Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Reaction time: 0.5 h

Procedure:
3.0 g (5.5 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 20 ml (250 mmol) of hydroxymethyl-cyclopropane and 0.7 g (3 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness, the residue is taken up in chloroform and stirred for 0.5 hour with 30 ml of a saturated potassium fluoride solution. The resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 190°-191°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:11][O:10]1.[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1>O>[CH:12]1([NH:16][CH2:11][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[OH:10])[CH2:15][CH2:14][CH2:13]1
Reactant: Clc1cccc(C2CO2)c1Cl
Reactant: NC1CCC1
Solvent: O
Product: OC(CNC1CCC1)c1cccc(Cl)c1Cl
Temperature: 60 °C

Procedure:
To 2,3-dichlorophenyloxirane prepared in step 1 (assumed 0.3 mmol) was added cyclobutylamine (5.86 mmol, 0.5 ml). The solution was heated at 60° C. in a capped test tube overnight. The solution was diluted with water (1 ml), extracted with ethyl acetate (1 ml) and washed with water (2×1 ml). The solution was concentrated by vacuum centrifuge overnight to give 2-cyclobutylamino-1-(2,3-dichlorophenyl)ethanol and used without further purification.
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=[NH:13])=[CH:6][CH:5]=1.[CH:15]([CH:17]([CH2:23][CH3:24])[C:18](OCC)=O)=[O:16]>C(O)C>[CH2:23]([C:17]1[C:15](=[O:16])[N:13]=[C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[NH:14][CH:18]=1)[CH3:24]
Reactant: N=C(N)CCc1ccc(F)cc1
Reactant: CCOC(=O)C(C=O)CC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCc1c[nH]c(CCc2ccc(F)cc2)nc1=O
Temperature: 25 °C
Yield: 79.8 %

Procedure:
Sodium (0.23 g) in dry ethanol (10 ml) was treated with 3-(4-fluorophenyl)propionamidine hydrochloride (Int. A108) (1.02 g). Ethyl 2-formylbutyrate (0.72 g) was added and the mixture refluxed for 6 h then maintained at room temperature for a further 24 h. The reaction mixture was concentrated in vacuo, and the residue treated with water and acidified with conc. hydrochloric acid. The white precipitate was filtered off, washed with water and dried in vacuo at 40° C. overnight, to give the title compound, (982 mgs, 80%) 1H-NMR (CDCl3) δ 1.22 (3H, t), 2.52 (2H, q), 2.94 (2H, m), 3.09 (2H, m), 6.96 (2H, m), 7.24 (2H, m), 7.84 (1H, s) and 13.06 (1H, br. s). (APCI+) Found (M+1)=247, C14H15FN2O requires 246.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[N:20]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[S:22][CH:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:30][C:31](O)=[O:32])=[C:9]2[CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:42][NH:43][OH:44].Cl>C(Cl)Cl.C(N(CC)CC)C.O.O1CCCC1.CC(N(C)C)=O>[OH:44][N:43]([CH3:42])[C:31](=[O:32])[CH2:30][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)[CH:12]=2)[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]=1[CH3:34]
Reactant: CNO
Reactant: Cc1c(CC(=O)O)c2cc(OCc3csc(-c4ccccc4)n3)ccc2n1Cc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1c(CC(=O)N(C)O)c2cc(OCc3csc(-c4ccccc4)n3)ccc2n1Cc1ccccc1
Temperature: 5 °C
Yield: 56.6 %

