Combinatorial synthesis via DNA encoded library (DEL) has evolved as a technology of great importance in drug discovery. However, the idiosyncratic aqueous, dilute, DNA-sensitive parameters and infinitesimal scale of this system present new challenges for traditional organic reactions. A detailed protocol aiding the transition from organic reactions to reactions with DNA-bound molecules was developed using a tactical combination of kinetic analysis and reaction screening. As an example, the venerable Giese addition was applied to forge high-value C−C bonds, including all-carbon quaternary centers, on DNA, representing the first radical-based synthesis in DEL that expands the traditional toolbox beyond pericyclic, carbonyl-based, and two-electron cross-couplings.

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their 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(sp 3 )−C(sp 3 ) 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 a radical-based synthesis in DEL.