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The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.

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

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We developed a novel method for synthesizing seven-membered ring carbocycles via a palladium-catalyzed intramolecular allylic alkylation?isomerization?Cope rearrangement cascade. Using easily available lactone derivatives as substrates, the target cascade reaction proceeded in the presence of 5 mol-% of Pd(dba)2 and 6 mol-% of 1,3-diphenylphosphinopropane (dppp) in THF, affording a series of seven-membered ring carbocycles in 59?88 % yield (11 examples). DFT calculations suggested that, in addition to the reaction cascade including the cis-divinylcyclopropane Cope rearrangement, there is another possible pathway based on the palladium-catalyzed intramolecular allylic substitution to construct the seven-membered ring through a retro-cyclopropanation-mediated oxidative addition.

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

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Substituted 4-/7-halo-1H/-indenes and 5-methyl-3-bromo-4-/6H-cyclopenta[b] thiophenes were shown to be convenient starting materials for Suzuki-Miyaura, Negishi, and Murahashi protocols to give the corresponding aryl-subsituted indenes and cyclopenta[b]thiophenes of importance for further synthesis of ansa-metallocenes. Alternatively, (2-methyl-1H-inden-4-yl)boronic acid and (1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)boronic acid as well as the respective organozinc and -magnesium reagents can be used for synthesizing aryl-subsituted indenes via the Pd-catalyzed reactions with aryl halides. These synthetic methods were shown to have a very broad scope to afford libraries of aryl-substituted indenes. Finally, synthesis and structure characterization of several representative chiral ansa-zirconocenes, potentially useful as components of highly active and stereoselective olefin polymerization catalysts, have been performed.

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

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Novel strategies for the preparation of rigid cartwheel pincer metal complexes have been developed. The aromatic backbone of these materials ensures a high rigidity, which is expected to be important for a high retention when these multimetallic nanosize complexes are applied as homogeneous catalysts in a nanomembrane reactor. The ligand precursors C6[C6H3(CH2Y)2- 3,5]6 (10, Y = NMe2; 11, Y = SPh; 12, Y = PPh2; 13, Y = pz = pyrazol-1-yl) have been prepared in high yields from the key intermediate C6[C6H3 (CH2Br)2-3,5]6 (9). The hexakis(pincer) palladium(II) complexes C6[(PdX)-4-C6H2(CH2Y)2-3, 5]6 (14, Y = SPh, L = Cl; 15, Y = PPh2, L = Cl; 16, Y = pyrazol-1-yl, L = OAc; 17, Y = pyrazol-1-yl, L = Cl) have been prepared via direct electrophilic palladation of the corresponding ligands. The (tris)pincer ligand C6H3[Br-4-C6H3(CH2 NMe2)2-3,5]3-1,3,5 (20) was prepared via a triple-condensation reaction of 4-bromo-3,5-bis[(dimethylamino)methyl]acetophenone (19). Reaction of 20 with Pd(dba)2 yielded the tripalladium complex C6H3[(PdBr)-4-C6H3(CH2 NMe2)2-3,5]3-1,3,5 (21). The crystal structure of 21 shows a propeller-like structure with D3 symmetry and a fixed bromine-bromine distance of 17.4573(4) A, approximately forming a triangle with a height of 15.2 A. These nanosize cartwheel pincer metal complexes based on tridentate Y,C,Y? pincer ligands have been used as homogeneous Lewis-acid catalysts. Moreover, the influence of the donor substituent Y on the catalytic activity of cationic mono-Y,C,Y? PdII complexes as Lewis-acid catalysts in the double Michael reaction between methyl vinyl ketone and ethyl alpha-cyanoacetate, as a model reaction, has been investigated. It was found that cationic N,C,N?-type pincer complexes (1a, Y = NMe2; 1b, Y = pz; 1c, Y = pz* = 3,5-dimethylpyrazol-1-yl; 23) were superior to the P,C,P?- and S,C,S?-pincer complexes (1d, Y = PPh2-Le, Y = SPh). The nanosize cationic tri-N,C,N? PdII complex 23 was found to have a catalytic activity per catalytic site in the double Michael reaction of the same order of magnitude as the monopincer analogue 1a (k = 279 ¡Á 10-6 s-1 for 1a vs k = 232 ¡Á 10-6 s-1 for 23). The combination of the nanosize dimensions, the catalytic activity, and the high thermal and air stability makes these complexes excellent candidates for application in a continuous process in a nanomembrane reactor.

