A set of 46 functional groups were selected as molecular building blocks. The solvent was represented by integer variables to indicate the number of each functional group present in the solvent molecule. To ensure that only chemically feasible combinations of functional groups are generated during the optimization process and to limit the size of the solvent, a set of chemical feasibility and complexity constraints was imposed. For instance, constraints were used to ensure the octet rule . Since the solvent designed must be in the liquid phase at reaction conditions, the normal melting point (T m ) and the boiling point (T b ) of the solvent were added as design constraints. Two physical properties, namely, flash point (T f p ) and octanol/water partition coefficient (K ow ), as well as the oral rat median lethal dose (LD 50 ) of the solvent were constrained to reduce health, safety, and environmental impact. In total, the problem consists of 115 linear inequality and 5 linear equality constraints, where one auxiliary categorical and 7 binary variables were introduced to formulate the constraints. The types of design variables and the property prediction model used are summarized in Tables and. For a comprehensive description of the mathematical formulation used, the reader is referred to Gui et al. and section 2.3 therein.