Transition-metal catalyzed C‒C activation has garnered significant interest over the past decades. The activation and subsequent functionalization of C‒C bonds offer an efficient, atom-economic, and straightforward approach to constructing the backbone structures of complex molecules. However, compared to the more reactive C‒H or C‒X bonds, C‒C bond activation is thermodynamically and kinetically disfavored, requiring additional driving forces such as ring strain release, the formation of strong bonds (e.g., M‒CN bonds in cyanide activation or C=X bonds in alcohol β-elimination), or the use of indigenous directing groups. These limitations on substrate patterns have hindered broader applications. Since 2016, our group has focused on expanding C‒C activation to a wider range of substrates, particularly unstrained ketones. We incorporated aminopyridines as transient directing groups, which reversibly condense with ketones under reaction conditions to form pyridinyl imines. This strategy has enabled various transition-metal catalyzed transformations, including cyclopentanone-to-tetralone ring rearrangement, Suzuki-type cross-coupling, and ‘cut-and-sew’ annulation. Despite progress in C‒C activation of ketones, similar transformations for other carbonyl compounds, such as amides, remain rare due to significant challenges. First, unlike ketones, amides primarily undergo transamidation upon mixing with amines. Second, C‒N bond activation often competes as a side reaction, given that C‒N bonds are more polar and less sterically hindered than C‒C bonds. Third, selectivity issues arise during the directing group removal step between aminopyridines and secondary amines on the amide moiety. To date, only a few scattered examples of amide C‒C activation exist, relying on specific substituents and limited transformations. In this thesis, I will present my work on C‒C activation of common amides. In Chapter 2, I will discuss our development of the ‘hook-and-slide’ strategy for amide homologation. We first designed a phosphine-assisted amide condensation method to install the directing group almost quantitatively. This enabled branched-to-linear isomerization of α-alkyl amides using a structurally well-defined Rh complex as the catalyst. Combined with α-alkylation, this approach facilitates multi-carbon homologation of amides or carboxylic acids, a process that otherwise requires multiple reiterative steps. Mechanistic studies and DFT calculations were performed to elucidate the reaction pathway. In Chapter 3, I will introduce our work on lactam ring contraction. Using a milder Ti-catalyzed directing group installation method with silylated aminopyridines, we achieved efficient conversion of medium-sized lactams to their thermodynamically more stable analogues. This strategy enabled transformations such as ‘6-to-5’, ‘7-to-5’, and ‘8-to-5’ ring contractions with broad functional group tolerance. Through careful selection of directing groups and ligands, we also achieved selective ‘7-to-6’ ring contraction. In Chapter 4, I will present preliminary results on intramolecular ‘cut-and-sew’ transformations between lactams and alkenes or alkynes, enabling the efficient construction of various multicyclic structures. Collectively, this work significantly broadens the scope of C‒C activation and introduces novel skeletal modification methods for amides, with promising applications in the synthesis and derivatization of complex bioactive molecules.