A hybrid distillation process for pure ethyl acetate production was studied in the presented work. Ethyl acetate was produced via direct esterification of ethanol by acetic acid in a reactive distillation (RD) column with parallel production of glycols. Ethylene oxide hydration was considered as an auxiliary reaction to consume the esterification by-product – water. Thus, high level of process integration and intensification was achieved in the complex reactive system applying chemical reaction synergy. However, possible undesired side reactions should be considered in such complex reactive systems. In this work, three different reactive distillation column models assuming non-equilibrium (rate-based) stage approach were built to calculate the effect of side reactions. First case study assumed only basic reactions (main esterification and hydration); in the second case study, eight reactions were taken into account, and the last case study assumed splitting EO feed to achieve higher purity of product streams. Side reactions affect the process design significantly. To obtain the required products in sufficient purity, optimization of the RD column was performed using two different methods: conventional SQP algorithm, and genetic algorithm. Optimization results show that the conventional SQP algorithm can solve simple problems finding suitable solutions that meet the design requirements. This method failed when optimizing a complex reactive system. The genetic algorithm improved the solution found by the SQP method and the obtained results showed that parallel production of pure ethyl acetate and glycols in one reactive distillation column is a promising way to intensify the production process. Process modeling was performed using the Aspen Plus software and MATLAB.