Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1(/[CH:8]=[CH:9]\[CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CC#CC2(O)CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2C/C=C\C2(O)CCCCC2)cc1

Procedure:
4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (4.0 g., 0.01 mole) is dissolved in ethyl acetate (50 ml.) and hydrogenated at 25° C. and one atmosphere pressure over 1.0 g. of a 5% palladium on charcoal catalyst. The theoretical amount (0.01 mole) of hydrogen is absorbed in 110 minutes. The catalyst is removed by filtration and the solvent evaporated. The residual oil is chromatographed on 60 g. of silica gel with elution by 2% methanol is chloroform. The chromatographed product crystallizes and is recrystallized from butyl chloride to yield 1.4 g. of the title product, m.p. 118°-120° C.; pmr (CDCl3) δ5.14 (1H, m, --CH2 --CH=), 5.60 (1H, d, ##STR46##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][C:27]([CH3:29])=O.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([NH:11][CH:27]([CH3:29])[CH3:26])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(NC(C)C)c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A mixture of (2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine (Example 418, Step D) (270 mg, 0.843 mmol), acetic acid (0.243 mL, 4.22 mmol), acetone (3.10 mL, 42.2 mmol) and sodium cyanoborohydride (0.442 mL, 8.43 mmol) in methanol (4 mL) was heated to 65° C. overnight. After sixteen hours, an additional ten equivalents of sodium cyanoborohydride were added and heating continued for another five hours then equilibrated to room temperature and concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium hydroxide solution and ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford a yellow oil. The crude product was adsorbed onto silica and purified by chromatography (24 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 30 to 100% ethyl acetate gradient in hexane. Fractions containing product were combined and concentrated to afford the title compound as a colorless glass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:31][C:27]3[S:28][CH:29]=[CH:30][C:26]=3[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cc2ccsc2s1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccsc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example D4 above), the title compound was prepared as a solid. The product was purified by tituration from Et2O/hexanes.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15]2[CH:16]=[C:17]([C:28]([NH2:30])=[O:29])[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[C:15]2[CH:16]=[C:17]([C:28]([NH2:30])=[O:29])[C:18]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)CCCC[C@@H]2N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of (S)-9-tert-butoxycarbonylamino-3-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid amide (198 mg, 0.475 mmol) in DCM (1 mL) was added TFA (1 mL). After 10 min, the reaction was allowed to warm to rt and after 1 h, the reaction was evaporated to dryness. The material was used without further purification for the next step.
Reaction SMILES: [N:1]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)([CH3:11])[CH3:10])=[CH:7][N:8]=1)=[N+]=[N-]>CO.C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([C:6]2[N:5]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:4]([NH2:1])=[N:8][CH:7]=2)([CH3:11])[CH3:10])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(C)(C)c2cnc(N=[N+]=[N-])n2-c2ccc(F)cc2)ccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(N)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A solution of 2-azido-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.126 g, 0.33 mmol) was added MeOH-THF (3 mL, 1:1, v/v) was sparged with argon briefly. Next 5% Pd on CaCO3 poisoned with lead was added to the flask, which then was purged with hydrogen and stirred under 1 atm hydrogen. After 3 h, when the reaction was shown to be complete by LCMS, the mixture was filtered through Celite™ and concentrated in vacuo to afford 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-amine (93 mg) as a beige solid. MS (EI) m/z 360 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C(Cl)CCl.O[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)=[O:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:15][CH:14]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)=[O:30])=[CH:17][CH:18]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCCC(=O)OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Reaction time: 8 h

Procedure:
To butyric acid in pyridine was added EDC, DMAP, and tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139), and the solution was capped and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl butyrate (E148).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:31]=[C:32]([O:36][CH3:37])[CH:33]=[CH:34][CH:35]=1>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=[CH:34][CH:33]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12f and 3-bromoanisole
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH:23]1[C:33]2[CH:32]=[CH:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH:31]=[CH:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2,4-bis(1,1-dimethylethoxy)pyrimidine (50 g) in dry tetrahydrofuran (11) at -78° C. was added n-butyllithium (69 ml of a 2.5M solution in hexanes) dropwise. After 0.5 hours, a solution of 5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) was added. The reaction mixture was stirred at -78° C. for three hours and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (400 ml) was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give the crude 5-(2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol which was used directly.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:6]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:7]=1.[S:32]1(=[O:38])(=[O:37])[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH2:34][CH2:35][CH2:36][S:32]4(=[O:38])=[O:37])=[CH:7][C:6]=3[N:8]3[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]3=[O:15])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 37.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidine-2,4-dione (149 mg) described in Preparation Example 256 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (66 mg) was obtained.
Reaction SMILES: [NH2:1][OH:2].C[O-].[Na+].[C:6]([C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=O)#[N:7].Cl>CO>[C:6]([C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:1][OH:2])=[O:16])#[N:7]
Reactant: NO
Reactant: CCOC(=O)CCCCCC(C#N)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#CC(CCCCCC(=O)NO)(c1ccccc1)c1ccccc1
Yield: 85.7 %

