Nucleophilic aromatic substitution (SNAr) is used on a daily basis by pharmaceutical chemists around the world to construct the prototypes for biologically-active compounds. In the typical SNAr reaction, an electron-deficient aromatic ring containing a nucleofugal group, such as a halogen, undergoes ipso-substitution by a nucleophile to form an intermediate Jackson-Meisenheimer σ X complex followed by loss of the halide (Scheme 1A). An analogous, yet less-frequently encountered transformation is the nucleophilic aromatic substitution of hydrogen (SNH), in which a nucleophile substitutes a hydrogen atom on a nitro(hetero)arene. The intermediate σ H adduct can be converted to the product by vicarious nucleophilic substitution (VNS) if the nucleophile possesses a leaving group positioned such that an elimination step is possible (Scheme 1B). In the absence of a leaving group, the σ H adduct can oxidatively rearomatize to complete the process known as the oxidative nucleophilic substitution of hydrogen (ONSH, Scheme 1C). To date there are several hypotheses for the mechanism of oxidation. While some proposals consider oxidation by the nitroarene substrate , other studies support atmospheric oxygen as the oxidant. We attempted to prepare compound 3 as an intermediate for a recent medicinal chemistry program via the SNAr reaction between 2-amino-5-methylpyridine (1a) and 2-chloro-4-nitropyridine (2a) (Scheme 2A) using LiHMDS. We did not observe the desired product 3, however, and were instead surprised to isolate the brightly orange-colored solid 4, whose structure was confirmed by single crystal X-ray diffraction. The formation of 4 suggested that both SNAr and ONSH reactions occurred sequentially, with the substitution pattern indicating that ONSH occurred first with the pendant amine before the pyridyl nitrogen displaced the chloride. ONSH reactions are well known to outcompete SNAr reactions on nitro(hetero)arenes substituted with halogens. 3A ONSH aminations on electron-poor nitroarene derivatives have been studied for decades. The Beier group recently employed the addition of superstoichiometric lithium anilides to nitro(hetero)arenes at deeply cryogenic temperatures (< -100 °C), followed by quenching with potassium permanganate in liquid ammonia (Scheme 2B). 8 The Wróbel group has effected nitrobenzene aminations under mild conditions with t-BuOK to form nitrosoarenes in synthetically useful yields (Scheme 2B). Recognizing the relative favorability of our reaction setup compared to the precedent, we wondered whether our conditions could be extrapolated to a more general nitro(hetero)arene amination protocol. We began our investigations using aniline 1b and chloronitropyridine 2a as model substrates. We were surprised to find that the reaction between 1.0 equiv 1b and 1.0 equiv 2a in the presence of 1.0 equiv LiHMDS generated the ONSH adduct 5a in 44% NMR yield in a nearly instantaneous reaction at room temperature (Table , Entry 1). Compound 5a represents a class of sterically hindered 2,3,4-trisubstituted pyridines that to our knowledge have not been accessed before. Encouraged by this result, we sought to improve the yield by increasing the loading of aniline 1b since an excess of aniline was optimal in the aforementioned work by Beier. Unfortunately there was no improvement in yield when either 1b or 2a was used in excess while maintaining 1.0 equiv LiHMDS (Entries 2-3). The yield was likewise not improved when 2.0 equiv LiHMDS was added to 1.0 equiv of each of the starting materials (Entry 4) or with excess aniline and excess base (Entry 5). The yields were improved, however, with excess nitropyridine and base (Entries 6-8) up to 75% isolated yield when using 3.0 equiv of nitroarene and LiHMDS each (Entry 8). We speculated that 1) excess nitroarene reagent could be acting as a sacrificial oxidant in the reaction or 2) more nitroarene was productively reacting with the anilide species. Lowering the temperature of the reaction (Entries 9-10) or switching to other HMDS counterions (Entries 11-12) did not improve the yield of the reaction. Switching to other bases (Entries 13-16) was detrimental. Although the isolated yield was higher in the case of 3.0 equiv 2a and 3.0 equiv LiHMDS (Entry 8), for economic reasons, we preferred to develop the reaction as in Entry 6. Table . Optimization of the ONSH reaction.