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Cross-linked polymer supports are now ubiquitous throughout the fields of combinatorial chemistry, organic synthesis, and catalysis (
1
,
2
). However, problems associated with the heterogeneous nature of the ensuing chemistry and with “on-bead” spectroscopic characterization have meant that soluble polymers are developing as alternative matrices for combinatorial library production and organic synthesis (
3
,
4
). Synthetic approaches that utilize soluble polymers, termed “liquid-phase” chemistry or soluble polymer-supported chemistry, couple the advantages of homogeneous solution chemistry—high reactivity, lack of diffusion phenomena, and ease of analysis—with those of solid phase methods—use of excess reagents and easy isolation and purification of products. Separation of the functionalized matrix can be achieved by a number of processes. Methods include solvent or heat precipitation, membrane filtration, and size-exclusion chromatography. This chapter will detail both the different areas of synthetic and combinatorial chemistry in which soluble polymer supports are used and the experimental techniques exploited.