Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:45]([O:51][CH2:52]I)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.1 g) in N,N-dimethylformamide (41 ml) was added iodomethyl pivalate (1.55 g) at 0° C., and the mixture was stirred for 15 minutes at the same temperature. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium bicarbonate and water, followed by drying over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(3.75 g).
Reaction SMILES: Cl.Cl.C([O:5][C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+].O.CO>[C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCC1CCNCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 3(S)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.35 g) in 1N sodium hydroxide solution (8 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (1.5 ml), the mixture is subjected to column chromatography on MCI gel (CHP 20P, 150-300μ, Mitsubishi Chemical) using water-methanol (2:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[1(S)-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.2 g) as colorless powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[OH:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:20][OH:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCN(CCO)CCO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCN(CCO)CCO
Temperature: 80 °C
Yield: 41.1 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 30 ml of N-methylpyrrolidinone, 2.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 1.72 g of triethylamine. The reaction medium was heated at 80° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 1.5 g of 2[[2-(4-nitro-2-methylphenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (17) were obtained.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[O:22]=[CH:23][C:24]1[CH:32]=[CH:31][C:29](O)=[C:26]([O:27][CH3:28])[CH:25]=1>>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH:32]=[CH:31][C:29]=1[O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:23]=[O:22]
Reactant: CS(=O)(=O)OCCN1c2ccccc2Sc2ccccc21
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1OCCN1c2ccccc2Sc2ccccc21
Yield: 71.2 %

Procedure:
The title compound (2.5 g, 71%) was prepared as a white solid from 2-(phenothiazin-10-yl)ethyl methanesulfonate (3.0 g, 9.3 mmol) and vanillin (1.7 g, 11.2 mmol) using a similar procedure to that described in preparation 4. mp: 130° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].IC.[C:50](OCC)(=O)C>CN(C)C=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@@H:34]([N:37]([S:38]([CH3:41])(=[O:40])=[O:39])[CH3:50])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N(C)S(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 150 mg (0.227 mmol) (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml dimethylformamide were added 15 mg (0.34 mmol) sodium hydride (55% dispersion in mineral oil) at room temperature. After stirring at room temperature for 30 min 39 mg (27 mmol) iodomethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml ethyl acetate and washing with 10 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 120 mg (78%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30]CC)=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([OH:30])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ccc(Cl)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.39 mmol, see step (b) Example 9) and 4-chlorophenylboronic acid (110 mg, 0.68 mmol). Yield 140 mg (74%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12.[Cl:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:32][C:11]1[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=3)=[CH:15][CH:14]=2)[CH:9]=[C:6]2[C:5]=1[N:4]1[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]1[N:2]([CH3:1])[C:7]2=[O:8]
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc2N2C1=N[C@@H]1CCC[C@@H]12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 0 °C
Yield: 44.7 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (38 mg, 0.082 mmol) is dissolved in a mixture of CCl4 and DMF (8/1, v/v). The solution is cooled to 0° C., and then a solution of N-chlorosuccinimide (10.9 mg, 0.082 mmol) in CCl4 and DMF (8/1, v/v) is added dropwise. The reaction mixture is stirred at room temperature for half an hour. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (16.5 mg, yield 45%). MS (ESI) m/z 450.1 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccccc1I
Reactant: NS(=O)(=O)c1cccc(N=C=S)c1
Product: NS(=O)(=O)c1cccc(NC(=S)Nc2ccccc2I)c1

Procedure:
The subject compound was prepared utilizing the procedure described above from 3-isothiocyanatobenzenesulfonamide and 2-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.52 (s, 1H), 8.01-7.37 (m, 9H), 7.04 (m, 1H); (M+H)+ (434).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H]1C(=O)NC2C=CC=CC=2OC1)=O)(C)(C)C.C(N[C@@H](C(O)=O)CO)(OC(C)(C)C)=O.[CH:55]([C:58]1[CH:65]=[CH:64][C:61]([CH2:62]Cl)=[CH:60][CH:59]=1)([CH3:57])[CH3:56].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:15](=[O:16])[N:14]([CH2:62][C:61]2[CH:64]=[CH:65][C:58]([CH:55]([CH3:57])[CH3:56])=[CH:59][CH:60]=2)[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1COc2ccccc2NC1=O
Agent: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)COc3ccccc32)cc1

