2-Oxazolines are well-known organic compounds which are included in a variety of complex biologically active structures and play a role as catalyst ligands and intermediates for functional compounds. In addition, 2-oxazolines serve as monomers for the synthesis of substituted poly(imine)s by cationic ring-opening polymerization. For the latter application, the feasibility of preparing new 2-substituted-2-oxazolines was investigated using an automated synthesizer. The reaction of various nitriles with 2-aminoethanol under Lewis acid catalysis was utilized for this purpose. Twenty-nine different substituted nitriles were selected out of more than 2000 commercial available nitriles to form the corresponding 2-oxazolines. At first, the reaction conditions were optimized for seven nitriles with regard to solvent and catalyst, including reproducibility tests in an automated parallel robot system. In the next step, the synthesis of all 29 2-oxazolines was screened in an automated parallel manner, whereby the reactions were monitored by GC-MS measurements providing novel insights in the scope of this synthesis route. These insights resulting from the high-throughput screening were validated by performing representative larger-scale syntheses of selected 2-oxazolines.