- Reactivity of secondary N-alkyl acrylamides in Morita–Baylis–Hillman reactions
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The Morita–Baylis–Hillman (MBH) reaction of secondary N-alkyl acrylamides, discarded up to now from investigations of the scope of activated alkenes, was studied. Optimization of the reaction conditions revealed that a balance must be found between activation of the MBH coupling reaction and that of the undesired competitive aldehyde Cannizzaro reaction. Using 3-Hydroxyquinuclidine (3-HQD) in a 1:1 water-2-MeTHF mixture provides the appropriate conditions that were applicable to a wide range of diversely substituted secondary N-alkyl acrylamides and aromatic aldehydes, giving rise to novel amide-containing MBH adducts under mild and clean conditions.
- Ahmar, Mohammed,Queneau, Yves,Verrier, Charlie,Yue, Xiaoyang
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p. 319 - 330
(2021/10/29)
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- A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia
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Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
- Marín-Ramos, Nagore I.,Balabasquer, Moisés,Ortega-Nogales, Francisco J.,Torrecillas, Iván R.,Gil-Ordó?ez, Ana,Marcos-Ramiro, Beatriz,Aguilar-Garrido, Pedro,Cushman, Ian,Romero, Antonio,Medrano, Francisco J.,Gajate, Consuelo,Mollinedo, Faustino,Philips, Mark R.,Campillo, Mercedes,Gallardo, Miguel,Martín-Fontecha, Mar,López-Rodríguez, María L.,Ortega-Gutiérrez, Silvia
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supporting information
p. 6035 - 6046
(2019/08/02)
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- Clickable coupling of carboxylic acids and amines at room temperature mediated by SO2F2: A significant breakthrough for the construction of amides and peptide linkages
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The construction of amide bonds and peptide linkages is one of the most fundamental transformations in all life processes and organic synthesis. The synthesis of structurally ubiquitous amide motifs is essential in the assembly of numerous important molecules such as peptides, proteins, alkaloids, pharmaceutical agents, polymers, ligands and agrochemicals. A method of SO2F2-mediated direct clickable coupling of carboxylic acids with amines was developed for the synthesis of a broad scope of amides in a simple, mild, highly efficient, robust and practical manner (>110 examples, >90% yields in most cases). The direct click reactions of acids and amines on a gram scale are also demonstrated using an extremely easy work-up and purification process of washing with 1 M aqueous HCl to provide the desired amides in greater than 99% purity and excellent yields.
- Wang, Shi-Meng,Zhao, Chuang,Zhang, Xu,Qin, Hua-Li
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p. 4087 - 4101
(2019/04/30)
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- COMPOSITONS AND METHODS FOR MODULATING UBA5
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting ubiquitin-like modifier activating enzyme 5.
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Paragraph 0633; 0634; 0636; 0671
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR INHIBITING RETICULON 4
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting reticulon 4(RTN4).
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Paragraph 0645; 0647; 0685
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR MODULATING PPP2R1A
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Disclosed herein, inter alia, are compositions and methods useful for modulating PPP2R1 A and for the treatment of cancer.
