The development of the unprecedented ortho-regioselective inverse-electron-demand hetero-Diels-Alder (IEDHDA) reaction is described. It has been demonstrated that by proper choice of reactants and reaction conditions the inverse-electron-demand hetero-Diels-Alder cycloaddition can be realized with unprecedented regioselectivity arising from the reaction between the terminal carbon atom of the dienophile and the heteroatom of the heterodiene.