On the basis of AZT as a nucleosidic model, the protocols herein describe the synthesis of various bis(S-acyl-2-thioethyl) phosphotriester derivatives. These compounds, bearing transient phosphate-protecting groups, were designed to liberate the corresponding 5'-mononucleotide inside the cell through an esterase-mediated activation process. Two synthetic approaches are presented using either phosphoramidite intermediates or esterification of a nucleoside 5'-monophosphate.