Chemically generated libraries of small, non-oligomeric compounds are being widely embraced by researchers in both industry and academia. There has been a steady development of new chemistries and equipment applied to library generation so it is now possible to synthesize almost any desired class of compound. However, there are still important issues to consider that range from what specific types of compounds should be made to concerns such as sample resynthesis, structural confirmation of the hit identified, and how to best integrate this technology into a pharmaceutical drug discovery operation. This paper illustrates our approach to new lead discovery (individual, diverse, drug-like molecules of known structural identity using a simple, spatially addressable parallel synthesis approach to prepare Multiple Diverse as well as Universal Libraries) and describes some representative examples of chemistries we had developed within these approaches (preparation of bis-benzamide phenols, thiophenes, pyrrolidines, and highly substituted biphenyls). Finally, the manuscript concludes by addressing some the present concerns that still must be considered in this field.
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