A method for calculating potential energy barriers of chemical reactions involving large molecules is presented and validated through evaluation of its performance for two classes of reactions. The method is based on the extrapolation of reactivity from small molecular systems (for which high-level quantum chemical calculations can be performed) to large ones via low-level (and thus low computational cost) calculations. The notation RESLIR (Reactivity Extrapolation from Small to Large molecular systems via the formalism of Isodesmic Reactions for transition states) is proposed for ease of reference. The RESLIR method is a further development of the technique of isodesmic reactions for transition states (IRTS). Unlike the previous applications of the IRTS technique, it does not rely on the existence of extensive experimental information on the kinetics of at least one (reference) reaction within the class. Instead, high-level predictive calculations are performed for the reference reaction, which is chosen in such a way as to include only small molecules. Predictive performance of the method is evaluated for two classes of reactions: eleven Diels-Alder reactions and twenty reactions of the addition of CH3 and CF3 radicals to C=C double bonds.