Modification of nucleosides via cross-coupling processes has been carried out extensively on unprotected halonucleosides to produce functionalized nucleosides that are often developed for incorporation into oligonucleotides or used as fluorescent probes. This approach requires protection of the 5 -OH with the 4,4 -dimethoxytrityl (DMTr) group, which is complicated and a common cause of reaction failure. Here we report a method for direct functionalization of 5 -O-DMTr-5-iodo-2 -deoxyuridine via Suzuki-Miyaura cross-coupling, Heck alkenylation, and carboamidation. This approach facilitates rapid synthesis of a variety of C5-substituted 5 -O-DMTr-2 -deoxyuridine derivatives. © 2022 Wiley Periodicals LLC. BasicProtocol 1: Synthesis of the SerrKap palladacycle complex Basic Protocol 2: Suzuki-Miyaura coupling of 5 -O-DMTr-5-iodo-2deoxyuridine using SerrKap palladacycle Basic Protocol 3: Heck coupling of 5 -O-DMTr-5-iodo-2 -deoxyuridine using SerrKap palladacycle Basic Protocol 4: Heck coupling of 5 -O-DMTr-5-iodo-2 -deoxyuridine with Ruth linker using Pd(OAc) 2 /PTABS Basic Protocol 5: Carbonylative amidation of 5 -O-DMTr-5-iodo-2deoxyuridine using Pd(OAc) 2 /PTABS

Etherification of chloroheteroarenes was performed at low temperatures under metal‐free, ligand‐free and base‐free conditions, that is, the reaction is promoted by the cooperative effect of DMSO (solvent) as a promoter and K3PO4 providing the catalytic surface (rather than a base). The protocol exhibits good substrate scope under mild reaction conditions and has also been explored mechanistically.