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-
Paragraph 0599; 0600; 0607; 0649
(2018/08/26)
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- Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity
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Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
- Bateman,Nguyen,Roberts,Miyamoto,Ku,Huffman,Petri,Heslin,Contreras,Skibola,Olzmann,Nomura
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supporting information
p. 7234 - 7237
(2017/07/11)
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- MANUFACTURING METHOD OF β-SUBSTITUTED PROPIONIC ACID AMIDE AND N-SUBSTITUTED (METH)ACRYLAMIDE
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PROBLEM TO BE SOLVED: To provide a method for industrially manufacturing β-alkoxy propionic acid amide, β-amino propionic acid amide and N-substituted (meth)acryl amide using (meth)acrylic acid ester as starting material at high yield and high purity. SOLUTION: There is provided a method for obtaining N-substituted (meth)acryl amide represented by target compound formula (7) by conducting an amidation reaction with amine using β-substituted propionic acid ester represented by the formula (1) of a product of a Michael addition reaction of (meth)acrylic acid ester and alcohol or amine in presence of a metal complex as a catalyst to obtain β-substituted propionic acid amide represented by the formula (3) and conducting a thermal decomposition reaction of β-substituted propionic acid amide in presence of the metal complex as the catalyst to eliminate alcohol or amine. A-CH2-C(R1)H-C(=O)-OR2 (1), A-CH2-C(R1)H-C(=O)-N(R3)R4 (3), CH2=C(R1)-C(=O)-N(R3)R4 (7) SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0055; 0057; 0060
(2018/07/03)
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- Efficient and facile synthesis of acrylamide libraries for protein-guided tethering
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A kinetic template-guided tethering (KTGT) strategy has been developed for the site-directed discovery of fragments that bind to defined protein surfaces, where acrylamide-modified fragments can be irreversibly captured in a protein-templated conjugate ad
- Allen, Charlotte E.,Curran, Peter R.,Brearley, Andrew S.,Boissel, Valerie,Sviridenko, Lilya,Press, Neil J.,Stonehouse, Jeffrey P.,Armstrong, Alan
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supporting information
p. 458 - 460
(2015/03/03)
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- Effective nitration of anilides and acrylamides by tert-butyl nitrite
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Nitro compounds are important intermediates in synthetic organic chemistry and the chemical industry. Herein, the efficient copper-catalyzed [10% Cu(NO3)2·3H2O] nitration of anilides was developed by using TBN (tert-butyl nitrite) as a nitrating reagent to give the corresponding nitro-substituted aromatic products in good to excellent yields. The use of TBN also led to the selective nitration of acrylamides at room temperature to afford only the (E) isomer of the nitration product. A series of anilides and acrylamides with a broad array of functional groups were well-tolerated by this procedure. This synthetic method has many advantages, which include inexpensive starting materials, mild reaction conditions, a fast reaction rate, and high yields. A mechanistic investigation indicates that a nitro radical, which is generated from the thermal homolysis of TBN, is involved in the two nitration processes. The efficient nitration of both anilides and acrylamides was achieved by using TBN (tert-butyl nitrite) as a metal-free nitrating reagent. This synthetic method has many advantages such as mild reaction conditions, a fast reaction rate, good to excellent yields, and a broad substrate scope. Our investigation indicates that a nitro radical is involved in the reaction mechanism.
- Ji, Yi-Fei,Yan, Hong,Jiang, Qi-Bai
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p. 2051 - 2060
(2015/03/18)
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- Application of SiO2-Pr-SO3H as an efficient catalyst in the Ritter reaction
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Sulfonic-acid-functionalized silica was applied as an efficient heterogeneous acid catalyst in the Ritter reaction to prepare amides by reaction of various benzylic, allylic, and tertiary alcohols with various nitriles in good to excellent yields under solvent-free conditions. The simplicity of the reaction, recovery of catalyst without loss of reactivity, high yield of products, and short reaction time represent improvements over many existing methods.
- Mohammadi Ziarani, Ghodsi,Badiei, Alireza,Dashtianeh, Zeinab,Gholamzadeh, Parisa,Mohtasham, Nina Hosseini
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p. 3157 - 3163
(2013/09/23)
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- Safe and efficient ritter reactions in flow
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Efficient mixing, temperature control and small environmental exposures allow reactions carried out in microfluidic de-vices to perform superior to their batch-type counterparts in conventional flasks. The Ritter reaction has been optimised for flow conditions leading to short reaction times and higher yields and also is more feasible with regards to safety, productivity and tolerance towards substrate functionalities.
- Brandt, Johan C.,Elmore, Simon C.,Robinson, Richard I.,Wirth, Thomas
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experimental part
p. 3099 - 3103
(2011/02/25)
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- RAFT polymers for protein recognition
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A new family of linear polymers with pronounced affinity for arginine- and lysine-rich proteins has been created. To this end, N-isopropylacrylamide (NIPAM) was copolymerized in water with a binding monomer and a hydrophobic comonomer using a living radical polymerization (RAFT). The resulting copolymers were water-soluble and displayed narrow polydispersities. They formed tight complexes with basic proteins depending on the nature and amount of the binding monomer as well as on the choice of the added hydrophobic comonomer.