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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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The complexes Pd(diphos)(o-An)(I) (o-An = o-MeOC6H4; diphos = dppe (3), (S,S)-Chiraphos (4), (R,R)-Me-Duphos (5), (R,S) -t-Bu-Josiphos (6), (R)-Tol-Binap (7)) were prepared. Complex 6 catalyzed the coupling of PH(Me)(Ph)(BH3) (2) with o-AnI in the presence of base to yield PAMP-BH3 (P(Me)(Ph)(o-An)(BH3) (1)) in low enantiomeric excess. The course of stoichiometric reactions of 3-7 with 2 and NaOSiMe3 depended on the diphosphine ligand. Complexes 6 and 7 gave PAMP-BH3 (1) and Pd(0) species; no intermediates were observed. With 3, the intermediate Pd(dppe)(o-An)(P(Me)(Ph)(BH3)) (10) was observed by 31P NMR, while 4 gave the isolable diastereomeric palladium complexes (Sp)-Pd((S,S)-Chiraphos)(o-An)(P(Me)(Ph)(BH3)) (11a) and (RP)-Pd((S,S)-Chiraphos)(o-An)(P(Me)(Ph)(BH3)) (11b), whose absolute configurations were determined by X-ray crystallography after separation. The analogous Pd((R,R)-Me-Duphos)(o-An)(P(Me)(Ph)(BH3)) diastereomers (12a,b) were also separated and isolated. Treatment of 4 with highly enantioenriched 2 (R or S) gave 11a or 11b in high diastereomeric excess with retention of configuration at phosphorus. P-C reductive elimination from either isomer of highly diastereoenriched 11 in the presence of excess diphenylacetylene yielded Pd((S,S)-Chiraphos)(PhC?CPh) (14) and highly enantioenriched PAMP-BH3 (1), with retention of configuration.

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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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We report a newly developed carbazoyl-derived P,N-type phosphine ligand (L1) for the monoarylation of acetone with aryl chlorides. The proposed Pd(dba)2/L1 catalyst exhibited remarkable catalytic reactivity toward highly electron rich and sterically congested aryl chlorides, with catalyst loading as low as 0.1 mol % of Pd along with excellent chemoselectivity. A reaction rate study of the system using electronically diverse aryl chlorides determined the mechanisms regarding the rate-limiting steps in this reaction. The oxidative addition adduct of Pd-PhenCar-Phos with p-chlorotoluene showed the participation of N-Pd coordination in the metal complex. The isolated palladium complex C1 could be utilized as a precatalyst in the transformation and achieved performance comparable to that of the in situ generated palladium species.

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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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? Iodoanilines bearing a diene side-chain at the 3-position were converted to tricyclic fused indole derivatives under palladium catalysis. This cascade reaction proceeds through an intramolecular Heck insertion of the diene, followed by an allylic amination reaction sequence. Experimental and computational studies indicated that K3S-allylpalladium complex-mediated substitution was operative for the latter cyclization.

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

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3-Fluoro-2-mercuri-6-methylaniline Nucleotide as a High-Affinity Nucleobase-Specific Hybridization Probe

A 3-fluoro-6-methylaniline nucleoside was synthesized and incorporated into an oligonucleotide, and its ability to form mercury-mediated base pairs was studied. UV melting experiments revealed increased duplex stability with thymine, guanine, and cytosine opposite to the probe and a clear nucleobase-specific binding preference (T > G > C > A). Moreover, the 3-fluoro group was utilized as a spin label that showed distinct 19F NMR resonance shifts depending on the complementary nucleobase, providing more detailed information on Hg(II)-mediated base pairing.

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

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Sterically demanding, sulfonated, triarylphosphines: Application to palladium-catalyzed cross-coupling, steric and electronic properties, and coordination chemistry

Tri(2,4-dimethyl-5-sulfonatophenyl)phosphine trisodium (TXPTS ¡¤Na3) and tri(4-methoxy-2-methyl5-sulfonatophenyl)phosphine trisodium (TMAPTS¡¤Na3) both provide more active catalysts for Suzuki and Sonogashira couplings of aryl bromides in aqueous solvents than tri(3-sulfonatophenyl)phosphine trisodium (TPPTS ¡¤Na3). In the Heck coupling, TXPTS ¡¤Na3 provides the most effective catalyst system. Cone angles determined from DFT-optimized structures show that both TXPTS¡¤Na3 (206) and TMAPTS¡¤Na3 (208) are significantly larger than TPPTS¡¤Na3 (165). The identity of the counterion had a significant effect on the calculated cone angles for these ligands. The electronic properties of these ligands determined by the CO stretching frequencies of trans-RhL2(Cl)CO complexes were identical, although calculated electronic parameters suggest subtle differences between these ligands. Similar to TPPTS¡¤Na3, both TXPTS¡¤Na3 and TMAPTS¡¤Na3 react with Pd(OAc)2 in aqueous solvents to give LnPd0 complexes and the corresponding phosphine oxide. The reduction of palladium(II) by TXPTS¡¤Na3 is significantly slower than is seen with TMAPTS¡¤Na3 or TPPTS¡¤Na3 at room temperature. Evidence of palladacycle complexes derived from TXPTS¡¤Na3 and TMAPTS¡¤Na3 by activation of an ortho-methyl substituent was also observed in ligand coordination studies and under catalytic reaction conditions.

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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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Access to beta-lactams by enantioselective palladium(0)-catalyzed C(sp3)-H alkylation

beta-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd0-catalyzed C-H functionalization for aryl-aryl couplings, related reactions involving the formation of saturated C(sp3)-C(sp3) bonds are elusive. Reported here is an asymmetric C-H functionalization approach to beta-lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp3)-C(sp3) and strain-building reductive eliminations to for the four-membered ring. In general, the beta-lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.

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