DNA-encoded library technologies require high-throughput, compatible, and well automatable platforms for chemistry development, building block rehearsal, and library synthesis. An affinity-based process using Watson–Crick interactions was developed that enables purification of DNA-tagged compounds from complex reaction mixtures. The purification relies on a single-stranded DNA-oligonucleotide, called capture strand , which was covalently coupled to an agarose matrix and to which a DNA-compound conjugate from a DNA-encoded library (DEL) reaction can be reversibly annealed to. The thus-formed DNA duplex tolerated surprisingly stringent washing conditions with multiple solvents to remove excess reactants and reagents. The tolerated solvents included aqueous buffers, aqueous EDTA solutions to remove metal ions, aqueous mixtures of organic solvents, and even pure organic solvents. The purified DNA-conjugate was eluted with aqueous ammonia and could be used for reaction analysis or for instance in DNA-encoded library synthesis. The lab equipment for purification was tailored for automation with open-source hardware and constructed by 3D printing.