Procedure:
Obtained analogously to the directions in Example 1a) starting from 4.8 g of (R)-3-(tert-butoxycarbonyl-amino)-2,3-dihydro-1,5-benzoxazepin-4-one (prepared analogously to (S)-3-(tert-butoxycarbonylamino)-2,3-dihydro-1,5-benzoxazepin-4-one, starting from N-Boc-(D)-serine), 4.4 g of p-isopropylbenzyl chloride, 2.9 g of potassium carbonate and 166 mg of potassium iodide. Rf value (eluant: hexane/ethyl acetate 4:1): 0.33.
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[CH:27]=O)([CH3:23])([CH3:22])[CH3:21].C1C=CC=CC=1>O>[C:33]([C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:31]=1[OH:32])[CH:27]=[N:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:15])([Cl:17])[Cl:16])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12)([CH3:35])([CH3:36])[CH3:34]
Reactant: CC1=CS[C@@H]2[C@H](N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: c1ccccc1
Product: CC1=CS[C@@H]2[C@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of 2.14 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-2-cephem-4-carboxylate and 1.3 g. of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde in 60 ml. of benzene was refluxed for 1.5 hours in a vessel equipped with a water separator. After evaporation of the solvent, a small amount of cyclohexane was added to the residue. Insolubles were filtered off, and the filtrate was purified by a dry silica gel column chromatography (4.5 × 15 cm, eluent; ethyl acetate-cyclohexane, 1 : 10) to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[NH:9]1[CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11][CH2:10]1.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:9]1[CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11][CH2:10]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ccncc1Br
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ccncc2Br)CC1
Yield: 33.2 %

Procedure:
General procedure C was followed using 3-bromo-4-chloro-pyridine (0.10 g, 0.52 mmol) and isonipecotamide (67 mg, 0.52 mmol) NMP (2 mL) and triethylamine (0.14 mL, 1.0 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 99:1 to 95:5) to furnish the title compound as a white solid (49 mg, 33%), LC-MS (ESI) Rt 0.80 min, m/z 284 (100%, [M+H]+); m/z (ESI) C11H15BrN3O requires 284.0393 found [M+H]+ 284.0392.
Reaction SMILES: [CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[C@H:48]([CH2:49][OH:50])[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:58][CH2:59][CH2:60][O:61][CH3:62]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:51]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[C@H:48]([CH2:49][O:50][CH2:58][CH2:59][CH2:60][O:61][CH3:62])[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:52][CH2:53][CH3:54]
Reactant: COCCCBr
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2COCCCOC)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of (S)—N,N-dibutyl-4-chloro-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamide (Example 91, 21 mg, 0.028 mmol) in DMF (900 μL) was cooled to 0° C., and NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) was added followed by 1-bromo-3-methoxypropane (9 mg, 0.061 mmol). The resulting reaction mixture was stirred warming to room temperature over 1 h and then heated at 130° C. for 3 h. Additional NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) and 1-bromo-3-methoxypropane (9 mg, 0.061 mmol) were added, and stirring was continued overnight at 130° C. Additional NaH (2 mg, 0.061 mmol, 60% suspension in mineral oil) and 1-bromo-3-methoxypropane (9 mg, 0.061 mmol) were added, and the reaction mixture was stirred at 135° C. for 24 h. TBAI (10 mg, 0.027 mmol) was then added, and stirring was continued at 140° C. for 72 h. After quenching with sat. aq. NH4Cl solution, the reaction mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification using preparative HPLC provided the title compound (4 mg, 18%) as an off-white solid after lyophilization. 1H NMR (CD3OD, mixture of amide rotamers) δ 8.82-8.69 (m, 1H), 8.29-8.20 (m, 1H), 8.16-7.92 (m, 5.5H), 7.78-7.57 (m, 3H), 7.31-7.05 (m, 3H), 6.94-6.85 (m, 0.5H), 5.24-5.36 (m, 1H), 5.09-4.91 (m, 1H), 4.53-4.47 (m, 0.5H), 4.30-4.16 (m, 1.5H), 3.64-2.73 (m, 12H), 2.62-2.49 (m, 1H), 2.38-2.24 (m, 4H), 1.83-0.86 (m, 13H), 0.80-0.70 (m, 2.5H), 0.67-0.60 (m, 0.5H); MS(ESI+) m/z 842.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:5]
Reactant: CCNCC
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCN(CC)C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diethylamine.
Reaction SMILES: [C:1](=C1N=CC=N1)=[S:2].[NH2:8][CH2:9][CH:10]1[CH2:14][N:13]([C@@H:15]([CH2:19][CH3:20])[C:16]([NH2:18])=[O:17])[C:12](=[O:21])[CH2:11]1>CN(C=O)C>[N:8]([CH2:9][CH:10]1[CH2:14][N:13]([C@@H:15]([CH2:19][CH3:20])[C:16]([NH2:18])=[O:17])[C:12](=[O:21])[CH2:11]1)=[C:1]=[S:2]
Reactant: CC[C@@H](C(N)=O)N1CC(CN)CC1=O
Reactant: S=C=C1N=CC=N1
Solvent: CN(C)C=O
Product: CC[C@@H](C(N)=O)N1CC(CN=C=S)CC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
In a 100 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 4.5 g (22.7 mmoles, 1 eq) of thiocarbonylimidazole are dissolved in 25 ml of DMF and the mixture cooled down to 0° C. 4.53 g (22.7 mmoles, 1 eq) of (2S)-2-[4-(aminomethyl)-2-oxo-1-pyrrolidinyl]butanamide 412 in 25 ml of DMF are added dropwise over 30 min, the mixture is stirred 3 hours at room temperature and left overnight. The mixture is concentrated to dryness, the residue is dissolved in 20 ml of toluene, concentrated again to dryness, and the residue is purified by Prep LC (350 g SiO2 CH2Cl2/MeOH/NH4OH, 93.4:6:0.6) to give 3.1 g of crude 49. It is triturated in 20 ml of ether, filtered and the residue (1.9 g) crystallised from 15 ml of acetonitrile to give 1.2 g of pure 49 (22%).
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]([CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42]C(=O)COC3C=CC=CC=3)[C:40](=[O:53])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:16].P([O-])(O)(O)=O.[K+]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH2:42])[C:40](=[O:53])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:25])=[O:16]
Reactant: COC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 3 h