Procedure:
A mixture of the compound of Example 40 (1.0 g, 2.13 mmol), methylene chloride (50 mL) and dimethylacetamide (0.15 mL) is cooled to 5° C. and with stirring, a solution of oxalyl chloride (0.45 mL, 5.3 mmol) in methylene chloride (10 mL) is added slowly. After stirring at room temperature for 30 minutes, the reaction mixture is poured into a solution containing tetrahydrofuran (11 mL), water (1.1 mL), triethylamine (1.8 mL) and N-methylhydroxylamine hydrochloride (0.7 g, 8.5 mmol). After stirring at room temperature for 1 hour, the reaction mixture is diluted with methylene chloride (150 mL), poured into 2N HCl (150 mL) and the layers are separated. The aqueous layer is washed again with methylene chloride (100 mL). The combined methylene chloride extract is washed with water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated under reduced pressure to give 1.0 g of a crude solid. The solid is recrystallized from ether/methylene chloride to give 0.6 g of white crystalline product in 57 % yield, m.p. 171°-173° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)CC2C=CC(OC)=CC=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:34]1[CH2:41][CH:40]([NH2:42])[C:38](=[O:39])[NH:37][CH2:36][CH2:35]1.CN1C(=O)CCC1.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH:31]1([NH:21][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:42][CH:40]3[CH2:41][CH2:34][CH2:35][CH2:36][NH:37][C:38]3=[O:39])[CH:3]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: NC1CCCCNC1=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CC3)cc(NC3CCCCNC3=O)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A microwave tube was charged with 6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (35 mg, 0.075 mmol), DL-alpha-Amino-epsilon-caprolactam (96 mg, 0.750 mmol), and NMP (1 mL). The reaction mixture was irradiated (300 W) at 100° C. for 40 minutes. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=35.053 minutes) was isolated and lyophilized to dryness. The resulting material was dissolved in DCM (2 mL) and treated with TFA (0.5 mL, 6.49 mmol). Reaction was stirred at room temperature for three hours, and then concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC(YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=30.556 minutes) was isolated and lyophilized to dryness to afford 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-(2-oxoazepan-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 13.73%). 1H NMR (400 MHz, DMSO) δ ppm 11.24 (1H, s), 8.73 (1H, d, J=2.77 Hz), 8.45 (1H, d, J=5.54 Hz), 8.39 (1H, t), 8.01 (1H, s), 7.84 (1H, t, J=6.04 Hz), 7.66 (1H, s), 6.99 (1H, s), 6.31 (1H, s), 4.54 (1H, d, J=9.57 Hz), 2.98-3.24 (3H, m), 1.80-2.02 (2H, m), 1.67 (1H, d, J=14.10 Hz), 1.37-1.59 (2H, m), 1.20-1.32 (1H, m), 0.73-0.85 (2H, m), 0.54-0.70 (2H, m). HPLC Rt=3.633 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=439.0.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].II>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A tetrahydrofuran solution of 3-(benzyloxy)cyclobutanecarboxylic acid (2.5 gm, 11.36 mmol) was added to a solution of sodium borohydride (0.52 gm, 13.63 mmol) in tetrahydrofuran. Iodine (1.44 gm, 5.68 mmol) in tetrahydrofuran solution was added to solution at 0° C., after about 15 minutes, and the mixture was stirred at room temperature for about 2 hours. It was quenched with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[CH2:22]([O:24][C:25]([C@:27]1([N:40]=[N+:41]=[N-:42])[C@H:32](O)[CH2:31][C@@H:30]2[C@H:28]1[C@@:29]2([F:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26])[CH3:23].CCOCC>ClCCl>[CH2:22]([O:24][C:25]([C@:27]1([N:40]=[N+:41]=[N-:42])[C@H:32]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])[CH2:31][C@@H:30]2[C@H:28]1[C@@:29]2([F:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reaction time: 1.5 h

