The paradigm setting concept of solid phase peptide synthesis relies on the covalent attachment of a growing macromolecule to an insoluble solid support to produce a peptide-resin polymer network. Once synthesized, purification and handling of peptides is dominated by non covalent adsorption onto a variety of supports such as those used for chromatography. The utility of this Reversible Absorption of Macromolecules to a Solid Support (RASS) for facilitating synthetic transformations has been recently explored in our lab. We find that the approach has potential to improve peptide handling over multiple step bioconjugation reactions, as well as facilitating the transfer of unprotected peptides to organic solvent to facilitate selective reactions requiring a strong base. In related work, the structural diversity of DNA Encoded Libraries has been limited since the hydrophilic, unprotected nature of the DNA tag severely limits the repertoire of compatible chemical reactions. Rather than pursuing the optimization of individual synthetic organic reactions for water compatibility, we reasoned that a general strategy for transferring DNA-substrates into organic solvents could significantly expand the structural diversity explored by DEL. This RASS strategy was adapted for DEL through a polystyrene based, quaternary ammonium resin. Adsorption of DNA headpiece substrates to this resin was found to facilitate transfer to organic solvents such as DMA, THF, and CH2Cl2. This RASS approach for DEL has enabled the development of Ni-mediated carbon-carbon (C(sp2)-C(sp3)) and carbon-heteroatom (C-N, C-S, C-P) cross couplings with broad substrate scope and with excellent DNA compatibility. The immobilization of the DNA has also facilitated the use of electrochemical transformations. This expanded scope of reaction conditions compatible with DEL library generation has the promise to contribute to the generation of conformationally diverse scaffolds with drug-like properties.