Methods for tagging DNA-encoded libraries

A method of tagging a first library comprising an oligonucleotide-encoded chemical entity, said method comprising:

• (i) providing a single-stranded oligonucleotide headpiece having a first functional group and a second functional group, wherein said headpiece comprises at least one terminal 2′-substituted nucleotide comprising said second functional group, wherein said at least one terminal 2′-substituted nucleotide is at the 5′-terminus and/or the 3′-terminus of said headpiece;
• (ii) binding said first functional group of said headpiece to a first component of said chemical entity, wherein said headpiece is directly connected to said first component or said headpiece is indirectly connected to said first component by a bifunctional linker;
• and
• (iii) ligating said second functional group of said headpiece to a single-stranded oligonucleotide first building block tag to form a complex, wherein said first building block tag comprises at least one terminal 2′-substituted nucleotide at the 5′- and/or the 3′-terminus and said ligating forms a covalent bond between a 2′-substituted nucleotide on the headpiece and a 2′-substituted nucleotide on the first building block tag, and wherein the ligating is carried out using enzymatic ligation;
• wherein said steps (ii) and (iii) can be performed in any order;
• and
• wherein said first building block tag encodes for the binding reaction of said step (ii), thereby providing a tagged library.