Procedure:
48 μL of pyridine and 78 μL of trifluoromethane sulfonic acid anhydride dissolved in 0.4 mL of dichloromethane were added dropwise to 120 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 20 mL of dichloromethane at −75° C., and the mixture was stirred for 1.5 hours at ice-cooling under a nitrogen atmosphere. 24 μL of pyridine and 39 μL of trifluoromethane sulfonic acid anhydride dissolved in 0.2 mL of dichloromethane were added dropwise thereto at −75° C., and the mixture was stirred for 25 minutes at ice-cooling. 10 mL of ether was added thereto, and after the solids were filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 166 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.Cl.Cl[CH2:23][C:24]1[N:28]([CH2:29][CH2:30][CH3:31])[CH:27]=[N:26][CH:25]=1.O>O1CCCC1.CO>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH2:23][C:24]3[N:28]([CH2:29][CH2:30][CH3:31])[CH:27]=[N:26][CH:25]=3)[NH:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: CCCn1cncc1CCl
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCn1cncc1CSc1nc2ccc([N+](=O)[O-])cc2[nH]1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
To a solution of 2-mercapto-5-nitrobenzimidazole (3.0 g) and triethylamine (12.5 ml) in tetrahydrofuran (30 ml) was added dropwise a solution of 5-chloromethyl-1-propylimidazole hydrochloride (3.0 g) in methanol (30 ml) under nitrogen atmosphere at 0° C. After the mixture was allowed to be at room temperature and stirred for 10 minutes, water was added to the mixture and the mixture was extracted with ethyl acetate twice. The mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:8→methanol:ethyl acetate=1:4), which was recrystallized from diisopropyl ether-ethyl acetate, to give 5-nitro-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (3.33 g) as yellow crystals.
Reaction SMILES: CS(C)=O.[CH2:5]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12]([CH2:51]OS(C)(=O)=O)=[C:11]([Cl:57])[N:10]=1)[CH2:6][CH2:7][CH3:8].[N-:58]=[N+:59]=[N-:60].[Na+].[Na+].[Cl-]>CCOC(C)=O>[N:58]([CH2:51][C:12]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[N:10][C:11]=1[Cl:57])=[N+:59]=[N-:60]
Reactant: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of intermediate (11c) (15 g, 20 mmol) was added sodium azide (3.9 g, 60 mmol). The mixture was stirred at room temperature for 20 minutes. EtOAc (500 mL) and saturated aqueous NaCl (100 mL) were added and the layers were separated, retaining the organic layer. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11d) as a yellow solid (12 g), which was used directly in the next step. MS m/z: [M+H+] calcd for C41H36ClN9, 690.29. found 690.5.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6]1.[BH4-].[Na+]>CO>[OH:2][CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6]1
Reactant: COC(=O)CC1NC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(CCO)c2ccccc21
Reaction time: 8 h
Yield: 97.8 %

Procedure:
2,3-Dihydro-3-oxo-1H-isoindole-1-acetic acid methyl ester (1.5 g, 7.5 mmol) is added to a solution of NaBH4 (1.4 g, 37.6 mmol) in 50 mL of methanol at room temperature, and the mixture is stirred overnight. The reaction is quenched by addition of gaseous HCl until the pH=1. The methanol is evaporated, and the remaining solid is stirred in 100 mL of CH2Cl2 for 15 minutes. The solid is removed by filtration through Celite® 545. Evaporation of the filtrate gives 1.3 g (90% yield) of 1,3-dihydro-3-(2-hydroxyethyl)-2H-isoindol-1-one as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([NH2:26])=[C:21]([Cl:27])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:35]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([NH2:26])=[C:21]([Cl:27])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-2-(4-amino-3,5-dichlorophenylamino)-ethylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=2)[C:17]([O:19]CC)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])[CH:24]=2)[C:17]([OH:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1

Procedure:
To a solution of ethyl (2RS,3RS)-3-[3-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (10.7 g, 21.2 mmol, crude) in methanol (50 ml) was added. 2N aqueous sodium hydroxide solution (21 ml, 42 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The obtained crude crystals were washed with hexane to give the objective substance (7.90 g, 49% in 3 steps).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[O:9][C:10](=O)[C:4]2=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][N:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:5](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:9])[C:6]1=[O:7]
Reactant: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)N(c3ccccc3)C(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.9 %

