Studies on simultaneous synthesis of the reaction-separation processes are limited. The initial step is choosing a method to generate all possible arrangements. In this work, the Separation matrix algorithm previously developed by the authors has been expanded to include the reaction part of the process to form a Reaction/Distillation matrix. In order to achieve a comprehensive algorithm, initially all feasible matrices have been analyzed to find common points among non-synthesizable matrices. The ability of new matrix to include a broad selection of flowsheets has then been investigated. A single two-component reaction, is assumed to prevail within a four-component mixture, the fourth being the initially nonexistent reaction product. A systematic approach is presented to determine a large selection of sequences for a four-component system including three distillation columns (simple or complex) and a reactor. A practical case study of the isomerization of n-Butane has been analyzed using the procedure developed here. Published by Elsevier Ltd.