Optimization-based scheduling in the chemical industry is highly beneficial but also highly difficult due to its combinatorial complexity. Different modeling and optimization techniques exist, each with individual strengths. We propose Benders decomposition to integrate mixed-integer linear programming (MILP) and discrete-event simulation (DES) to solve flow shop scheduling problems with makespan minimization objective. The basic idea is to generate valid Benders cuts based on sensitivity information of the DES sub problem, which can be found in the critical paths of DES solutions. For scaled literature flow shops, our approach requires at least an order of magnitude fewer iterations than a genetic algorithm and provides optimality gap information. For a real-world case study, our approach finds good solutions very quickly, making it a powerful alternative to established methods. We conclude that the Benders-DES algorithm is a promising approach to combine rigorous MILP optimization capabilities with high-fidelity DES modeling capabilities.