Nucleoside reverse transcriptase inhibitors are the only drugs so far approved for the treat-ment of AIDS. Several nucleoside analogs are potent inhibitors of human immunodeficiency virus (HIV) in cell culture. However, in many cases the nucleoside derivatives have a poor affinity for nu-cleoside kinases. Nucleoside 5'-phosphorothioates is relatively resistant to enzymatic transformations. In this paper, 2', 3'-O-alkoxymethylidene adenosine 5'-thiophosphoramidates were synthesized through a highly efficient approach. The new compounds were characterized by NMR, IR and ESI-MS.