With these optimal reaction conditions, we next set out to evaluate the generality of this method. Because of the challenges impeded by the heteroaryl cores, more specifically base sensitive heteroaryls such as pyrazole, thiophene, thiazole, benzothiophene, benzofuran as well as 2pyridyls in cross-coupling, we first turned our attention to synthesize heterobiaryls (Fig. ). Gratifyingly, both electron-rich and electron-poor pyridyl bromides were coupled with 4-iodo-1-methyl-1H-pyrazole successfully, providing the corresponding biheteroaryls in good yields, irrespective of pyridyl bromide regiochemistry (13, 18-22). The electron-rich pyridyl bromides afforded the desired products in 65-82% yields with excellent cross-selectivity. While no side products were obtained from the corresponding coupling partners in case of 13, 18, 19, only protodehalogenation product from pyridyl bromide coupling partner was obtained in 10% yield in case of 20. The electron-deficient pyridyl halide afforded the desired cross-coupled product 21 in poor yield (20%) with our optimized reaction conditions. Re-examination of the other bases led to a new set of conditions utilizing PMP instead of Cs2CO3 that completely suppressed the side reactions (i.e. homocoupling and protodehalogenation from both the partners) and delivered the products 21, 22 in 70% and 78% yields, respectively (see Supplementary Table ). Sterically demanding pyrazole substrate with 3,5-disubstitution could also be coupled with pyridyl bromide in 62% yield (23). Interestingly, neither homocoupling nor protodehalogenation products were observed in this case. This method was effective for the synthesis of various bipyridyl and pyridylpyrimidine cores (24-27), which are the key structural elements of antibiotics such as caerulomycins and collismycins, fungicides as well as tyrosine kinase inhibitors . The synthesis of bipyridyls where both the pyridyl cores are electron-deficient remain a challenging task in cross-coupling because of the instability, and expensiveness of the electron-deficient boronic acids, which not only requires an extra step but also demands special care to their synthesis from the much cheaper, stable, and easily available halide analogues. This protocol was quite effective in synthesizing challenging electron-deficient bipyridyls 24, 25 in 65% and 60% yields by directly utilizing the respective pyridyl halides. The substrate containing the challenging 2pyridyl electrophilic fragment successfully provided the corresponding crosscoupled products 26, 27 in 63% and 72% yields, respectively with exclusive selectivity. Notably, the natural product (±)-cytisine, a partial agonist at neuronal nicotinic receptors can be synthesized in three step from 26, which was previously synthesized via insitu Stille or Suzuki coupling in poor yield (40%) . While the synthesis of biheterocycles comprising of 6-/5-membered heteroaryls and 6-/6-membered heteroaryls proved to be viable, we found that the coupling between much more electronically richer 5-membered heteroaryl halides led to low yields due to consumption of only a minimal amount of substrate. Relative to six-membered heteroaryls, five-membered heteroaryls are considered to be a difficult class of substrates in the domain of Pd-catalyzed cross-coupling mainly because of the three reasons --a) instability of their boronic acid derivatives, b) ability to coordinate strongly with Pd, promoting catalyst deactivation with the displacement of the supporting phosphine ligand, c) presence of acidic CH bond leading to the decomposition of sensitive five-membered cores and often suffer from regioselectivity issue in basic medium . Interestingly, re-evaluation of other ligands revealed that PhSudipPhos (L80) was an effective ligand for the coupling of pyrazole with thiophene and thiazole, providing the corresponding cross-coupled products in 50-87% yields (28-31) with excellent cross-selectivity (see Supplementary Table 10). It is important to mention that the free (NH)-heteroarene was well tolerated in this method without competing C-N coupling and other side reactions (31). Coupling of fused heteroaryls with heteroaryls was also achieved using this protocol to produce various combination of biheterocycles in 52-78% yields (32-38; Fig. ). We next examined the scope of this protocol for the coupling of heteroaryl halides with aryl halides (Fig. ). Both electron-rich and electronpoor aryl halides were coupled successfully with pyrazolyl, pyrimidyl, and