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TLR7/8 ANTAGONISTS AND USES THEREOF

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as TLR7/8 antagonists.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Mechanistic Studies of Palladium-Catalyzed Aminocarbonylation of Aryl Chlorides with Carbon Monoxide and Ammonia

Mechanistic information on a reliable, palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia is reported. The reaction occurs with ethylene complex 1 as catalyst, and mechanistic information was gained by isolation of catalytic intermediates and kinetic measurements, including the first mechanistic data on the oxidative addition of aryl chloride to a palladium(0) complex in the presence of CO. Arylpalladium and phenacylpalladium halide intermediates were synthesized, and kinetic measurements of the formation and reactions of these intermediates were undertaken to determine the mechanism of the oxidative addition of aryl bromides and chlorides to a Pd(0) dicarbonyl compound in the presence of CO and the mechanism of the reaction of ammonia with a Pd(II) phenacyl complex to form benzamide. The oxidative addition of aryl chlorides and aryl bromides was determined to occur with rate-limiting reaction of the haloarene with a three-coordinate Pd(0) species bearing a bidentate phosphine and one CO ligand. A primary 13C kinetic isotope effect suggested that this step involves cleavage of the carbon-halogen bond. Our data show that the formation of benzamide from the reaction of phenacylpalladium halide complexes with ammonia occurs by a pathway involving reversible displacement of chloride from a phenacylpalladium chloride complex by ammonia, deprotonation of the bound ammonia to form a phenacylpalladium amido complex, and reductive elimination to form the C-N bond. Consistent with this mechanism, the reaction of an aryl palladium amido complex with CO formed the corresponding primary benzamide. A catalyst deactivation pathway involving the formation of a Pd(I) dimer also was elucidated.

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Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Formation of four different aromatic scaffolds from nitriles through tandem divergent catalysis

A zinc bromide complex, formed by the sequential reaction of nitriles with a Reformatsky reagent and terminal alkynes, is used as an intermediate for divergent palladium-catalyzed reactions. The reaction pathway of the intermediate is precisely controlled by the choice of the reaction solvent or the palladium catalyst to quickly form four different aromatic scaffolds – arylamines, aminoindenes, pyrroles, and quinolines – starting from readily available nitriles.

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Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Easily attachable and detachable ortho-directing agent for arylboronic acids in ruthenium-catalyzed aromatic C-H silylation

(Chemical Equation Presented) o-C?H silylation of arylboronic acids has been achieved using 2-pyrazol-5-ylaniline as an orthodirecting agent, which was temporarily attached to the boronyl group via Ru-catalyzed silylation with hydrosilanes. Condensation products of arylboronic acids with2-pyrazol-5-ylaniline were prepared in situ and subjected to reaction w ith triorganosilanes in the presence of RuH2(CO)(PPh3) 3 at 135C. Regioselective silylation at their ortho-positions proceeded in good yields for phenylboronic acids bearing para-substituents such as chloro, fluoro, methyl, methoxy, and trifluoromethyl groups. p-Methoxycarbonyl-substituted phenylboronic acid provided thecorresponding silylated product in moderate yield. m-Tolyl- and 2-napht hylboronic acids underwent silylation selectively at the less stericallyhindered ortho-positions. The silylated products were utilized in Suzuk i?Miyaura coupling, followed either by iodination with ICl or by Tamao oxidation to furnish iodine- or hydroxy-substituted biaryls.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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A facile stereocontrolled approach to CF3-substituted triarylethenes: Synthesis of panomifene

The stereoselective preparation and Pd-catalyzed cross-coupling reaction of boronates 2 provides a new general and convenient route to CF 3-substituted triaryl ethenes 3, in which the CF3 and Ar3 groups are cis to each other. The synthetic potential was demonstrated by the total synthesis of panomifene (Ar1 = Ar 3 = Ph, Ar2 = 4-(OHCH2CH2NHCH 2CH2O)-C6H4). Bpin = (pinacolato)boryl.

