Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:20])=O.[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:22][CH3:21])=[O:20]
Reactant: O=C(O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a stirred solution of compound (xvi) (50 mg, 0.15 mmol) in DMF (5 mL) were added HATU (85 mg, 0.22 mmol) DIPEA (0.1 mL, 0.45 mmol) and methyl amine solution (0.26 mL, 0.15 mmol) at 0° C. and the reaction mixture was stirred at RT. After 12 h the reaction mixture was diluted with water and the precipitated solid was filtered to give 6-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (xvii) (30 mg, 58%) as a white solid. ESI-MS m/z calculated for [M+H]+: 348.01; found: 347.90.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[F:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][O:21]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]2[O:21][C@@H:22]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OCC2CCC=CO2)cc1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
389 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and 300 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran, prepared as described above, were dissolved in 10 ml of diethyl ether. A catalytic amount (2 drops) of phosphorus oxytrichloride was added to the resulting solution and the mixture allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 214 mg of the isomer of lesser polarity of trans-6-(4-fluorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 211 mg of the isomer of greater polarity and 143 mg of a mixture of these isomers.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH:1]1([CH2:7][NH:8][C:38]([C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:29]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:17]4[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:27][CH:26]=2)[C:30]([CH3:42])=[C:31]3[CH3:41])=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCC1CCCCC1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3CCCCC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using cyclohexylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:28])[C:8]2[O:14][C:13]3[C:15]([Cl:24])=[CH:16][C:17]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[CH:18][C:12]=3[CH2:11][S:10](=[O:26])(=[O:25])[C:9]=2[CH:27]=1)=[O:4].[CH3:29][NH:30][CH3:31].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:28])[C:8]2[O:14][C:13]3[C:15]([Cl:24])=[CH:16][C:17]([NH:19][C:20](=[O:23])[CH2:21][N:30]([CH3:31])[CH3:29])=[CH:18][C:12]=3[CH2:11][S:10](=[O:25])(=[O:26])[C:9]=2[CH:27]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN(C)C)cc(Cl)c1O2

Procedure:
A mixture of Example 133 (0.4 g, 0.9 mmol), dimethylamine.HCl (0.44 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.0 mmol) in 10 mL of dry DMF was stirred at 80° C. for 2 h. The reaction mixture was filtered and the solid obtained was washed with water. The filtrate was concentrated, treated with water and extracted with chloroform. The organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.26 g, (63.73%); 1H NMR (DMSO-d6): δ 1.96 (s, 6H, 2CH3), 2.17 (s, 2H, CH2), 2.3 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 4.45 (s, 2H, CH2), 7.29 (s, 1H, Ar), 7.55 (s, 1H, Ar), 7.67 (s, 1H, Ar), 7.95 (s, 1H, Ar), 9.26 (s, 1H, NH); MS: m/e (EI+) 451 (M+1).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: C1CCNC1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M pyrrolidine-trimethylaluminium in benzene (7.6 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 6 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (775 mg, yield 78%) as a pale brown solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].Br[CH2:18][C:19]1[S:27][C:26]2[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:24][C:23]([Cl:34])=[N:22][C:21]=2[CH:20]=1.CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C.C(Cl)Cl>[Cl:34][C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:26]2[S:27][C:19]([CH2:18][N:11]3[CH2:12][CH2:13][N:8]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:9][C:10]3=[O:14])=[CH:20][C:21]=2[N:22]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C(=O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-BOC-piperazinone (0.3 g, 1.6 mmol) in DMF (3 mL) at 0° C. was added NaH (60% in mineral oil, 1.9 mmol). Next, 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine (0.6 g, 2 mmol) was added and the reaction stirred for 15 min. The reaction was quenched with saturated NH4Cl and the aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. This intermediate was dissolved in CH2Cl2 (40 mL) and MeOH (40 mL) and Et2O (10 mL) and cooled to 0° C. To this solution was added 4 M HCl in dioxane (20 mL). The reaction was warmed to room temperature, stirred 18 h, then was concentrated in vacuo. To the residue was added CH2Cl2 (50 mL), Et3N (1.5 mL, 11 mmol), and MeSO2Cl (0.6 mL, 8 mmol). The reaction mixture stirred 42 h at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo (0.25 g, 28% over 3 steps). MS (Q1) 446 (M)+
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]=1)[CH2:19]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH2:19][C@:3]1([C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]1=[O:1])[CH2:26]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (R)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamate from Step C (13.4 g 27.8 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (1.9 mL, 27.8 mmol) and 10 N sodium hydroxide (6 mL, 60 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (1 L). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (35 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Cl:18][C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:19]([Cl:18])=[O:21])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Yield: 272.1 %

