A series of pyrazine-based calixarene extractants was prepared by a stepwise functionalization, comprising palladium-catalyzed exhaustive cross-coupling of di- and tetrasubstituted calixarenes bearing chloropyrazine moieties. The extraction behavior of the synthesized ligands was studied on Am–Eu mixtures under acidic feed conditions similar to those prevailing in nuclear wastes. Phosphorylpyrazine-bearing extractants exhibited a very high acid resistivity and a high affinity for americium giving D values as high as 794 at pH 1. The synergistic effect of the chlorinated cobalt bis(dicarbollide) anion [(B9C2H8Cl3)2Co]− (CCD-anion), as well as the effect of the calixarene platform compared to monovalent ligands, was investigated. The presence of 1 mM CCD resulted in a 105 times increase in the D value.