- Tominey, Alan F.,Liese, Julia,Kraft, Arno,Wei, Sun,Kowski, Klaus,Schrader, Thomas
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supporting information; experimental part
(2010/11/05)
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- Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 3-nitroisoxazoles
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Novel reaction of tetranitromethane (TNM) with electrophilic alkenes in the presence of triethylamine yielding substituted 3-nitroisoxazoles was found and studied. Triethylamine increases the reactivity of TNM toward electrophilic alkenes promoting their heterocyclization, and the reactions proceed in an unusual way. A variety of α,β-unsaturated aldehydes, ketones, esters, amides, phosphonates, and nitro and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 3-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic aspects are discussed.
- Volkova, Yulia A.,Averina, Elena B.,Grishin, Yuri K.,Bruheim, Per,Kuznetsova, Tamara S.,Zefirov, Nikolai S.
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supporting information; experimental part
p. 3047 - 3052
(2010/07/15)
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- Exploring the scope of the 29G12 antibody catalyzed 1,3-dipolar cycloaddition reaction
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29G12 is a murine monoclonal antibody programmed to catalyze the regio- and enantioselective 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide 1a and N,N-dimethylacrylamide 2a (Toker, J. D.; Wentworth, P., Jr.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 3244). Given the unique nature of 29G12 as a protein biocatalyst for this chemical reaction, we have investigated both the substrate specificity and mechanistic parameters of the 29G12-catalyzed process. These studies have shown that while 29G12 is specific for its dipole substrate Ia, the antibody is highly promiscuous with respect to the dipolarophiles it can process. 29G12 accepts a bulky hydrophobic dipolarophile cosubstrate, with rates of product formation up to 70-fold faster than with the original substrate 2a. In all cases, the respective isoxazoline products are produced with exquisite regio- and stereochemical control (78-98% ee). Comparison between the steady-state kinetic parameters from the 29G12-catalyzed reaction of 1a with the most efficient versus the original dipolarophile cosubstrate (2m and 2a, respectively), reveals that while the effective molarities (EM)s are almost identical (EM (2m) 26 M; EM(2a) 23 M), the affinity of 29G12 for the larger dipolarophile 2m is more than 1 order of magnitude higher than for 2a [Km(2m) 0.44 ± 0.04 mM; Km(2a) 5.8 ± 0.4 mM]. Furthermore, when 2m is the cosubstrate, the affinity of 29G12 for its dipole 1a is also greatly improved [Km(1a) 0.82 ± 0.1 mM compared to Km(1a) 3.4 ± 0.4 mM when 2a is the cosubstrate]. An analysis of the temperature dependence of the 29G12-catalyzed reaction between 1a and 2m reveals that catalysis is achieved via a decrease in enthalpy of activation (ΔΔH? 4.4 kcal mol-1) and involves a large increase in the entropy of activation (ΔΔS? 10.4 eu). The improved affinity of 29G12 for the nitrile oxide Ia in the presence of 2m, coupled with the increase in ΔΔS? during the 29G12-catalyzed reaction between 1a and 2m supports the notion of a structural reorganization of the active site to facilitate this antibody-catalyzed reaction.
- Toker, Jonathan D.,Tremblay, Martin R.,Yli-Kauhaluoma, Jari,Wentworth, Anita D.,Zhou, Bin,Wentworth Jr., Paul,Janda, Kim D.
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p. 7810 - 7815
(2007/10/03)
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- Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes
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Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine ph
- Welch, Karen T.,Virga, Kristopher G.,Whittemore, Neil A.,Oezen, Can,Wright, Edward,Brown, Cynthia L.,Lee, Richard E.,Serpersu, Engin H.