Procedure:
A mixture of 4-(4-trifluoromethylphenoxy) piperidine (0.6 g, 2.45 mmol), triphosgene (0.25 g, 0.86 mmol), and pyridine (0.4 ml, 4.90 mmol) in toluene (6 ml) was heated under reflux for 2.5 hours. To which ethyl acetate was added, and the mixture was washed with 10% hydrochloric acid, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenoxy)piperidine-1-carbonylchloride (0.72 g, yield 96%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[S:10]2(=[O:34])=[O:33])[CH:5]=[CH:6][C:7]=1[F:8].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[S:10]2(=[O:33])=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1(=O)N(CCN2CCNCC2)c2ccccc2N1c1ccc(F)c(F)c1
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.34 g, 0.69 mmol) in dichloromethane (5 mL) was treated with hydrogen chloride (2.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2 g, 74%) as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].C[CH:20](C)[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1C)O.[CH2:40](P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:21]([CH3:20])([C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[N:25][CH:24]=2)[CH3:40])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-2-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[C:3]=1[NH2:11].Cl[C:13]1[S:14][CH:15]=[CH:16]N=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:13]1[S:14][CH:15]=[CH:16][N:7]1[C:5]2=[O:6]
Reactant: Clc1nccs1
Reactant: NC(=O)c1cccc(F)c1N
Product: O=c1c2cccc(F)c2nc2sccn12
Yield: 78.6 %

Procedure:
15.4 g of 3-fluoroanthranilamide and 13.1 g of 2-chlorothiazole were stirred for 7 hours at 150° C. After working up in the conventional manner there was obtained 17.3 g (79%) of the above compound; m.p. 187°-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](Cl)(=[O:38])=[O:37])=[C:20]1[CH3:40]>ClCCl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:38])(=[O:37])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:20]1[CH3:40]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of aniline (0.022 mL), triethylamine (0.051 mL) and dichloromethane (0.5 mL) was treated with [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.10 g), and resulting mixture was stirred at room temperature for 4 days. The mixture was diluted with dichloromethane, washed with water and concentrated under reduced pressure to afford the title compound as a colourless gum (0.078 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[CH3:15][NH:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[S:2]([CH:18]1[O:19][CH2:20][CH2:21][NH:16][CH2:17]1)(=[O:4])=[O:3]
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 1.0 g) was dissolved in 20 mL of ethyl acetate and morpholine (Aa, 1.0 mL, 3 eq) was added. The mixture was stirred at room temperature for 2 hours, then extracted with 15 mL of 0.5M HCl. The organic layer was washed with H2O and brine, and the solvent evaporated to yield 4-(methylamino)-3-(morpholino-sulfonyl)-benzoic acid (1.3.Aa) as an off-white powder (0.30 g, 30% yield). MS analysis (m−1)=299.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCC(=O)CC2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Compound 447 (150 mg, 0.517 mmol) was dissolved in DMF (2.5 mL), and isonicotinic acid (191 mg, 1.55 mmol), EDC hydrochloride (298 mg, 1.55 mmol) and 1-hydroxybenzotriazole monohydrate (237 mg, 1.55 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 448 (115 mg, 66%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCOCC.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:22][C:21](=[O:23])[CH2:20][C:16]1[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1cncc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A 2.0 M solution of trimethylsilyldiazomethane in ether (10.3 mL, 20.5 mmol) was added dropwise to a mixed solution of (5-bromo-pyridin-3-yl)-acetic acid (4.04 g, 18.7 mmol) in toluene (17.3 mL) and methanol (11.5 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:3) to give the title compound (3.12 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:16])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(c1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(=O)N2C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 104.1 %

