We report on a strategy for using SABRE (signal amplification by reversible exchange) for polarizing (1)H and (13)C nuclei of weakly interacting ligands which possess biologically relevant and nonaromatic motifs. We first demonstrate this via the polarization of acetonitrile, using Ir(IMes)(COD)Cl as the catalyst precursor, and confirm that the route to hyperpolarization transfer is via the J-coupling network. We extend this work to the polarization of propionitrile, benzylnitrile, benzonitrile, and trans-3-hexenedinitrile in order to assess its generality. In the (1)H NMR spectrum, the signal for acetonitrile is enhanced 8-fold over its thermal counterpart when [Ir(H)2(IMes)(MeCN)3](+) is the catalyst. Upon addition of pyridine or pyridine-d5, the active catalyst changes to [Ir(H)2(IMes)(py)2(MeCN)](+) and the resulting acetonitrile (1)H signal enhancement increases to 20- and 60-fold, respectively. In (13)C NMR studies, polarization transfers optimally to the quaternary (13)C nucleus of MeCN while the methyl (13)C is hardly polarized. Transfer to (13)C is shown to occur first via the (1)H-(1)H coupling between the hydrides and the methyl protons and then via either the (2)J or (1)J couplings to the respective (13)Cs, of which the (2)J route is more efficient. These experimental results are rationalized through a theoretical treatment which shows excellent agreement with experiment. In the case of MeCN, longitudinal two-spin orders between pairs of (1)H nuclei in the three-spin methyl group are created. Two-spin order states, between the (1)H and (13)C nuclei, are also created, and their existence is confirmed for Me(13)CN in both the (1)H and (13)C NMR spectra using the Only Parahydrogen Spectroscopy protocol.