First-row transition metal catalysts have become essential tools in organic synthesis, exhibiting unique reactivity and selectivity profiles in reductions, oxidations, and cross coupling chemistry. While catalysts based on Fe and Ni have been touted as sustainable alternatives to precious metal catalysts, their application is limited in high-throughput discovery campaigns due to the dearth of precedented pre-catalysts, reported commercial ligands, and the risk of deleterious speciation events. The selection of new metal precursor and ligand combinations is oftentimes non-intuitive with limited understanding of why reactions succeed or fail. This talk will discuss the development of several reactions that rely upon small molecule ligand scaffolds for Fe and Ni that achieve substrate generality in dearomative and decarboxylative couplings using Informed High Throughput Experimentation (I-HTE), a strategy that relies on experimental catalyst descriptors to maximize the probability of successful reaction outcomes in HTE.