A nano-compartmentalized one-solvent (ONE-FLOW) procedure was developed for the two-step synthesis of Rufinamide, employing a combined simulation and experimental approach. Computer-aided solvent selection was combined with reagent/catalyst compartmentalization in a continuous flow set-up. The synthetic route encompassed azidation of benzyl chloride, followed by a Cu-catalyzed azide alkyne cycloaddition (CuAAC) reaction. A functional solvent was chosen via a COSMO-RS based method, which allowed a one-phase reaction while facilitating a thermally induced final product separation from the reaction mixture. To perform azidation and CuAAC reactions in a microfluidic system, both azidation reagent and Cu(I) catalyst were immobilized, on a packed bed and in the hydrophobic membrane of polymer vesicles, respectively, as this allowed a higher reaction efficiency, facile regeneration of azidation reagent, and recovery of the metal catalyst. This ONE-FLOW process has great benefits for the pharmaceutical industry in their quest to scalable, efficient and safe synthetic processes with minimal waste generation.