C-H activations have over the recent decades risen from a mere curiosity to a viable synthetic strategy. However, challenges in terms of accessible transformations, selectivity and functional group tolerance limit the widespread applicability of this approach. The aim of the work presented in this thesis was to develop directed ortho C-H activation methodologies specifically designed for applications in drug discovery. The [Cp*Ir(III)] catalytic system was key for the herein described transformations.

Chapter 2 covers the development of selective monoiodination of benzoic acids. A mono/di selectivity >20:1 was observed throughout a range of diversely functionalized substrates. Mechanistic investigations revealed the key role of the Ag(I) additive in controlling selectivity.

Chapter 3 discusses C-H methylations applied to a wide range of benzoic acids, including examples of late-stage functionalization of marketed drugs. The methodology also allows for introduction of CD₃ groups. Biological studies demonstrated positive effect on biological and physical properties of pharmaceuticals as the result of methylation.

In chapter 4 the C-H amination and sulfonamidation of benzoic acids is described, with applications for the synthesis of aminated analogues of drug-like molecules. Rapid synthesis of conjugates relevant to drug discovery is also demonstrated.

Chapter 5 is dedicated to the development of a general C-H amination protocol, successfully applied to 21 distinct directing groups. The utility of the method is demonstrated by the functionalization of 11 complex drugs and natural products. Directing group informer libraries and functional group tolerance studies enabled the generation of guidelines for reaction outcome prediction.