A novel approach to the synthesis of fully substituted pyrimidine derivatives armed with an oxy-functionalized acetate chain at the ring is described. The manifold uses amidines as the nitrogen source and activated skipped diynes as the electrophilic reactive partners in a coupled domino strategy. In the first domino reaction, two consecutive aza-Michael additions assemble the six-membered ring heterocycle, while in the second domino process, a [H]-shift and a [3,3]-sigmatropic rearrangement lead to the aromatization of the product. ; This research was supported by the Spanish Ministerio de Economía y Competitividad (MICINN) and the European Regional Development Fund (CTQ2011- 28417-C02-02). S.L.T. thanks the Spanish MEC for an FPU grant. ; Peer Reviewed