Procedure:
7-Methoxy-4H-benzo[1,4]oxazin-3-one (11.61 g, 0.065 mol) in 100 mL dry DMF was stirred at 0° C. under nitrogen. Sodium hydride (60%, 2.85 g, 0.072 mol) was added in portions over 30 minutes, after which methyl iodide (4.44 mL, 0.071 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 2.5 hours, then poured into 1400 mL water. The resulting aqueous mixture was extracted four times with 400 mL EtOAc, and the combined organic layers were washed with water, then brine, dried (MgSO4), filtered, and evaporated under reduced pressure to provide 13.07 g of 7-Methoxy-4-methyl-4H-benzo[1,4]oxazin-3-one. (M+H)=194.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: CI
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2

Procedure:
The title compound was prepared by the method of Preparation 2b using (R)-1-(4-fluoro-phenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and iodomethane. 1H NMR (CDCl3): δ 7.47-7.40 (m, 3H), 7.19-7.12 (m, 2H), 6.32-6.29 (d, 1H, J=2.2 Hz), 4.45-4.30 (d, 1H, J=14 Hz), 4.27-3.92 (bs, 1H), 3.29 (s, 3H), 3.19-3.13 (d, 1H, J=9.1 Hz), 3.09-2.97 (d, 2H, J=16 Hz), 2.92-2.65 (m, 2H), 2.59-2.46 (m, 1H), 2.40-2.20 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[CH2:6]([N:8]([CH2:47][CH3:48])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[C@H:19]([CH3:46])[C@@H:20]2[C@@H:37]([C@H:38]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:39])[C:36](=[O:45])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])=[O:10])[CH3:7].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH2:47]([N:8]([CH2:6][CH3:7])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([C:18]1[C@H:19]([CH3:46])[C@@H:20]2[C@@H:37]([C@H:38]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:39])[C:36](=[O:45])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:24])=[O:2])=[O:10])[CH3:48]
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Yield: 83.4 %

Procedure:
122 mg (1.45 mmol) of sodium hydrogencarbonate were added to 6 ml of a methylene chloride solution containing 304 mg (0.486 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 34). The mixture was then placed in an ice bath while 105 mg (0.487 mmol) of m-chloroperbenzoic acid (80% purity) were added, with stirring. The reaction mixture was stirred for 1 hour at the same temperature, after which it was diluted with methylene chloride and washed with an ice-cooled dilute aqueous solution of sodium hydrogencarbonate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 25 g of silica gel. Elution with a 2:1 by volume mixture of ethyl acetate and hexane afforded 260 mg (yield 83%) of the title compound as a foam-like solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Cl.[NH2:17]O>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:17])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCCC(N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-one (6 g, 27.8 mmol) in ethanol (60 ml) was added hydroxylamine hydrochloride (5.79 g, 83.3 mmol) and the reaction heated to reflux and stirred for 16 h. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed twice with water, dried over sodium sulfate and concentrated in vacuo. The crude oxime was then dissolved in ethanol (100 ml) and Raney nickel (approx 1 g) added. The reaction was stirred under a balloon of hydrogen for 72 h. The reaction was filtered though celite (washing with ethanol) concentrated in vacuo, adsorbed onto silica gel and purified by flash column (50-80% ethyl acetate in hexanes) to yield the title compound (5 g, 83%) as colourless crystals.