A methodology is presented to integrate reactor and distillation sequences and identify the optimal one with sufficient operational flexibility. The minimum Gibbs free energy principle and non-key component matrix are used to identify the composition of reactor's product and all distillation sequences. For distillation columns, key parameters are calculated based on Fenske-Underwood-Gilliland method, and the design variables, such as diameter and plate spacing, are identified to guarantee operational flexibility. The procedure is proposed for identifying the optimal distillation sequence with sufficient flexibility and minimum total annualized cost. For the studied styrene production process, the optimal sequence is identified from 14 possible sequences; its cost for producing unit product decreases by 26.19%, and the reactor's optimal inlet temperature is 930 K. For the ethylbenzene production process, the cost of unit product decreases by 38.6%, and the optimal byproduct recycling ratio is 1.