substituted pyridyl halides (39-42, 44, 46, 47, 51-53). The coupling of pyrimidyl bromides with electron-deficient aryl iodides led to very poor yield of the corresponding products. Re-examination of reaction conditions revealed that a combination of organic base (PMP) and PhSudipPhos ligand was able to afford the desired products (41, 42, and 43) in 63-76% yields suppressing the competitive homocoupling (see Supplementary Table ). Notably, in these three cases there was no byproduct formation from pyrimidyl bromide, while very small amount of homodimer product of aryl iodides were obtained (<9% yields). Ortho-substituted aryl halides were also proved to be viable substrates for this protocol, affording the desired products (43, 45, 48-50, 54) in good yields without any side product formation. Highly reactive functional group such as aldehyde was tolerated in this protocol to afford the desired heterobiaryl 55 in 80% yield. The instability of polyfluoroaryl boronic acids and heteroaryl boronic acids make them a challenging class of substrates for Suzuki-Miyaura cross-coupling reaction. In addition, these boronic acids are generally 5-21 times more expensive as compared to their halide analogue. To our delight, we were successfully able to couple diverse electron-poor and electron-rich heteroaryl halides with polyfluorinated aryl halides in moderate to good yields with excellent crossselectivity, thereby providing a cost-and step-economic method for the synthesis of polyfluorinated heterobiaryls (56-61; Fig. ). It is important to note that no side products either from heteroaryl halides or polyfluorinated aryl halides were observed. This cross-electrophile coupling technology was also successful for a range of simple aryl halides. Diverse functional groups including amine, ether, ester, sulfonamide, and cyano groups were well tolerated with this protocol, affording the corresponding unsymmetrical biaryls in synthetically useful yields (62-67; Fig. ). To further demonstrate the potential value of this new versatile catalytic paradigm in medicinal chemistry campaigns, we next sought to achieve a modular synthesis of (hetero)biaryl core of several pharmaceuticals (Fig. ). Toward this aim, the biaryl core of Felbinac, Xenbucin (antiarthritic drug), Flufenisal, potent inhibitor of the antiapoptotic protein Bcl-xL, ARB-272572 (PD-L1 inhibitor), Magnolol, Telmisartan, Bifonazole (antifungal drug), A-349821 (histamine H3 receptor antagonist), and CPI-1612 (EP300/CBP histone acetyltransferase inhibitor) were readily synthesized from cheap and commercially available (hetero)aryl halides in reasonable yields (68-76). This protocol was also effective for the direct synthesis of biaryl containing small molecule drugs such as OTBN (77) and Abametapir (78). In case of ARB-272572 (71), Magnolol (72), and Abametapir (78), the (hetero)biaryl core was achieved via homo-coupling of corresponding aryl iodide and heteroaryl bromide respectively in excellent yields. Finally, this cross-electrophile coupling technique could be extended to the selective modification of peptides (Fig. ). Initial exploration on the coupling of peptide with (hetero)aryl halides using our standard reaction conditions were unsuccessful. However, the use of a solvent combination of CH3CN and H2O (CH3CN:H2O = 10:1) were effective to provide the desired cross-coupled products in 51-76% yields (79-81). In case of the coupling of peptide with electron-rich and electron poor heteroaryl bromide, neither protodehalogention nor homodimer products were obtained from any of the partners. Whereas, we observed small amount (20%) of the homodimer formation of iodo peptide as side product in case of coupling with electronpoor aryl bromide (81). To the best of our knowledge, this is the first instance of (hetero)arylation reaction of peptide via cross-electrophile coupling at room temperature. Because of the mild reaction conditions, this bioconjugation strategy would open up a new avenue for chemical biologists to modulate biomolecule structure and function in the context of discovery of new drugs, vaccine candidates as well as therapeutics, novel diagnostic and medical tools, and also in the exploration of complex biological processes The coupling of (hetero)arylbromides with (hetero)aryl triflates were performed using RuPhos as ligand. The coupling of (hetero)arylchlorides with (hetero)aryl triflates were performed using XantPhos as ligand. See Supplementary Information for exact conditions.