Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](=O)[CH3:14])[N:12]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+].CO>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](=[N:33][OH:34])[CH3:14])[N:12]=1
Reactant: NO
Reactant: CC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=NO)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Yield: 50.8 %

Procedure:
To a 50 mL RB flask attached with Vigreux column was added compound 1-[2-(2-Chloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazol-4-yl]-ethanone (162 mg, 359 μmol), hydroxylamine-HCl (200 mg, 2.87 mmol), sodium acetate (238 mg, 2.90 mmol), MeOH (12 mL) and H2O (6 mL). The reaction solution was allowed to stir at reflux for 2 hrs prior to TLC analysis. The reaction solution was diluted with EtOAc (150 mL), washed with aq. NaCl (100 mL), partitioned, dried over Na2SO4, filtered, and concentrated on the Rotavapor. The crude product was chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 80% EtOAc to afford 85 mg (51% yield) of the title compound as a mixture of E and Z isomers. The isomers were separated by chromatography with a Reverse Phase HPLC using a C18 Preparative column. Characterization for one single oxime isomer: 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.15 (t, 1H), 8.02 (d, 1H), 7.90 (d, 1H), 7.85 (s, 1H), 7.80 (d, 2H), 7.72 (t, 1H), 7.64 (d, 1H), 7.47-7.44 (m, 3H), 7.35 (d, 2H); MS (ES): 466.1 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:36](=[O:37])[C:35]4[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]3=[O:42])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione was prepared by the procedure of Example 5 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.2 mmol), sodium hydrogen carbonate (281 mg, 3.34 mmol) and N-ethoxycarbonyl phthalimide (732 mg, 3.3 mmol) in acetonitrile and water (4 mL each). The product was obtained as a white solid (314 mg, 22% yield): mp, 173.0-175.0 ° C.; 1H NMR (CDCl3); δ 1.61-2.05 (m, 8H, C5H8), 2.84 (s, 3H, CH3), 3.80 (dd, J=4.9, 14.4 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.54 (dd, J=9.9, 14.4 Hz, 1H, CHH), 4.77-4.82 (m, 1H, OCH), 5.90 (dd, J=4.9, 9.9 Hz, 1H, NCH), 6.82 (d, J=8.3 Hz, 1H, Ar), 7.09-7.17 (m, 2H, Ar), 7.69-7.75 (m, 2H, Ar), 7.81-7.86 (m, 2H, Ar); 13C NMR (CDCl3) δ 24.08, 32.77, 41.53, 48.98, 54.99, 56.03, 80.59, 111.92, 114.57, 120.37, 123.55, 129.55, 131.67, 134.20, 148.02, 150.38, 167.82; Anal Calcd for C23H25NO6S+0.1 CH2Cl2 : C, 61.38; H, 5,62; N, 3.10. Found: C, 61.05; H, 5.60; N, 2.96.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@@H:10]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:37]=[C:36]([CH3:38])[S:35][C:34]=4[CH3:39])[N:30]=[C:29]([C:40]4[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=4)[N:28]=3)[CH2:11][CH2:12]1)[C:7](=[O:49])[NH:6]2)=[O:4].C(C1N=C(C2C=C(O[C@H]3C[C@@H]4N(C(=O)N(C)CCCCC=C[C@H]5[C@](C(O)=O)(NC4=O)C5)CC3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)#C>>[CH3:39][C:34]1[S:35][C:36]([CH3:38])=[CH:37][C:33]=1[C:31]1[N:30]=[C:29]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[N:44]=2)[N:28]=[C:27]([O:26][C@@H:10]2[CH2:9][C@@H:8]3[N:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]4[C@:5]([C:3]([OH:4])=[O:2])([NH:6][C:7]3=[O:49])[CH2:23]4)[CH2:12][CH2:11]2)[CH:32]=1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@H](Oc3cc(-c4cc(C)sc4C)nc(-c4nc(C(F)(F)F)cs4)n3)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Product: Cc1cc(-c2cc(O[C@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)nc(-c3nc(C(F)(F)F)cs3)n2)c(C)s1
Yield: 90 %

