Highly active anti-retroviral therapy (HAART) combination regimens have dramatically decreased the morbidity and mortality among patients with HIV infections. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become the key components in the combination regimens.  Three NNRTIs, efavirenz, nevirapine, and delavirdine, have been approved by FDA for the treatment of the HIV infection. Unfortunately, emergence of resistant strains of human immunodeficiency virus type 1 (HIV-1) requires new anti-HIV agents that are effective against these resistant mutants. The indole aryl sulfone (IAS) L-737,126 (1) is an NNRTI discovered at Merck that potently inhibits the growth of HIV-1 expressing wide type RT.   However, it loses significant activity vs clinically resistant strains expressing the K103N or Y181C mutation.  Research showed that substituents on the IAS common pharmacophore improved activity vs key clinical resistance mutations. Our research efforts focused on replacing the aryl sulfone, and we designed, synthesized and evaluated the activity of novel indole alkyl sulfones.  These compounds were tested for their ability to inhibit both WT and mutant RTs in a polymerase assay and in a cell based viral replication assay.  The best indole alkyl sulfones were potent inhibitors of WT RT, and in contrast to L-737,126, showed good activity in the presence of the Y181C mutation.  However, the K103N mutant retained resistance.  The chemistry to prepare a key intermediate, ethyl 5-chloro-3-thioindole-2-carboxylate (2) will be presented, along with its reaction with a variety of electrophiles to give the desired alkylation products.  The NNRTI and in vitro antiviral activity of this series of compounds will be discussed.