Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:38](=[O:47])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]2[C:41]1=[O:42])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 12.5 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (1.65 g), ethyl 2-bromo-10-phthalimidodecanoate (2.4 g), acetonitrile (100 ml) and triethylamine (0.75 g) is heated at 80° C. for 4 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (100 ml) are added to the residue. The ethyl acetate layer is dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16](=[O:34])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1>>[CH3:14][O:15][C:16](=[O:34])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([F:24])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-trifluoromethyl-benzaldehyde and [4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester; the isolated product was further purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([NH:30][C:17]([C:16]2[CH:15]=[N:14][N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:19])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 427.4 [(M+H)+]; mp 258-260° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][O:24][CH3:25])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28].[CH3:29][N:30]1[C:34]([CH3:36])([CH3:35])[C:33](=[O:37])[NH:32][C:31]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:14]([F:17])([F:16])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[C:33](=[O:37])[C:34]([CH3:36])([CH3:35])[N:30]([CH3:29])[C:31]2=[O:38])=[C:8]([CH2:26][CH2:27][CH3:28])[CH:9]=1)([O:22][CH2:23][O:24][CH3:25])[C:18]([F:21])([F:20])[F:19]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCCBr
Reactant: CN1C(=O)NC(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCCN1C(=O)N(C)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
4-[1,1,1,3,3,3-Hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyl 4-bromobutyl ether (70 mg, 0.15 mmol), 1,5,5-trimethylimidazolidine-2,4-dione (24.8 mg, 0.17 mmol) and potassium carbonate (31.1 mg, 0.23 mmol) were added, followed by stirring overnight at room temperature. The reaction solution was extracted with ethyl acetate-water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=3:1) to obtain 78.8 mg of the title compound (yield: 100%) as a colorless oil.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>>[C:1]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Yield: 90 %

Procedure:
The filtered catalyst was added to oleic acid (1.41 g, 5 mmol) and ethanol (10 ml) and the procedure, above, was repeated. No loss in catalytic activity was observed and ethyl oleate (1.39 g, 90% yield) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[NH:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:11][C:12]1[N:17]([CH2:2][C:3]#[N:4])[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1
Reactant: N#CCCl
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)cc(Cl)n(CC#N)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroactonitrile (16.5 g) and potassium carbonate (29.3 g) were added to a solution of 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (20 g) in DMF (200 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and evaporated to dryness to obtain a residue. A resulting residue was dissolved in chloroform and H2O, and the organic layer was washed with water and dried. The solvent was evaporated to dryness to give a syrup, which was purified by column chromatography on silica gel to give a crystalline product. Recrystalization of the crude crystals from ethyl acetate-isopropylether gave colorless prisims (21.1 g, 87%), mp. 83°-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH2:9]1)=[O:7].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[N:24]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1OC
Product: COc1ccc(C(=O)N2CCC(N3CCc4ccccc43)c3ccccc32)cc1OC
Yield: 54.3 %

Procedure:
Starting with 1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (390 mg, 1.19 mmol) prepared in Reference Example 2 and indoline (425 mg, 3.57 mmol), the same procedure as shown in Example 1 was repeated to give the product of interest, i.e., 4-(2,3-dihydro-1H-indol-1-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoline (268 mg, yield: 54%) as a white crystal.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)O)=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:11]([CH:32]([CH3:34])[CH3:33])[N:10]=1)C1C=CC=CC=1.ClCCl>C(O)C.[C].[Pd]>[CH:32]([N:11]1[C:12]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:13]([CH2:14][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:9](=[O:8])[NH:10]1)([CH3:33])[CH3:34]
Reactant: COc1ccc(-c2c(C(O)c3ccc(OC)cc3)c(OCc3ccccc3)nn2C(C)C)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Cc2c(-c3ccc(OC)cc3)n(C(C)C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of [3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]4-methoxy-phenyl methanol (0.11 g) in ethanol (4 mL) was added a catalytic amount of 10% palladium-carbon powder and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Dichloromethane was added to the mixture and the insoluble material was removed by filtration. The solvent of filtrate was removed under reduced pressure to give the title compound (0.076 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](SC2C=CC=CN=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1SC(=O)CC[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:37]2)=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)Sc2ccccn2)CC1
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)C2CCCC2)CC1

