DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in pharmaceutical industry, mainly due to its powerful diversity and incredible number of molecules. In the past two decades since its disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL-setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C–C bonds on DNA was studied, which represents the first radical-based synthesis in DEL.