Procedure:
To a solution of hydroxylamine (38.5 g, 0.55 mol) in methanol (300 ml) was added a solution of 28% sodium methylate in methanol (165 ml, 0.83 mol). To the mixture was added, while stirring under ice-cooling, a solution of ethyl 7-cyano-7,7-diphenylheptanoate (18.7 g, 0.055 mol) in methanol (50 ml). The mixture was stirred for 1.5 hour. After completion of the reaction, pH of the reaction mixture was made acidic with 1N HCl. The reaction mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate--hexane to give 15.2 g of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[BH4-].[Na+]>COCCOCCOC>[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C@@H:8]3[CH2:13][CH2:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][C@H:7]3[C:6]=2[CH:5]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CN(Cc1ccccc1)CC3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1ccc2c(c1)[C@@H]1CN(Cc3ccccc3)CC[C@H]1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]indole monohydrochloride (39.5 g), prepared as described in J. Org. Chem. 44:1063-1068 (1979), in 2-methoxyethyl ether (250 ml) was stirred and cooled in an ice bath, under a N2 flow. Sodium borohydride (11.7 g, solid) was added in 8 portions. The mixture was stirred overnight at room temperature, then cooled to 5° C. Ice water (500 ml) was added dropwise. Precipitation resulted. The mixture was stirred for 2 hours. The precipitate was filtered off. 1,4-Dioxane (350 ml) was added and the mixture was stirred. HCl (200 ml, 12N) was slowly added and the mixture was heated to reflux temperature. The mixture was stirred and refluxed for 1 hour, then cooled and the solvent was evaporated. The residue was stirred in water (300 ml) and this mixture was alkalized with an aqueous NaOH solution. The mixture was stirred for 1 hour. The mixture was extracted with DCM (2×200 ml). The combined extracts were dried, filtered and the solvent was evaporated. The residue was dissolved in DIPE (300 ml), then filtered and the filtrate was evaporated, yielding 11.3 g (32%) of (±)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]indole (intermediate 8).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH3:12][OH:13].Cl>O1CCCC1>[CH3:12][O:13][CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)CC(=O)OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 73695.8 %

Procedure:
In a 2 liter four-necked flask were charged 88.0 g (2.2 mol) of 60% sodium hydride and 753 ml of tetrahydrofuran in a nitrogen stream, and a mixture of 150.6 g (1.0 mmol) of methyl 4-chloro-3-oxo-butyrate and 35.2 g (1.1 mol) of methanol was added thereto dropwise at room temperature (22 to 24° C.). After the addition, the mixture was stirred at room temperature (22 to 24° C.) for 1 hour. The reaction mixture was cooled with ice, and 600 ml (1.2 mol) of 2N hydrochloric acid was added dropwise. The tetrahydrofuran was recovered from the reaction mixture, and 400 ml of toluene was added to the residue. The aqueous phase was extracted with three 200 ml portions of toluene. The organic phase was washed with a 5% sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The residue was distilled under reduce pressure (boiling point: 90° C./1000 Pa) to give 107.7 g (74%) of methyl 4-methoxy-3-oxobutyrate as liquid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Cl:9]N1C(=O)CCC1=O>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: OCc1ccsc1Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Cl)sc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-3-hydroxymethylthiophene from Example 1, Step 1 (13.0 g, 67.3 mmol) in THF (100 mL) and water (10 mL) was added N-chlorosuccinimide (9.88 g, 74.0 mmol) and the mixture was stirred at r.t. for 5 h and concentrated in vacuo. The residue was worked up as above to afford the desired product. The crude product was used directly.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[NH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:32])[CH:28]=2)[N:23]=1>>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[NH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:32][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:28]=2)[N:23]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=482.6 (M+H+).
Reaction SMILES: Cl.[NH2:2][OH:3].[NH2:4][CH:5]1[CH:8]2[S:9][CH2:10][C:11]3[CH:15](O)[O:14][C:13](=[O:17])[C:12]=3[N:7]2[C:6]1=[O:18].C(=O)([O-])O.[Na+]>O>[NH2:4][CH:5]1[C:6](=[O:18])[N:7]2[C:12]([C:13]([OH:14])=[O:17])=[C:11]([CH:15]=[N:2][OH:3])[CH2:10][S:9][C@H:8]12
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(C=NO)CS[C@H]12
Reaction time: 8 h

