Chemical modifications of oligonucleotides are frequently for genetic analyses or oligonucleotide therapeutics. Chemical linkers are essential for covalent bonding between oligonucleotides and exogenous molecules. We have developed highly reactive amino-linkers for terminal modifications of oligonucleotides. These linkers enable high-throughput purification and high-yield modifications of functional oligonucleotides. We have also developed interstrand cross-linkers that can site-specifically conjugate a complementary duplex. Cross-linked duplexes form extraordinarily stable helices, enabling enzyme immobilization on electrode and construction of therapeutic agents.