Procedure:
The title compound was prepared analogously to step 7 of example B(29)where 4-[4-(pyridin-2-ylsulfanylcarbonyl)-butyl]-piperidine-1-carboxylic acid tert-butyl ester from step 5 above, was substituted in place 3-cyclohexyl-thiopropionic acid S-pyridin-2-yl ester. 1H NMR (400 MHz, CDCl3): δ 1-1.42 (m, 8H), 1.45 (s, 9H), 1.50-1.84 (m, 14H), 2.42-2.46 (m, 2H), 2.62-2.7 (m, 2H), 2.82-2.87 (m, 1H). ESIMS (MH+): 337.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].Cl.[F:19][CH2:20][CH:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1COCC1>>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:23]1[CH2:24][CH2:25][O:26][CH:21]([CH2:20][F:19])[CH2:22]1)#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Reactant: FCC1CNCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1I
Temperature: 90 °C
Yield: 36.5 %

Procedure:
A mixture of ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (718 mg, 0.00186 mol), 2-(fluoromethyl)morpholine hydrochloride (348 mg, 0.00224 mol) and TEA (1.0 mL, 0.0072 mol) in THF (7.1 mL, 0.088 mol) was flushed with argon and then heated at 90° C. overnight. The reaction mixture was concentrated and purified by column chromatography to give ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 36.4%). LCMS: (FA) ES+ 425, 1H NMR (400 MHz, d1-chloroform) δ: 4.57 (d, 1H), 4.46 (d, 1H), 4.34 (q, 2H), 4.12-4.05 (m, 1H), 4.02-3.77 (m, 4H), 3.34-3.25 (m, 1H), 3.22-3.14 (m, 1H), 1.37 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[O:5][C:6]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([OH:26])[CH:18]=2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[K+].[Br-]>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[C:6]([O:5][C:4]3[CH:27]=[CH:28][C:29]([NH2:30])=[C:2]([OH:1])[CH:3]=3)=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=2)=[CH:18][C:19]=1[OH:26]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3ccccc3cc2Oc2ccc([N+](=O)[O-])c(O)c2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2cc3ccccc3cc2Oc2ccc(N)c(O)c2)cc1O
Yield: 82.4 %

Procedure:
2,3-Bis(4-amino-3-hydroxyphenoxy)naphthalene was synthesized in a manner analogous to Example 2 from 2,3-bis(3-hydroxy-4-nitrophenoxy)naphthalene. Yield: 82.4%; mp 196˜197° C., IR (KBr) 3292, 3352, 1497 cm−1; MS (EI) m/z 374 (M+, 100); Elemental Anal. Calcd. for C22H18N2O4: C, 70.59; H, 4.81; N, 7.49. Found: C, 70.38; H, 4.87; N, 7.43.
Reaction SMILES: [Sn:1](I)([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[F-:15].[K+]>>[Sn:1]([F:15])([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [F-]
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: [K+]
Product: CCCC[Sn](F)(CCCC)CCCC

Procedure:
Bu3SnI will react on the column with KF to give Bu3SnF, which rapidly reacts with the silica. The purified product in ether is recovered and then dried on a vane pump. Bu3SnI+KFaq→Bu3SnF↓+Klaq
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH2:4]C)C.C(N(CC)CC)C.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[C:14]([N:16]([S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([Cl:21])=[CH:12][C:11]=1[O:22][CH3:23])[CH3:4]
Reactant: CCN(CC)CCNC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(N(S(C)(=O)=O)S(=O)(=O)N(C)C)cc1C(=O)NCCN(C)C

Procedure:
A solution of N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (570 mg), triethylamine (914 mg) and N,N-dimethylsulfamoyl chloride (1.3 g) in methylene chloride (30 ml) is refluxed for 40 hours. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(dimethylaminoethyl)-4-chloro-5-[N-(dimethylaminosulfonyl)-methanesulfonamido]-2-methoxybenzamide obtained as a residue is mixed with 10% aqueous sodium hydroxide (10 ml) and methanol (10 ml) and refluxed for 10 minutes. The reaction mixture is concentrated to remove methanol and the residue is once acidified with 6N hydrochloric acid, neutralized with aqueous sodium hydrogen-carbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and the methylene chloride is evaporated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride to 1% methanol/methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate-isopropyl ether to give N-(diethylaminoethyl) -4-chloro-5-(N-dimethylaminosulfonyl)amino-2-methoxybenzamide (410 mg) as crystals melting at 110° to 110.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 1 h