Procedure:
(1S,4R,6S,18S)-18[6-(2,5-Dimethylthien-3-yl)-2-(4-trifluoromethylthiazol-2-yl)-pyrimidin-4-yloxy]-13-N-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.4.0.0*4,6*]-nonadec-7-ene-4-carboxylic acid 42v was synthesized from compound 41v (69 mg, 1.0 eq.), according to the procedure as described for compound 38, as a yellow oil in 90% yield. MS (ESI, EI−) m/z=703(MH−).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([CH2:18][NH2:19])[OH:17]>>[OH:17][CH2:16][CH2:18][NH:19][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NCCO
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Product: Cc1cnc2c(NCCO)nc3ccccc3n12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with ethanolamine according to a procedure that is similar to that followed in example 3 there is obtained 4-(2-hydroxyethylamino)-1-methyl imidazo[1,2-a]quinoxaline. m.p. (DSC)=173.4° C. (onset); IR (KBr): 3415, 3217, 1558 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7.÷7.2 (3H,m), 7.2 (1H,m), 6.6 (1H,m), 5.3 (1H,sb), 3.85 (3H,m), 2.8 (3H,s); UV (EtOH): λmax =225, 242, 271, 301, 314, 327 nm. Elementary analysis for C13H14N4 (m.w. 242.28): calcd. C 64.45, H 5.82, N 23.12%; found C 64.29, H 5.91, N 23.13%.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25].[Cl:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:28][CH2:29][CH2:30][O:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25]
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc2cccc(OCCCl)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
3.8 g (22 mmol) of diethylazo dicarboxylate was added to a solution containing 5 g (22 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide, 1.8 g (22 mmol) of 2-chloroethanol and 5.8 g (22 mmol) of triphenylphosphine in 50 ml of THF, and the mixture was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, then concentrated and purified by column chromatography (hexane/ethyl acetate=2/1) to obtain 1.66 g (yield: 26%) of the desired product. Melting point: 177°-179° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC(=O)O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccccc2)[nH]c1C

Procedure:
About 40 g of 5-methyl-2-phenylimidazole-4-acetic acid, 100 ml of absolute ethanol, 1 g of p-toluenesulfonic acid and 650 ml of benzene is heated under reflux with azeotropic removal of water overnight (about 15 hours). The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to yield the product, ethyl 5-methyl-2-phenylimidazole-4-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:18][C:8]2[N:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:11]=[C:12](Cl)[C:7]=2[CH:6]=1)=[O:4].N#N>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:18][C:8]2[N:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(Cl)nc(S(C)(=O)=O)nc2s1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2cnc(S(C)(=O)=O)nc2s1
Reaction time: 6 h

Procedure:
To a solution of 4-chloro-2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (700 mg, 2.2 mmol) in THF/MeOH (10/10 mL) purged with N2 was added Pd/C (700 mg). The reaction mixture was purged with N2, evacuated and purged with H2 three times. After 6 h, the mixture was filtered via Celite and concentrated. The residue dissolved in MeOH/CH2Cl2 and the solid was filtered. The filtrate containing the product was concentrated and used without further purification. ESIMS calcd 273 (M++H), found 273 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].C(O)C.[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C:30](=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Br:1])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COP(=O)(Cc1ccccc1Br)OC
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2ccccc2Br)CC1

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (5.5 g, 18.7 mmol) in THF was added slowly to a mixture of NaH (0.8 g of a 60% mineral oil dispersion, 20 mmol) in THF (75 ml) and ethanol (0.5 ml) and the mixture was stirred for 45 min. A solution of 1-(tert-butyloxycarbonyl)-hexahydro-4 H-azepin-4-one (3.98 g, 18.7 mmol) in THF was added dropwise and the mixture was heated to reflux for 5 hr. The mixture was cooled and quenched with water. The mixture was diluted with ethyl acetate, washed with water, and dried with brine. The organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexane to give 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]-hexahydro4 H-azepine as a clear oil that solidified upon standing (4.3 g, 62.8%).
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[I:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([N:52]=[C:53]=[O:54])[CH:47]=1>CN(C1C=CN=CC=1)C.ClCCl>[I:45][C:46]1[CH:47]=[C:48]([NH:52][C:53]([N:31]2[C:21]3[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=[C:19]([C:16]4[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]5[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=5)[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[N:18][CH:17]=4)[C:20]=3[CH2:33][CH2:32]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: O=C=Nc1cccc(I)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(I)c3)cn2)cc1
Temperature: 25 °C

Procedure:
To a dichloroethane solution (10 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (540 mg), DMAP (12.2 mg) and 1-iodo-3-isocyanato-benzene (490 mg) were added, followed by refluxing for 17 hours. This was cooled to room temperature, and dichloromethane (40 ml) was added. After washing with saturated aqueous ammonium chloride solution (30 ml), the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (hexane/dichloromethane/ethyl acetate=4/4/1 to 1/2/1), to obtain the desired compound as a crude product (404 mg, 51%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([O:21][CH3:22])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5]>[Pd].CO>[NH2:18][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-fluoro-5-methoxy-N-(1-methyl-4-piperidyl)-4-nitro-benzamide Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 25° C. under Hydrogen at 1 bar pressure for 18 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(N2CCN(CCO)CC2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Methyl 3-bromo-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate (100 mg, 0.291 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.9 mL). Under ice-cold conditions, sodium hydride (15.2 mg, 0.350 mmol) and benzyl bromide (38 μL, 0.320 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added water under ice-cold conditions, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (43 mg (yield 34.3%)) was obtained as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]2[C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[Cl-:22].[Li+].C(OCC)(=O)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][C@@H:11]([Cl:22])[CH2:10][C@H:9]2[C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1cccnc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1Cc1cccnc1
Reaction time: 4.5 h
Yield: 88.4 %

