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MeO-CH<sub>2</sub>-CH<sub>2</sub>-O-(CH<sub>2</sub>-CH<sub>2</sub>-O)n-CH<sub>2</sub>-CH<sub>2</sub>-OH
PEG proved suitable for this purpose since it is soluble in a wide variety of aqueous and organic solvents and its solubility provides homogeneous reaction conditions even when the attached molecule itself is insoluble in the reaction medium. Separation from the solution of the polymer and the synthesized compounds bound to it can be achieved by precipitation and filtration. The precipitation requires concentrating the reaction solutions then diluting with [[diethyl ether]] or tert-butyl methyl ether. Under carefully controlled precipitation conditions the polymer with the bound products precipitates in crystalline form and the unwanted reagents remain in solution.
In the solid phase, S&P synthesis a single compound forms on each bead, and as a consequence, the number of compounds can't exceed the number of beads. So, the theoretical maximum number of compounds depends on the quantity of the solid support and the size of the beads. On 1 g polystyrene resin, for example, a maximum of 2 million compounds can be synthesized if the diameter of the resin beads is 90
The above limitation is completely removed if the solid support is omitted
An important modification was introduced in the synthesis of DNA encoded combinatorial libraries by Harbury and Halpin.<ref>Harbury DR, Halpin DR (2000) WO 00/23458.</ref> The solid support in their case is replaced by the encoding DNA oligomers. This makes it possible to synthesize libraries containing even trillions of components and screen them using affinity binding methods.
A different way of carrying out solution-phase S&P synthesis is applying [[scavenger resin]]s to remove the byproducts. Scavenger resins are polymers having functional groups that make it possible to react with and bind components of the excess of reagents then filtered them out from the reaction mixture<ref>Steven V. Ley, Ian R. Baxendale, Robert N. Bream, Philip S. Jackson, Andrew G. Leach, Deborah A. Longbottom, Marcella Nesi, James S. Scott, R. Ian Storer and Stephen J. Taylor Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation J. Chem. Soc., Perkin Trans. 1, 2000, 3815–4195.https://doi.org/10.1039/B006588I</ref> Two examples: a resin containing primary amino groups can remove the excess of acyl chlorides from reaction mixtures while an acyl chloride resin removes amines.
A fluorous technology was described by Curran<ref>Dennis P. Curran Strategy-Level Separations in Organic Synthesis: From Planning to Practice Angew. Chem. Int. Ed. 1998, 37, 1174 – 1196.https://onlinelibrary.wiley.com/doi/epdf/10.1002/%28SICI%291521-3773%2819980518%2937%3A9%3C1174%3A%3AAID-ANIE1174%3E3.0.CO%3B2-P</ref> The fluorous synthesis employs functionalized perfluoroalkyl (Rf) groups like 4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl {CF<sub>3</sub>(CF<sub>2</sub>)<sub>4</sub>CF<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>-} group attached to substrates or reagents. The Rf groups make it possible to remove either the product or the reagents from the reaction mixture. At the end of the procedure, the Rf groups attached to the substrate can be removed from the product. By attaching Rf groups to the substrate the synthesis can be carried out in solution and the product can be separated from the reaction mixture by liquid extraction using a fluorous solvent like perfluoromethylcyclohexane or perfluorohexane. It can be seen that the function of the Rf groups in the synthesis is similar to that of the solid or soluble support. If the Rf tag is attached to reagent its excess can be removed from the reaction mixture by extraction.
Polymer supported reagents are also used in S&P synthesis.<ref>Stephen W Kaldor, Miles G Siegel Combinatorial chemistry using polymer-supported reagents. Current Opinion in Chemical Biology (1997) 101–106. {{doi|10.1016/S1367-5931(97)80115-9}}.</ref>
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====Self-assembling DNA encoded libraries====
[[File:Self assembling DNA encoded libraries.png|thumb|left|Self-assembling library. Circle and pentagon are BBs, blue and red rectangles are their codes. Green rectangles are hybridizing domains]]
One of the best examples of the special features caused by DNA encoding is the synthesis of the self-assembling library introduced by Mlecco et al.<ref>Melkko S, Scheuermann J, Dumelin CE, Neri D (2004) Encoded self-assembling chemical libraries Nat Biotechnol 22; 568-574.</ref> First, two sublibraries are synthesized. In one of the sublibraries BBs are attached to the 5’ end of an oligonucleotide containing a dimerization ___domain followed by the codes of the BBs. In the other sublibrary the BBs are attached to the 3’ end of the oligonucleotides also containing a dimerization ___domain and the codes of another set of BBs. The two sublibraries are mixed in equimolar quantities, heated to 70 °C then allowed to cool to room temperature, heterodimerize and form the self-assembling combinatorial library. One member of such two pharmacophore library is shown in the figure. In affinity screening, the two BBs of the pharmacophore may interact with the two adjacent binding sites of the target protein.
====DNA templated libraries====
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====Synthesis in Yoctoreactor====
The yoctoreactor method introduced by Hansen et al.<ref>Margit Haahr Hansen, Peter Blakskjær, Lars Kolster Petersen, Tara Heitner Hansen, Jonas Westergaard Højfeldt, Kurt Vesterager Gothelf, Nils Jakob
====Sequence encoded routing====
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