An integrated online screening system was developed to rapidly screen homogeneous catalysts for activity toward a selected synthesis. The continuous-flow system comprises standard HPLC pumps for the delivery of substrates, an HPLC autosampler for the injection of homogeneous catalysts, a thermostated reactor to mediate synthesis, and a single-stage quadrupole mass spectrometer (MS) equipped with atmospheric pressure chemical ionization for the determination of product formation. MS detection offers sensitivity, specificity, and speed when applied to the analysis of dynamic processes in the condensed phase. By applying the present methodology for the study of substrate conversion mediated by homogeneous catalysts, the concentration of substrates and reaction product could be monitored while information about the catalysts could also be obtained. In an initial screening application, the performance of a selected number of Lewis acids in the multicomponent synthesis of a highly substituted 2-imidazoline was determined. Limit of detection and limit of quantitation were determined by injecting different concentrations of 2-imidazoline standards and proved to be 1.6 and 5.2 nM, respectively. The results obtained with the new screening method were in good agreement with a traditional bench-scale experiment. Moreover, the system was capable of determining catalyst performance with very low catalyst and solvent consumption while the ruggedness of the system was exhibited with a 24-h continuous analysis of 280 successive catalyst injections with a peak area variation within 7% relative standard deviation. © 2008 American Chemical Society.