Highly selective and AI-predictable Se–N exchange chemistry between benzoselenazolones and boronic acids for programmable, parallel, and DNA-encoded library synthesis

Chemical reactions compatible with multiple functionalities are essential for rapid, programmable, and automatable synthesis of functional molecules. However, achieving such reactivity poses significant challenges. Here, we developed a novel multi-orthogonal C(sp²)-Se bond formation reaction between benzoselenazolones and boronic acids <i>via</i> Ag(i)-catalyzed selective selenium(ii)-nitrogen exchange. This chemistry is compatible with diverse functionalities, enabling sequential and programmable synthesis. Moreover, it features modular, high-yielding (485 examples, with yields or conversions exceeding 70% in 95% of cases), and switchable reaction systems under mild conditions. Its practical utility was exemplified through late-stage functionalization of natural products, peptide modification and ligation, diversified synthesis, sequential click chemistry, protecting group-free syntheses of sequence-defined oligo selenides (nonamers), on-plate nanomole-scale parallel synthesis (200 nmol, 412 selenides), and DNA-encoded library (DEL) synthesis (10 nmol, 92 examples). Notably, a target-based screening identified SA-16 as a potent CAXII inhibitor with an IC₅₀ value of 72 nM. Furthermore, a machine learning-based model (SeNEx-ML) was established for reaction yield prediction, achieving 80% accuracy in binary classification and 70% balanced accuracy in ternary classification. These results demonstrated that this chemistry serves as a powerful tool to bridge the selenium chemical space with the existing chemical world, offering transformative potential across multidisciplinary fields.