1. The synthetic route has been successfully applied to multikilogram-scale preparations in good yield and high quality.