Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp³) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp²)–C(sp³) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design–make–test–analyze (DMTA) cycle in drug discovery.