Oligonucleotide templated reactions can be used to control the activity of functional molecules based on the presence of a specific trigger sequence. We report an RNAcontrolled reaction system to conditionally restore the N-terminal amino group and thus binding affinity of azide-modified Smac mimetic compounds (SMCs) for their target protein X-linked Inhibitor of Apoptosis Protein (XIAP). Two templated reactions were compared: Staudinger reduction with phosphines and a photocatalytic reaction with Ru(bpy) 2 (mcbpy). The latter proved faster and more efficient, especially for the activation of a bivalent SMC, which requires two consecutive reduction steps.The templated reaction proceeds with turnover when 2 0 -OMe-RNA probes are used, but is significantly more efficient with PNA, catalyzing a reaction in the presence of low, substoichiometric amounts (1%-3%, 10 nM) of target RNA.