The synthesis of biologically active small molecules is crucial for drug discovery and treatment of diseases. Innovative C-C bond forming methods have the potential to revolutionize the synthesis of functionally diverse small molecules in a timely fashion. Among all methodologies, transition metal catalyzed cross coupling reaction is a reliable tool and has been widely used in both pharmaceuticals and industries nowadays. Traditional cross coupling reactions, such as Suzuki, Negishi, Kumada, Stille and so on, require prefunctionalized coupling partners (organoboron in Suzuki, organozinc in Negishi, Grignard reagents in Kumada and organotin in Stille). The downside of such strategies is that prefunctionalization requires significant effort and time. Thus, turning C-H bond directly into cross coupling partners without any prefunctionalization is more efficient and atom-economical. Much progress have been made the past two decades in C-H functionalization, including both sp2 and sp3 hybridized C-H bonds. Functionalization of sp2 hybridized C-H bonds has focused on arenes and heteroarenes and has been well developed. In contrast, sp3 hybridized C-H bonds are more difficult to functionalize. Early studies on sp3 hybridized C-H functionalization focused on C-H bond alpha to activating groups such ketone, ester, amide and others. Another strategy to functionalize those unactivated C-H bonds (pka>30) is to install directing groups to facilitate reactivity and selectivity. The addition and removal of directing groups, however, may limit the utility of this strategy. To date, intermolecular cross-coupling reactions of non- or weakly acidic C(sp3)-H bonds in the absence of directing group remains a challenge. The Walsh group set out to develop methods to for C(sp3)–H functionalization using a strategy called Deprotonative Cross Coupling Process (DCCP). DCCP takes advantage of reversible deprotonation under the conditions of the reaction as a method to achieve functionalization of weakly acidic C(sp3)-H bond using relatively mild condition. This dissertation describes two methods to functionalization of weakly acidic C(sp3)-H bonds, allylic substitution and arylation, with success on both Pd or Ni as catalyst. The first two chapters of the dissertation describe transition metal catalyzed allylic substitution with diarylmethane pronucleophiles (pka up to 32.3). Diarylmethane are among the least acidic pronucleophiles used to date in transition metal catalyzed allylic substitution reactions (Tsuji-Trost reaction). The widely accepted paradigm for classifying the mode of attack of nucleophiles on palladium π-allyl intermediates in the Tsuji−Trost reaction is based on the pKa of the pronucleophile: (1) stabilized or “soft” carbon nucleophiles and heteroatom nucleophiles (e.g., pronucleophiles with pKa‘s < 25), and (2) unstabilized or “hard” nucleophiles (those from pronucleophiles with pKa‘s > 25). One of the keys to the continuing development of asymmetric allylic substitution processes remains broadening the scope of “soft” nucleophiles. In Chapter 1, we successfully demonstrated the cut-off between soft and hard nucleophiles for Pd-catalyzed allylic substitution should be raised from pKa of 25 to at least 32. This discovery expands the scope of soft nucleophiles, and suggests the possibility of developing asymmetric allylic substitution for more weakly acidic substrates. In chapter 2, we further applied Ni catalyzed allylic substitution on diarylmethanes to develop a supplement to the Pd version. We were able to prove the same nucleophile behaves as soft nucleophile in both Pd and Ni catalyzed allylic substitution. More importantly, Ni has always been paired with hard nucleophiles to perform asymmetric allylic substitution, but we were able to identify a chiral ligand SL-J204-1 to do asymmetric allylic substitution using Ni as catalyst with soft nucleophile (diarylmethane) and got up to 91% yield with 92% e.e. This result suggests Ni catalyzed asymmetric allylic substitution can be done with both soft and hard nucleophiles, which makes Ni an appealing choice other than Pd for transition metal catalyzed allylic substitution. The second part of the dissertation focus on the arylation of weakly acidic substrates such as carboxylate and toluene (pKa = 44±1). The same strategy DCCP is applied to both types of substrates, through direct metalation and subsequent cross coupling of benzylic C(sp3)-H bonds. Chapter 3 describes alpha arylation of carboxylic acids. Significant works on alpha arylation have been done on carbonyl group containing substrates such as ketone, aldehyde, ester and amide. However, examples on alpha arylation of carboxylic acids remain scarce due to the difficulty of generating dienolate. We successfully demonstrated the reversible deprotonation could be applied to benzyl carboxylic acids and identified a catalyst system that could further cross couple dienolate with aryl chlorides and bromides. Finally, chapter 4 describes a direct arylation of toluene derivatives benzylic C-H bond. We used an unique catalyst with deprotonatable ligand NIXANTPHOS. The deprotonated ligand would carry the counter cation (alkali metal) of the base through out the catalytic cycle. Previously, our group had developed an activation strategy using η6-coordination of arenes to tricarbonylchromium to activate toluene benzylic C-H bond. In this chapter, we developed a new strategy using η6-coordination of toluene to potassium to activate benzylic C-H bond to perform DCCP. The mechanistic study showed the crucial role of potassium cation. The method is valuable in two points: 1. Direct arylation of toluene derivatives provides a strong tool transforming cheap, inert molecule to useful molecule diarylmethane. 2. The unique mechanism would inspire us to design more heterobimetallic systems with deprotonatable ligands to activate different kind of molecules.