As the ultimate test for our SuFEx ligation protocol, we focused on the direct modification of proteins in flow. By minimizing lysine competition (see Supplementary Information), we managed to exclusively install the electrophilic SO2F handle on tyrosine residues in just 1.5 minutes. To the best of our knowledge, this is one of the fastest methods for direct protein modifications reported to date . For instance, we merged a solution of β-Casein with the SO2F2-containing stream and observed predominantly single, chemoselective functionalization at different tyrosine residues with a Y180/Y193/Y114 = 10.7/2.4/1 regioselectivity ratio (Figure , compound 46). Notably, Myoglobin was obtained as a single Y103-modified adduct (Figure , compound 47), without observing denaturation or loss of the heme group, demonstrating the mild nature of the protocol. Remarkably, when we attempted to perform the same experiments in fed-batch mode, only a 16% conversion was obtained, while using a batch H-type reactor only yielded a complex mixture of products (Figure , bottom right). These results demonstrate that the enhanced mass transfer and confined access to the gaseous and hydrophobic SO2F2 observed in capillary flow reactors are critical to enable efficient SuFEx hub installation into complex macromolecular systems. Conversions reported as ratios of areas under the peak of product and starting compound obtained by LC/MS analysis. Peptides: Standard conditions for the SO2F2 generation: SO2Cl2 (40 equiv, 0.2 M in CH3CN) passed through a 3.8 mL cartridge filled with a 1:1 mixture of KF and glass beads at f.r. 0.5 mL/min. Peptide (1 equiv, 10 mM in CH3CN:H2O 1:1), Et3N (6 equiv), f.r. 0.25 mL/min, res. time 2 min at room temperature. [a] α-Endorphin (6 mM), SO2F2 (67 equiv). [b] β-Amyloid (3 mM), SO2F2 (133 equiv). [c] A picture of a general protein was chosen to represent β-Casein as no crystal structure is reported. Proteins: Standard conditions for the SO2F2 generation: SO2Cl2 (0.1 M in CH3CN) passed through a 3.8 mL cartridge filled with a 1:1 mixture of KF and glass beads at f.r. 0.1 mL/min. β-Casein (1 equiv, 5 mM in Tris buffer pH = 7.7), TMG (10 equiv), f.r. 0.9 mL/min, res. time 1.5 min at room temperature, SO2F2 (2.2 equiv). Myoglobin (1 equiv, 1 mM in 10 mM acetate buffer pH = 5), TMG (1 equiv), f.r. 0.9 mL/min, res. time 1.5 min at room temperature SO2F2 (11 equiv). TMG: 1,1,3,3-Tetramethylguanidine.