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p. 6252 - 6263
(2007/10/03)
-
- Ionic Liquid as a Suitable Phase for Multistep Parallel Synthesis of an Array of Isoxazolines
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(Equation presented) A parallel array of isoxazoline diamides was prepared using an ionic liquid [bmim][BF4] as the phase where a three-step procedure (Schotten-Baumann, 1,3-dipolar cycloaddition, ester amidation with Me3Al) was carr
- Rodriquez, Manuela,Sega, Alessandro,Taddei, Maurizio
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p. 4029 - 4031
(2007/10/03)
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- Scale up of a ritter reaction
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The Ritler reaction of secondary or tertiary alcohols with acrylonitrile provides easy access to acrylamides which would otherwise be difficult to prepare. A safe procedure for conducting this reaction is described.
- Chang, Sou-Jen
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p. 232 - 234
(2013/09/08)
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- Zeolite-HY : A selective and efficient catalyst for the synthesis of amides under microwave irradiations
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An efficient and selective method for the conversion of various acids into their corresponding amides in the presence of zeolite under microwave irradiation is described. The reaction proceeds efficiently at ambient pressure in high yields.
- Gadhwal, Sunil,Dutta, Manu Prakash,Boruah, Anima,Prajapati, Dipak,Sandhu, Jagir S.
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p. 725 - 727
(2007/10/03)
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- The phosphazo route to 2-alkenamides from acrylic acid and its derivatives
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2-Alkenamides are formed in good isolated yields (generally up to 70%) by the reaction of in situ-generated phosphazo compounds issued from aliphatic, alicyclic and aromatic primary amines, with acrylic acid and its derivatives.
- Cabral, Jose,Laszlo, Pierre,Montaufier, Marie-Therese,Lalatiana Randriamahefa
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p. 1705 - 1708
(2007/10/02)
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- THE PREPARATION AND REACTIONS OF 1-LITHIO-ALKYLAMINO-1-LITHIO-OXY-ALLENE DERIVATIVES
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The reaction of secondary α-keto-amide 2,4,6-tri-iso-propylbenzenesulphonylhydrazones with n-butyllithium generated, via a modified Shapiro reaction, the title carbanions -)NR1>.These reacted at carbon with deuterium oxide
- Adlington, R.M.,Barrett, A.G.M.
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p. 3935 - 3942
(2007/10/02)
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- Process for the manufacture of α,β-unsaturated N-substituted carboxylic acid amides
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Process for the manufacture of α,β-unsaturated N-substituted carboxylic acid amides of the general formula STR1 in which R1 represents H or CH3 R2 represents H or CH3, and Y represents a divalent straight-chain or branched organic radical having 2-30 carbon atoms, and R3 represents H or the radical of an amine of the formula --N(R4)(R5), in which R4 and R5 represent alkyl radicals having 1 to 4 carbon atoms, by reacting β-substituted carboxylic acid amides of the formula STR2 in which Z represents OH or the radical R6 O--, in which R6 is an alkyl radical having 1 to 4 carbon atoms, with amines of the general formula at temperatures in the range of 100° to 200° C., preferably 120° to 175° C., with the elimination of ammonia, and heating the resulting N-substituted β-hydroxycarboxylic or β-alkoxycarboxylic acid amides in the presence of catalysts, water or alcohol, respectively, being split off. The water is split off at temperatures of 100°-250° C. with acidic catalysts such as phosphoric acid, or basic catalysts such as sodium hydroxide, and alcohol is split off at 70°-150° C. with basic catalysts such as sodium or potassium hydroxide. The reaction product is separated by distillation, optionally in vacuo.
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-
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- A CONVENIENT SYNTHESIS OF MONOCYCLIC β-LACTAMS
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The intramolecular N-alkylation of β-bromopropionamide (1) under phase transfer conditions gave monocyclic β-lactams (2) in high yields.
- Takahata, Hiroki,Ohnishi, Yoshinori,Yamazaki, Takao
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p. 467 - 469
(2007/10/02)
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