within a distance of 30 nucleotides). In a sequence-programmed fashion oligonucleotides carrying one chemical reactant group were hybridized to complementary oligonucleotide derivatives carrying a different reactive chemical group. The proximity conferred by the DNA hybridization drastically increases the effective molarity of the reaction reagents attached to the oligonucleotides, enabling the desired reaction to occur even in an aqueous environment at concentrations which are several orders of magnitude lower than those needed for the corresponding conventional organic reaction not DNA-templated. Using a DNA-templated set-up and sequence-programmed synthesis Liu and co-workers generated a 64-member compound DNA encoded library of macrocycles. 3-Dimensional proximity-based technology (YoctoReactor technology) The YoctoReactor (yR) is a 3D proximity-driven approach which exploits the self-assembling nature of DNA oligonucleotides into 3, 4 or 5-way junctions to direct small molecule synthesis at the center of the junction. Figure 5 illustrates the basic concept with a 4-way DNA junction. The center of the DNA junction constitutes a volume on the order of a yoctoliter, hence the name YoctoReactor. This volume contains a single molecule reaction yielding reaction concentrations in the high mM range. The effective concentration facilitated by the DNA greatly accelerates chemical reactions that otherwise would not take place at the actual concentration several orders of magnitude lower. Building a yR library Figure 6 illustrates the generation of a yR library using a 3-way DNA junction. In summary, chemical building-blocks (BB) are attached via cleavable or non-cleavable linkers to three types of bispecific DNA oligonucleotides (oligo-BBs) representing each arm of the yR. To facilitate synthesis in a combinatorial manner, the oligo-BBs are designed such that the DNA contains (a) the code for an attached BB at the distal end of the oligo (colored lines) and (b) areas of constant DNA sequence (black lines) to bring about the self-assembly of the DNA into a 3-way junction (independently of the BB) and the subsequent chemical reaction. Chemical reactions are performed via a stepwise procedure and after each step the DNA is ligated and the product purified by polyacryamide gel electrophoresis. Cleavable linkers (BB-DNA) are used for all but one position yielding a library of small molecules with a single covalent link to the DNA code. Table 1 outlines how libraries of different sizes can be generated using yR technology. The yR design approach provides an unvarying reaction site with regard to both (a) distance between reactants and (b) sequence environment surrounding the reaction