Procedure:
4.4 ml of pyridine and 44 ml of an 8% strength suspension of phosphorus pentachloride in methylene chloride are added to a solution, which has been cooled to -17°, of 3.10 g (5.42 mmols) of diphenylmethyl 3-methoxycarbonylmethyl-7β-phenoxyacetylamino-3-cephem-4-carboxylate in 110 ml of methylene chloride and the mixture is then stirred for 3 hours in an ice bath. After cooling to -30°, 27 ml of absolute methanol are added and the residue mixture is stirred for 1 hour at -10°, for 1 hour at 0° and for 1 hour at room temperature. The pH is adjusted to 2.5 by adding a 0.5 M solution of potassium dihydrogen phosphate, the mixture is stirred for a further 0.5 hour and, for working up, the organic phase is separated off, the aqueous phase is subsequently extracted with twice 50 ml of methylene chloride and the combined methylene chloride phases are extracted by shaking with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated. Chromatography of the crude product over 100 g of silica gel and elution with toluene and 20-30% of ethyl acetate gives amorphous diphenylmethyl 3-methoxycarbonylmethyl-7β-amino-3-cephem-4-carboxylate, which according to thin layer chromatography is a single compound and which is characterised in the form of the crystalline toluenesulphonate; melting point 157°- 158° (decomposition); Rf 0.45 (on silica gel, with ethyl acetate); UV spectrum (in ethanol): λmax =257 nm; IR spectrum (in Nujol): bands at 2.87, 5.57, 5.72, 5.79 and 6.12μ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:9]
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)C=Cc1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NCCCNCCCCNCCCNC(=O)C=Cc1cccc(O)c1
Reaction time: 21 h
Yield: 26.6 %

Procedure:
According to the General Procedure using 3-hydroxycinnamic acid (160 mg, 0.97 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 2 h and coupling over 21 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 15-22 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.22, (108 mg, 32%), lyophilisation gave 90 mg of a yellow viscous gum whose spectroscopic data include: UVmax 213 (emax 3 500), 230sh and 375 (emax 3 800) nm; pmr (90 MHz, 2H2O) 1.4-2.0 (m, 8H, 4×CH2 --CH2), 2.6-3.0 (m, 10H, 5×CH2 --N), 3.35 (t, J=7, 2H, CON2H--CH2 --CH2), 6.4 (d, J=16, 1H, CH=CH--CO), 3.55 (s, 2H, Ar--CH2 --CO), 6.6-6.9 (m, 3H, 3×ArH 2,4,6), and 7.2-7.6 (m, 2H, ArH 5 and ArCH=CH)ppm; M+1 349 (FAB matrix m-nitrobenzyl alcohol) C19H32N4O2 requires M+ 348).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][S:25][CH2:26][CH2:27]O>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][S:25][CH3:24])=[CH:23][C:6]1=2
Reactant: CSCCO
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CSCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methylthioethanol.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([NH:14][CH3:15])=[O:13])C=CC=CC=1.[CH:28]([OH:30])=[O:29]>>[CH:28]([OH:30])=[O:29].[CH3:15][NH:14][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13]
Reactant: CNC(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CNC(=O)SCCN
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To N-triphenylmethyl-2-methylaminocarbonylthioethylamine (306 mg) which was prepared by the method of Reference 2 was added formic acid (98%; 5 ml). The reaction solution was stirred at a temperature of 50° C. for 30 minutes and was then concentrated under reduced pressure. The resultant residue was purified without after-treatment by silica gel chromatography using a solvent system of chloroform/methanol/water (6:5:1 v/v) to obtain 139 mg of the desired product with a yield of 95%.