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Different techniques can be applied for the automated production of small and large compound collections. Large libraries that are often generated and tested during the lead-finding stage of a project are typically produced by solid-phase chemistry. Libraries that are significantly smaller in size are often synthesized in solution. Chemistry in solution is rather versatile, offers numerous advantages and is therefore often the method of choice for generating small libraries during a lead optimization process. Fast and reliable purification procedures are required to yield compounds of high quality that can be immediately used in biological as well as pharmacological assays. Solution-phase chemistry combined with automated purification was applied to optimize initial lead inhibitors for the two human orexin receptors OX1 and OX2. Starting from a submicro-molar OX1 selective lead compound, low nanomolar analogues with improved physico-chemical properties were synthesized that antagonize either one or both orexin receptors.