Procedure:
In an atmosphere of nitrogen, (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-methylsulfonyloxypyrrolidine (84.65 g) was dissolved in polyethylene glycol-400 (400 ml) followed by addition of lithium chloride (40 g, 0.943 mol). The mixture was warmed to 85°-90° C. and stirred at that temperature for 4-5 hours. The reaction mixture was then cooled to -20°~-25° C. and ethyl acetate (800 ml)-water (400 ml) was added thereto for extraction. After phase separation, the aqueous layer was adjusted to pH 9-9.5 with 24% sodium hydroxide in water (pH prior to adjustment: 4.8) and extracted with ethyl acetate (400 ml) twice. The ethyl acetate layer was combined and washed with a saturated aqueous sodium chloride solution (200 ml). The ethyl acetate solution was then concentrated to dryness under reduced pressure to provide (2S,4S)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-chloropyrrolidine (60.6 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (2.260 g, 10.00 mmol) and 4-(trifluoromethyl)phenyl boronic acid (2.850 g, 15.00 mmol) in N,N-dimethylformamide (50 mL) was added sodium bicarbonate (3.360 g, 40.00 mmol) and water (5 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2, then Pd(PPh3)4 (579 mg, 0.50 mmol) was added, and the resulting mixture was heated at 70° C. until the starting material (6-bromo-3,4-dihydroquinolin-2(1H)-one) was no longer seen by TLC. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through a layer of celite, which was washed with 10% N,N-dimethylformamide in ethyl acetate (100 mL), and the filtrate transferred to a separation funnel. The organic phase was washed with 1N sodium carbonate (100 mL), 30% ammonium chloride (100 mL), and brine (100 mL). Solvent was removed under reduced pressure to provide a yellow solid. Methanol (5.0 mL) was added, and the mixture sonicated, filtered, washed with methanol (5.0 mL), and dried under reduced pressure to afford 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (2.184 g, 7.5 mmol, 75%). LCMS mz 292.0 (M+H), anal HPLC ca 94% in purity, 1H NMR (400 MHz; CDCl3) δ 7.98 (s, 1H); 7.66 (m, 4H); 7.40-7.50 (m, 2H); 6.86 (d, J=9.0 Hz, 1H); 3.06 (t, J=7.6 Hz, 2H); 2.70 (t, J=7.6 Hz, 2H).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([O-:5])=[O:4].[Na+].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10].O.S(=O)(=O)(O)O>C1COCC1>[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(Br)C(=O)[O-]
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reaction time: 0.21 h
Yield: 10.2 %

Procedure:
A suspension of 1.75 g of sodium α-bromopropionate in 20 ml of THF was added to 15 ml of a 0.67 M solution of p-isobutylphenyl magnesium bromide in THF. The mixture was heated under reflux for 1 hour, and then cooled. Then, 15 ml of water and then 5 ml of 20% sulfuric acid were added. The mixture was stirred for 10 to 15 minutes, and extracted with diethyl ether. The extract was washed with water, and then, extracted with a 1 N aqueous solution of potassium carbonate. The extract was washed with diethyl ether. The resulting aqueous layer was added to a mixture of 10 ml of concentrated hydrochloric acid and 20 ml of water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried, concentrated and purified by silica gel column chromatography to give 0.21 g (yield 10.2%) of α-(p-isobutylphenyl)propionic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: Cn1c(=O)oc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Cn1c(=O)oc2cc(C(=O)c3cccnc3)ccc21

Procedure:
The flask is equipped with a reflux condenser and taken to an oil bath at a temperature in the region of 45° C. 6 g (0.04 mol) of 3-methylbenzoxazolinone and 10.6 g (0.06 mol) of nicotinoyl chloride hydrochloride are introduced.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[O:19]1[CH2:18][CH2:17][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:6]3)[S:10][CH:11]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CCOCC5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 3-acetylthio-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (410 mg, 1.50 mmol) (obtained as described in Reference Example 11) in dimethylformamide (20 ml) was added hydrazine acetate (138 mg, 1.50 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (743 mg, 1.25 mmol) in acetonitrile (37 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.873 ml, 5.01 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate—10% methanol and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (485 mg, yield 62%).