DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on‐DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods.

A method for the construction of cyclophanebraced peptide macrocycles via Pd-catalyzed aminoquinolinedirected intramolecular C(sp 3 )−H arylation with aryl iodides is developed. Unlike our previous AQ-directed exo-type intramolecular C−H arylation of long alkyl tails, this endo-type C−H cyclization reaction takes places on the β-methyl group of Nmethyl alanine at the C-termini of peptides. Unusual C−N cleavage side products of Ala were observed and attributed to intramolecular deprotonation-assisted α,β-elimination of the palladacycle intermediate.

A photoredox-mediated δ-C(sp 3 )−H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.