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Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Original phenyl-P(O) bond cleavage at palladium(0): A combined experimental and computational study

The reaction of the diphosphine-phosphine oxide ligand {[o-iPr 2P-(C6H4)]2P(O)Ph} with Pd(PtBu 3)2 proceeds with cleavage of the Ph-P(O) bond to give an original kappaP,P(O),P-pincer complex. According to DFT calculations, this oxidative addition occurs via a three-center P,C ipso,Pd transition state. The Royal Society of Chemistry 2011.

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Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Functionalized chromans and isochromans via a diastereoselective Pd(0)-catalyzed carboiodination

A diastereoselective approach to isochromans and chromans via Pd(0)-catalyzed carboiodination is reported. The transformations using thismethodology display excellent yields and diastereoselectivities as well as broad functional group compatibility. The selectivity observed in these cyclizations, forming isochroman or chroman targets, is postulated to originate from the minimization of A1,2 strain and axial-axial interactions, respectively. This method has also been used to highlight the concept of reversible oxidative addition to carbon-iodine bonds in polyiodinated substrates.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Mechanistic studies on direct arylation of pyridine N -oxide: Evidence for cooperative catalysis between two distinct palladium centers

Direct arylations of pyridine N-oxide (PyO), a convenient method to prepare 2-arylpyridines, catalyzed by Pd(OAc)2 and PtBu3 have been proposed to occur by the generation of a PtBu3-ligated arylpalladium acetate complex, (PtBu3)Pd(Ar)(OAc) (1), and the reaction of this complex with PyO. We provide strong evidence that 1 does not react directly with PyO. Instead, our data imply that the cyclometalated complex [Pd(OAc)(tBu2PCMe2CH2)]2, which is generated from the decomposition of 1, reacts with PyO and serves as a catalyst for the reaction of PyO with 1. The reaction of PyO with 1 occurs with an induction period, and the reaction of 1 with excess PyO in the presence of [Pd(OAc)(tBu2PCMe2CH2)]2 is zeroth-order in 1. Moreover, the rates of reactions of PyO with bromobenzene catalyzed by [Pd(OAc)(tBu2PCMe2CH2)] 2 and [Pd(PtBu3)2] depend on the concentration of [Pd(OAc)(tBu2PCMe2CH2)]2 but not on the concentration of [Pd(PtBu3)2]. Finally, the reaction of 1 with a model heteroarylpalladium complex containing a cyclometalated phosphine, [(PEt3)Pd(2-benzothienyl)(tBu 2PCMe2CH2)], rapidly formed the arylated heterocycle. Together, these data imply that the rate-determining C-H bond cleavage occurs between PyO and the cyclometalated [Pd(OAc)(tBu 2PCMe2CH2)]2 rather than between PyO and 1. In this case, the resulting heteroarylpalladium complex transfers the heteroaryl group to 1, and C-C bond-formation occurs from (PtBu 3)Pd(Ar)(2-pyridyl oxide). This mechanism proposed for the direct arylation of PyO constitutes an example of C-H bond functionalization in which C-H activation occurs at one metal center and the activated moiety undergoes functionalization after transfer to a second metal center.

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Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Synthesis and photophysics of fully pi-conjugated heterobis- functionalized polymeric molecular wires via suzuki chain-growth polymerization

We present a fast and efficient in situ synthetic approach to obtain fully pi-conjugated polymers with degrees of polymerization up to 23 and near quantitative (>95%) heterobis-functionalization. The synthesis relies on the key advantages of controlled Suzuki chain-growth polymerization: control over molecular weight, narrow polydispersity, and ability to define polymer end groups. The first end group is introduced through the initiator metal complex tBu3PPd(X)Br, while the second end group is added by quenching of the chain-growth polymerization with the desired boronic esters. In all cases, polymers obtained at 50% conversion showed excellent end group fidelity and high purity following a simple workup procedure, as determined by MALDI-TOF, GPC, and 1H and 2D NMR. End group functionalization altered the optoelectronic properties of the bridge polymer. Building on a common fluorene backbone, and guided by DFT calculations, we introduced donor and acceptor end groups to create polymeric molecular wires exhibiting charge transfer and energy transfer as characterized by fluorescence, absorption, and transient absorption spectroscopy as well as by fluorescence lifetime measurements.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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COMPOUNDS THAT INHIBIT MCL-1 PROTEIN

Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula I, and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method