The use of a proper encoding methodology is one of the most important aspects when practicing DEL technology. A "headpiece"-based double-stranded DEL encoding method is currently the most widely used for productive DEL. However, the robustness of double-stranded DEL construction conflicts with the versatility presented by singlestranded DEL applications. We here report a novel encoding method, which is based on a "reversible covalent headpiece (RCHP)". The RCHP allows reversible interconversion between double-and single-stranded DNA formats, providing an avenue to robust synthesis and allowing for the applications in distinct setups. We have validated the versatility of this encoding method with encoded self-assembled chemical library and DNA-encoded dynamic library technology. Notably, based on the RCHP-settled library construction, a unique "ternary covalent complex" mediating ligand isolation methodology against non-immobilized targets was developed.

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Indole-based diversification is highly desired in the DNA-encoded chemical library construction. Herein, we present a general strategy for on-DNA synthesis of diverse C3-functionalized indole derivatives via indole π-activated alcohol formation followed by direct dehydrative coupling. Highly efficient bond linkages of C–C, C–N, and C–S were achieved to fuse building blocks that are widely commercially available. DNA-encoding compatibility of the method has been further demonstrated to pave an avenue for application in constructing indole-focused three-dimensional libraries.

The use of a proper encoding methodology is one of the most important aspects when practicing DEL technology. A "headpiece"-based double-stranded DEL encoding method is currently the most widely used for productive DEL. However, the robustness of double-stranded DEL construction conflicts with the versatility presented by singlestranded DEL applications. We here report a novel encoding method, which is based on a "reversible covalent headpiece (RCHP)". The RCHP allows reversible interconversion between double-and single-stranded DNA formats, providing an avenue to robust synthesis and allowing for the applications in distinct setups. We have validated the versatility of this encoding method with encoded self-assembled chemical library and DNA-encoded dynamic library technology. Notably, based on the RCHP-settled library construction, a unique "ternary covalent complex" mediating ligand isolation methodology against non-immobilized targets was developed.