Next, we sought to gain deeper insights into the catalytic system. Intrigued by the efficient sulfoximine cross-coupling with tert-butylamine, we performed in-situ 1 H-NMR spectroscopic analysis, which revealed that the coupling proceeds to completion within 18 minutes in the NMR tube without stirring at 60 °C (Figure ). Similarly, the aniline cross-coupling could be monitored in the NMR tube (Figure ). This allowed us to conveniently conduct "same-excess" experiments pioneered by Blackmond to probe for possible product inhibition or catalyst deactivation (Figure ). The experiments were performed by keeping the excess of the nucleophile and base constant while varying the initial aryl bromide concentration. Graphical comparison of the overlay of reaction profiles after reaching the same concentration demonstrates how robust catalysis can be maintained in a labile system involving rapid interconversion of various species, one or more of which exhibit catalytic competence (Figure ). The accumulation of HBr and product does not interfere with the catalyst, and the active catalytic species can be regenerated without irreversible deactivation which would result in a loss of catalytic performance. "Same-Excess" for Aniline Cross-Coupling Coordination Behaviour To gain a deeper understanding of the coordination behavior of different species within the catalytic system (Figure , C), we recorded 1 H-NMR spectra for solutions of aniline and tert-butylamine alone (C1), aniline with 5 mol% nickel (C2), and aniline with tert-butylamine and 5 mol% nickel (C3). Coordination of aniline with nickel resulted in a noticeable shift of the aromatic hydrogen signals (C2), indicating effective coordination. However, upon the addition of tert-butylamine (C3), the aniline signals shifted back to their original positions (C1 for reference), demonstrating the superior coordination ability of tertbutylamine. The preferential coordination of tert-butylamine made us question how the nucleophile properties influence reactivity. While anilines of varying electronic nature all lead to quantitative product formation with 4-bromobenzotrifluoride, slightly diminished yields were obtained for sterically more hindered anilines (Figure ). Therefore, we performed competition experiments to determine relative reaction rates with aniline as the reference nucleophile. Despite the dynamic nature of the system with various species in equilibrium, a clear trend in relative rates was observed, allowing for the classification of anilines based on their size as defined by the percent buried volume at nitrogen. Ortho-substituted anilines with Boltzmannweighted buried volumes (3.5 Å radius) above 45% exhibited slower rates compared to anilines with varying electronic properties, except for 4-(trifluoromethyl)aniline, which reacted at a rate comparable to 2,4,6-trimethylaniline (Figure ). The assessment of electronically and sterically differentiated anilines revealed significant reactivity differences that align well with computationally derived descriptors describing the electronic and steric properties of the anilines. For electronically varied anilines, a linear correlation with the nitrogen partial charge (determined from a natural population analysis (NPA) calculation) was established, showcasing that more electron-rich anilines exhibit faster reaction rates (Figure ). Similarly, a linear correlation with the buried volume at nitrogen was observed for sterically hindered anilines (Figure ). These results underscore the crucial role of aniline nucleophilicity on the product selectivity in competition experiments, emphasizing the importance of tert-butylamine/nucleophile exchange for product formation. Additionally, we examined the impact of the aryl bromide properties on the aniline cross-coupling. Consistent with previous nickel-photoredox catalyzed protocols and mechanistic studies, electron-rich aryl halides led to decreased reaction rates in competition experiments (bromobenzene used as the reference), demonstrated by a correlation with the Mulliken electronegativity of the aryl bromides (Figure ). Next, we turned our attention to the phenol coupling partners. Interestingly, the analogous NMR coordination experiment performed with aniline (Figure , C) indicates that, in the absence of tert-butylamine, DMA coordinates preferentially over phenol, consistent with the weak nucleophilicity of this coupling partner (Figure ). While the reaction still proceeds reliably in the NMR-tube, significantly prolonged reaction times were observed when compared to the reaction vial (Figure ). For electronically differentiated phenols, a similar correlation between the oxygen partial charge of phenols and their respective reaction rates was identified in competition experiments (Figure ). Interestingly, the NPA partial charge on oxygen had a significantly lower impact on reaction rate as compared to the analogous anilines. Performing cross-coupling reactions with electronically differentiated phenols in individual reaction vials still led to the same trend that the more nucleophilic phenols are noticeably faster, emphasizing the nucleophile's impact on the reaction rate (Figure ). These results underscore the importance of both coupling reagents on the reaction rate. The univariate linear correlations with accessible and interpretable molecular features not only provide a foundation for more sophisticated data science models capable of quantitative reaction outcome prediction but moreover enable qualitative reactivity estimation simply by evaluating the most fundamental properties of the reagents. The practicality of performing these reactions and predicting their outcomes is notable, given the complexity at the microscopic scale. The simplicity and versatility of the unified cross-coupling reaction conditions have proven highly efficient for the functionalization of biomolecules, whether employed as electrophiles or nucleophiles (Figure ). For instance, the use of diacetone-D-galactose and boc-L-tyrosine methyl ester as nucleophiles allows C(sp 2 )-O cross-coupling reactions for the functionalization of phenol and aliphatic alcohol, respectively, giving the desired products 46 and 47 in good isolated yields. The use of biomolecules as nucleophiles is demonstrated using darunavir (48) and famciclovir (49) in C-N cross-coupling reactions. When used as an electrophile, etoricoxib allows for efficient functionalization of the C(sp 2 )-Cl bond with sulfoximine (50). The system's simplicity becomes more apparent when applied to difunctionalization reactions, which involve forming one or two different chemical bonds to rapidly construct molecular complexity. Previously, we reported a nickel photoredox protocol for straightforward introduction of molecular complexity through sequential one-pot bifunctionalization of arenes and heteroarenes with C-S cross-coupling reactions, followed by various C-N cross-coupling reactions. However, sequential C-N/C-N and C-O/C-N cross-couplings posed challenges, such as the requirement for DABCO, which led to precipitate formation, and the self-coupling of additives like cyclohexylamine and TMG, complicating sequential transformations. The introduction of tert-butylamine has simplified these reactions. To our delight, alcohols, anilines, sulfoximines, and aliphatic amines could be employed in sequential one-pot difunctionalizations using tert-butylamine as the sole additive. For example, hexanol and aniline can be installed onto 1,3-dibromopyridine, giving the desired product 51 in a good 63% isolated yield considering a two-step transformation. Employing dimethylsulfoximine as the second nucleophile allowed for isolation of 57% of the respective product 52. An aniline coupling followed by pyrrolidine was successfully introduced onto 1,3dibromobenzene, 1,3-dibromopyridine, and 2,6-dibromopyridine, yielding the respective isolated products 53-55 in 33%-60%. Additionally, cross-coupling of two electronically different anilines to furnish the product 56 in 57% yield was accomplished, as well as the coupling of a β-lactam, followed by dimethylsulfoximine to yield the product 57 in 60%. The experimental simplicity of the sequential difunctionalizations is noteworthy. Following the first cross-coupling reaction, the second nucleophile and tert-butylamine are added to the reaction mixture, which is then photo-irradiated under nitrogen. Lastly, the homogeneous, precipitate-free reaction conditions facilitate convenient scale-up. Figure illustrates the effective performance of the system on a gram scale, demonstrating synthesis of 58-61 with yields of 78-91%. Additionally, the reactions can be performed with inexpensive nickel hydrate salts and low catalyst loadings (1.25 mol%) as exemplified for the cross-coupling reaction with sulfoximine (Table and).