Both nonreactive and reactive multiwell plate experiments were combined with Raman microscopy and band-target entropy minimization (BTEM) analysis. The multicomponent nonreactive experiments showed that accurate pure component spectral estimation is possible without recourse to any spectral libraries. The multicomponent reactive experiments showed that, in addition to accurate pure component spectral estimation, concentration profiles can be obtained for quantitative purposes. In the present case, the solvent and time dependence of a cycloaddition reaction was addressed as the high-throughput experimentation issue. A total of 1152 experimental spectra were collected and analyzed. Two methods were used, namely, (A) each solvent set was individually analyzed and (B) the entire set of spectra, from 4 different solvents, were analyzed all together. Method B provided very satisfactory results. The present study with combined Raman-multiwell plate-BTEM analysis establishes proof of concept. The new approach appears to be applicable to other frequently conducted combinatorial/high-throughput experimentations. These include, but are not restricted to, chemo- and regioselective studies, solid-phase syntheses, etc.