Procedure:
A mixture of 1.79 g (5.4 mmol) of ethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate and 0.324 g (8.1 mmol) of sodium hydroxide is treated with 8.5 ml of water and 27 ml of ethanol and heated to boiling under reflux for 30 minutes. Subsequently, the mixture is neutralized with 8.1 ml of 1 N hydrochloric acid, the ethanol is distilled off, the residue is diluted with about 70 ml of water and left to stand in an ice-bath for 1 hour. The precipitated material is filtered off under suction, washed with water and dried. There is obtained (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of melting point 244°-245°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:16]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(CCCCCl)c1c[nH]c2ccccc12

Procedure:
Using indole (1.00 g) and 5-chlorovaleryl chloride (1.68 ml) according to the same method as that of Reference Example 1, the title compound (1.55 g) was obtained as colorless crystals having a melting point of 165 to 167° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[S:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[S:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: OCc1cc2c3ccccc3[nH]c(=S)n2n1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
3.23 g (0.014 mole) of the product of Example 5 [2-(hydroxymethyl)pyrazolo[1,5-c]quinazoline-5(6H)-thione] is refluxed with 250 ml of glacial acetic acid for 20 hours under nitrogen. The solution is cooled and stripped to a solid residue which is dissolved in a mixture of ethyl acetate-absolute ethanol. The volume of solution is reduced and the concentrated solution set aside at 5°. The precipitate is filtered off to give the product. Recrystallization from ethyl acetate-absolute ethanol gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([OH:32])=[O:31])[C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[O:14])[C:7](=[O:33])[C:6]=2[CH:34]=1.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:43](=[O:44])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([OH:32])=[O:31])[C:17]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[O:14])[C:7](=[O:33])[C:6]=2[CH:34]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccccc1C(=O)O)CCO2
Product: O=C(O)C[C@H](NC(=O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O)C(=O)Nc1ccccc1C(=O)O

Procedure:
Treatment of (S)-2-[2-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-carboxy-propionylamino]-benzoic acid with benzylisocyanate as described in Example 1 d), gave (S)-2-[2-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5-H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-carboxy-propionylamino]-benzoic acid as acetate salt: mp. 166° C. (dec.); MS (ISP): 604 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1CCCC2
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(C(=O)O)c2c1CCCC2
Reaction time: 4 h

Procedure:
4-Nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid is described in Chem. Pharm. Bull., 1984, 32, 3968. The hydrogenation of 1.48 g of this nitro derivative is performed in methanol in the presence of Raney® nickel. After 4 hours with stirring, the catalyst is filtered off, the mixture is evaporated to dryness and the residue is taken up with ether and filtered off to obtain 1 g of the expected product. m.p.=180° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
3,4-Dichloro-beta-[2-[(4-chlorophenyl)amino]-2-oxoethyl]benzenepropanoic acid (4.0 g) in EtOAc (75 mL) was treated with carbonyldiimidazole (2.52 g) and N,N-dimethylaminopyridine (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (2.59 g) in H2O (40 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (100 mL), sat. NaHCO3 (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (3.81 g).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C>C(O)C.[Pd]>[O:16]=[C:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)CCC(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC(=O)CCc1ccccc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A solution of 98 (5.0 g, 21 mmol) in ethanol (50 mL) was hydrogenated over 10% Pd—C at 30 psi and room temperature for 4 hr. The catalyst was filtered off and a soluton of NaOH (1 g) in water (10 mL) was added. The solution was stirred for 1 hr then diluted with water and washed with ether. The aqueous solution was acidified with HCl and extracted with ether. The ether extracts were washed with brine, dried over MgSO4 and evaporated to give an oil 4.1 g, 94%.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:41])[C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.CCCCCC>[Cl:1][CH2:2][C:3](=[O:41])[C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of benzhydryl 7-[4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (12.65 g) and anisole (8.5 g) in dichloromethane (30 ml) was added trifluoroacetic acid (36.5 g) under ice-cooling and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was dropwise added to a mixture of isopropyl ether and n-hexane (1:1 400 ml) under stirring. The precipitates were collected by filtration and washed with n-hexane to give 7-[4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (7.3 g).