A directed iridium-catalyzed C-H amination methodology applicable to substrates with a wide range of directing groups and with outstanding functional group tolerance was developed. HTE applications facilitated not only rapid optimization of reaction conditions, but also allowed for reaction miniaturization to nanomolar scale and use of automation throughout the campaign. An important aspect of this study was exploring both the opportunities and limitations of the reaction, disclosing both successful and unsuccessful reactions. The directing group and LSF informer libraries, in combination with the functional group tolerance studies allowed for the generation of guidelines for predicting reaction applicability to complex substrates. In terms of demonstrated substrate scope, a broad range of building blocks with diverse directing groups were synthesized, and late-stage functionalization of a number of structurally complex drugs and natural products was demonstrated.