Solvents are widely used as reaction media in the chemical, fine chemical and pharmaceutical industries, but they present numerous environmental, health and safety (EHS) challenges that need to be managed and are subject to increasing regulatory scrutiny. The above issues, together with the principles of green chemistry, highlight the need to minimize and optimize the use of organic solvents as much as possible. One important step in optimizing organic solvent use is the identification of suitable ‘greener' solvents that can help to minimize the environmental, health and safety concerns during design and commercial manufacture of chemical products. A method for selecting appropriate ‘greener' solvents for the promotion of a class of organic reactions has been previously developed by Gani et al. This method employs estimates of thermodynamic properties to generate a knowledge base of reaction- and solvent-related properties that directly or indirectly influence a given reaction. In this work, the methodology has been extended through its application to several cases of increased process complexity involving multi-step reaction systems and solvent substitution for specific reaction steps in existing processing systems. The problems were formulated using the original methodology guidelines and incorporate knowledge of industrial practice in the currently available computer-aided tools for solvent design and property estimation. This presentation will describe the results obtained for a single reaction solvent screening problem, several solvent replacement problems and a multi-stage reaction system. In each example a list of solvent candidates is generated so they may be further investigated experimentally.