Many pharmaceuticals, specialty chemicals, pesticides, or monomers are manufactured in processes with a large number of reaction steps and separations between reactors. These coupled steps lead to the use of multiple plants consisting of reaction-separation systems, coupled by intermediate and recycle flows in a plant complex. Integrated plant complexes are also used for producing petrochemicals. Douglas (Synthesis of Multistep Reaction Processes. In Foundations of Computer-Aided Design; Siirola, J. J., Grossmann, I. E., Stephanopoulos, G., Eds.; Cache-Elsevier: Amsterdam, The Netherlands, 1990; pp 79-103) described a procedure for the conceptual design of such plant complexes that relies on heuristics and that can generate a number of alternative layouts. We describe a framework to automate the determination of mole balances around and between plants in such complexes. In this procedure, the plant complex is represented as a state task network and reaction invariants are used to formulate the component balances. Mole balances for mixing and splitting of component flows are identified automatically, which provides the structure of the coupling between plants and a systematic means to identify alternatives to make, buy, or make remotely for intermediates. The approach is demonstrated for production of Bisphenol A, adipic acid, and for an anticonvulsant drug. The methodology greatly reduces the engineering effort in formulating the overall balances for interconnected plants with many reactions.