Procedure:
A mixture of furopyrrole 7 (300 mg, 0.79 mmol), aniline (146 mg, 1.57 mmol), DCC (323 mg, 1.57 mmol), trifluoroacetic acid (2-3 drops) and DCM was stirred at room temperature for 144 hours. The solvent was removed, and washing with methanol gave the pyrrolopyrrole 8 as a red solid (173 mg, 55%), m.p. 255-256° C. δH (CDCl3) 7.88-7.83 (2H, m, Ar—H), 7.49-7.43 (5H, m, Ar—H), 7.40-7.26 (5H, m, Ar—H), 7.12-7.07 (2H, m, Ar—H) and 3.35 (3H, s, NCH3)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17]O)[CH2:15][S:16][C@H:11]12)=[O:8].[SH:24][C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1.P(OC)(OC)OC.Cl>C(OCC)(=O)C.O.CCOCC>[CH3:30][N:29]1[C:25]([S:24][CH2:17][C:14]2[CH2:15][S:16][C@@H:11]3[C@H:10]([NH:9][C:7](=[O:8])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[C:22](=[O:23])[N:12]3[C:13]=2[C:19]([OH:21])=[O:20])=[N:26][N:27]=[N:28]1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: COP(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 118.6 %

Procedure:
To 582 mg of 7β-[2-(2-thienyl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid and 174 mg of 5-mercapto-1-methyl-1H-tetrazole was added 12 ml of ethyl acetate to make a solution. To the solution were added in sequence 0.25 ml of trimethyl phosphite and 0.2 ml of ether solution of hydrogen chloride (5mol/l), and the mixture was stirred at 20 to 25° C. for 3hours. To the reaction solution was added 10 ml of water, whose pH was adjusted to 2 with 2N HCl, which was then allowed to form two layers. The aqueous layer was taken, to which was added 10 ml of ethyl acetate. The mixture was allowed to form two layers. The organic layers were combined and washed with 5 ml of aqueous saline, which was dried over anhydrous magnesium sulfate, which was then concentrated under reduced pressure. To the concentrate was added ether, then precipitating powdery product was collected by filtration, washed and dried to give 804 mg (yield: 89%) of 3-(1-methyl-1H-tetrazol-5-yl) thiomethyl-7β-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O-:25])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]([O-:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[C@H:37]2[CH2:42][O:41][C@@H:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:39][CH2:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C@@H:37]2[CH2:38][O:39][C@@H:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:41][CH2:42]2)=[CH:20][CH:21]=1)[C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)[O-])C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@@H](c3ccccc3)OC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O[C@H]2CO[C@H](c3ccccc3)OC2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 0.93 g (2 mmol) (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate and 1.34 g (4 mmol) cis-2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate in 18 mL was added potassium carbonate (0.55 g, 4 mmol). The mixture was heated in a microwave for 2 h at 100° C. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to afford 0.165 g (13%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[(trans-2-phenyl-1,3-dioxan-5-yl)oxy]benzyl}-L-glutamate. The benzylidene protected derivative (0.13 g, 0.2 mmoL)) was dissolved in methanol (15 mL) Palladium/C (10% Pd) was added and the mixture was stirred under hydrogen atmosphere over night. The mixture was filtered and the solvent was evaporated, yielding 0.11 g (100%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[(1,3-dihydroxypropan-2-yl)oxy]benzyl}-L-glutamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (2 g) obtained in Example 5 was suspended in ethanol (100 ml), and to the suspension was added 1N aqueous solution of sodium hydroxide (20 ml), and the mixture was stirred at room temperature for 12 hours. After evaporate the solvent under reduced pressure, 4N sodium hydroxide and methylene chloride were added to the residue for phase separation. To the aqueous layer was added 4N hydrochloric acid to a pH of 6, and the precipitated crystals were recovered by filtration to obtain the title compound (1.8 g, 96%).