Procedure:
A solution of 1.26 g of the hydrochloride of hydroxylamine in 7.5 ml of water is treated under stirring at 0° with 4.74 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin and stirred for ca. 8 hours at 0° under nitrogen. The pH of the reaction mixture is adjusted to 3.5 using solid sodium hydrogen carbonate. 7-Amino-3-[(hydroxy-imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with ca. 5 ml of cold water and 5 ml of acetone and dried. b) A suspension of 0.79 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin in 10 ml of dichloromethane is treated under stirring at 4° with 2.67 g of N,O-bis-(trimethylsilyl)acetamide. A clear solution is obtained within 10 minutes. 0.21 g of the hydrochloride of hydroxylamine are added. The reaction mixture is stirred for ca. 2 hours under nitrogen at 4° and the solvent is evaporated off. The residue is treated with 10 ml of isopropylalkohol, precooled to 1°. 7-Amino-3-[(hydroxy-imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost colourless crystals which are filtered off, washed with 5 ml of acetone and dried.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[Cl:5][C:6]1[CH:7]=[C:8]([C:12](=O)/[CH:13]=[C:14](\O)/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:11]=1.C(O)(=O)C>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[NH:4][N:3]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(/C=C(O)/C=C/c1ccc(O)cc1)c1cccc(Cl)c1
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc(/C=C/c2cc(-c3cccc(Cl)c3)n[nH]2)cc1
Temperature: 80 °C
Yield: 41 %

Procedure:
Hydrazine dihydro-chloride (0.263 g, 2.50 mmol) was added to a sealed tube charged with (2Z,4E)-1-(3-chlorophenyl)-3-hydroxy-5-(4-hydroxyphenyl)penta-2,4-dien-1-one (0.717 g, 2.39 mmol) in absolute ethanol (8 mL) and a catalytic amount of acetic acid. The reaction tube was sealed and heated to 80° C. After 12 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol and precipitated with water, and the solid was collected by vacuum filtration to provide the title compound in (288 mg, 41% yield) as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 7.79 (bs, 1H), 7.68 (bd, J=7.6 Hz, 1H), 7.37 (m, 3H), 7.29 (bd, J=7.6 Hz, 1H), 7.12 (d, J=16.4 Hz, 1H), 6.86 (d, J=16.4 Hz, 1H), 6.81 (bs, 1H), 6.77 (m, 2H); MS (EI) for C17H13 ClN2O: 297.1 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[O:10])=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34].Cl>CN(C)C=O.C(N(CC)CC)C>[NH:11]([C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[C@H:12]([C:18]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34])=[O:20])[CH2:13][CH2:14][C:15](=[O:16])[NH2:17]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
14.5 of Z-Gln-ONP and 10.8 g of H-Asn-Phe-OCH3, hydrochloride (Ann. 688, 259 [1965]) are dissolved together in 100 ml of dimethylformamide and to the solution 4.55 ml of triethylamine are added slowly. A thick paste forms which is diluted with 50 ml of dimethylformamide. After a reaction period of 24 hours at room temperature, the batch is filtered and the residue washed with dimethylformamide. The resulting Z-Gln-Asn-Phe-OMe can be recrystallized from much hot dimethylformamide. Melting point, 261°-265°C (decomp.). [α]20D = + 11° (c = 0.94 in hexamethylphosphoric acid triamide).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35](O)=[O:36])[CH:30]=[CH2:31].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)=[O:36])[CH:30]=[CH2:31]
Reactant: C=CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 ml) was added BSA (1.1 ml, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVd) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmoles) in methylene chloride (20 ml) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wakogel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VId) as an amorphous powder, yield 2.32 g (89%). Mp. 100°-115° C. (dec.).