Reaction clusters sere to carry out reactions whose thermodynamic yield is too low for practical large-scale application. They therefore play an important role in the economics of the process and can decisively control its environmental impact. Reaction cluster synthesis must address such economic and environmental considerations. This was successfully accomplished in this work, which is the first employing an optimization technique for this task. The problem formulation ensures that all mass balances are satisfied, that all reactions are thermodynamically feasible, and that they follow certain user-defined characteristics of a generalized chemical reaction. In addition, given a set of chemical species, all clusters are identified that can represent this reaction; the ones found first are the most promising candidates. The formulation is flexible, accommodating a different number of reactions per cluster and allowing specification of many attributes by the user.