Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)=[O:3]
Reactant: O=C(NC1CNC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC(NC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Add methyl chloroformate (60 μL, 73 mg, 0.78 mmol, 3.1 equiv) to a suspension of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (108 mg, 0.250 mmol, 1 equiv) and triethylamine (140 μL, 100 mg, 1.0 mmol, 4.0 equiv) in anhydr CH2Cl2 (3 mL). Observe a vigorous gas evolution. After stirring 4 h, rotary evaporate the reaction solution. Transfer the resultant material to a column of silica gel (80 mm×20 mm dia.) and elute (20-60% EtOAc/hex) to yield 84 mg (69%) of 3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylic acid methyl ester as an off-white foam. MS (m/e): 489.96 (M+1); 488.09 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:22])[C@@H:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:23][CH3:24].[Cl:25][C:26]1[S:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1.C[O-].[Na+].[OH-].[Na+]>CO>[Cl:25][C:26]1[S:27][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:22])[C@@H:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:13]([CH3:14])[CH3:15])=[CH:4][C:3]=2[O:23][CH3:24])=[CH:29][CH:30]=1
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C
Reactant: ClCc1ccc(Cl)s1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccc(Cl)s2)c(OC)c1)C(C)C

Procedure:
A mixture of 2.0 g of (S)-2-(ethylsulfonylamino)-3methyl-butyric acid N-[2-(4hydroxy-3-methoxy-phenyl)-ethyl]-amide, 1.2 g of 2-chloro-5-chloromethylthiophene and 12 ml of a 1 M sodium methanolate solution in methanol (prepared beforehand by dissolution of 23 g of sodium in 1 liter of methanol) is heated at reflux in 30 ml of methanol for 16 hours. After cooling, the reaction mixture is introduced into 300 ml of 2N sodium hydroxide solution. Extraction is carried out twice using 400 ml of tert-butyl methyl ether each time. The organic phases are washed once with 100 ml of 2N sodium hydroxide solution and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-{2-[4-(5-chloro-thiophen-2-yl-methoxy)-3-methoxy-phenyl]-ethyl}-amide, which can be purified by chromatography on silica gel with ethyl acetate/n-hexane 1:1 and recrystallisation from ethyl acetate/n-hexane, m.p. 124-127° C.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:3]1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>COC(OC)(C)C>[OH:22][C@H:3]1[C@H:2]([O:1][CH3:23])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CO[C@@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dimethoxypropane is added 0.51 g (26.2 mmol) p-toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60° C. and 96 h at 25° C. The reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol: 100/3) to give 0.12 g (0.34 mmol/16%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.29 (s, 3H), 3.25 (s, 3 H), 4.05 (q, 1H), 4.32 (d, 1H), 4.47 (dd, 1H), 6.61 (d, 1H), 7.19–7.46 (m, 5H), 7.54 (s, 1H), 7.72 (d, 1 H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27]COC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC1>>[N:22]1([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=2)[CH2:27][CH2:23]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and aziridine and isolated as white solid (4.9 mg, 30%). MS(m/e): 343.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [3.0 g, Reference Example 7(c)] in dimethylformamide (50 ml), was treated with benzoyl chloride (1.24 ml) and triethylamine (1.56 ml). After stirring at ambient temperature for 2.25 hours, the mixture was evaporated to dryness and the resultant solid washed with water before being fried in vacuo. The resulting white solid (3.8 g) was dissolved in dichloromethane (70 ml) and the solution was treated with trifluoracetic acid (20 ml). After stirring at ambient temperature for 45 minutes, the reaction mixture was evaporated. The residue was treated with toluene (70 ml), concentrated to dryness and the resultant material treated with dichloromethane (200 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound as a white foam (2.0 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>ClCCl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:12][CH2:11][CH2:9][OH:10])[N:6]=1
Reactant: Cc1nc(CCl)cs1
Reactant: NCCO
Solvent: ClCCl
Product: Cc1nc(CNCCO)cs1
Yield: 85 %

Procedure:
2-Methyl-4-(chloromethyl)thiazole (2.24 g) was treated with ethanolamine (11.6 mL, 10 equivalents) in dichloromethane at 25° C. for 16 hrs. The solvent was evaporated and the residue partitioned between ethyl acetate and brine. The organic layer was separated and extracted with ethyl acetate (5×). The organic layers were combined and washed with brine, dried over Na2SO4, and the solvents were evaporated to give 2.4 g (85%) of title compound.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:16]3[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:18][Li]>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:17][C:1]1[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2C3CCCCC32)cc1
Reactant: [Li]C
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
To the solution of 180 g of) 7-(Toluene-4-sulfonyl)-7-aza-bicyclo[4.1.0]heptane and 18 g of Copper(II)acetyl acetonate in 1500 ml of dry THF was added 86 ml of a 10 M solution of methyllithium dropwise over 30 min. The mixture was stirred under nitrogen atmosphere for 8 h. It was then washed with water and extracted with ethyl acetate twice. The combined organic layers were concentrated. The resulting residue was purified by chromatography (silica, hexan/ethyl acetate) to afford 120 g (62%) of 4-Methyl-N-(trans-2-methyl-cyclohexyl)-benzenesulfonamide
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23][C:22](=O)[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12].N1CCCCC1>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[CH2:24][CH2:23]/[C:22](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[C:18]=2[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(C)[nH]c2c1CCC2=O
Reactant: O=C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c2c1CC/C2=C1/C(=O)Nc2ccccc21
Temperature: 110 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
A mixture of oxindole (44 mg, 0.33 mmol) and 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid ethyl ester (Example A, 62 mg, 0.3 mmol) in DMF (5 mL)-piperidine (0.5 mL) was heated at 110° C. with stirring for 72 hours. Most of the solvent was removed under reduced pressure and the residue was diluted with ethanol. The resulted precipitate was collected by filtration, washed with ethanol and dried to give 56 mg (58%) of the titled compound as a yellow solid.
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[I:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(#N)C>[CH2:8]([NH:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[I:12])[CH:9]=[CH2:10]
Reactant: O=C(Cl)c1ccccc1I
Reactant: C=CCN
Solvent: CC#N
Solvent: CN1CCOCC1
Product: C=CCNC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
470 ml (4.28 mol) of N-methylmorpholine, followed by 224 ml (2.98 mol) of allylamine are added under ice cooling to 750 g (2.81 mol) of 2-iodo-benzoic acid chloride in 7.5 l of acetonitrile, and stirred for 60 min at RT. The precipitate is filtered off and the filtrate concentrated by evaporation on a RE. The residue of evaporation is dissolved in 4 l of EtOAc and 4 l of water, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water, sat. Na2CO3, water and brine, dried (Na2SO4) and concentrated by evaporation. Stirring of the residue in 2.5 l of hexane and filtering yields 2-iodo-benzoic acid allylamide; m.p. 105-106° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][N:15]=[N+:16]=[N-:17].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.COC(C)(C)C>C1(O)CCCCC1>[N:25]1([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@@H:3]3[CH2:14][N:15]=[N+:16]=[N-:17])[N:24]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H]1CN=[N+]=[N-]
Reactant: Clc1nccc(N2CCCCCC2)n1
Solvent: COC(C)(C)C
Solvent: OC1CCCCC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nccc(N3CCCCCC3)n2)[C@H]1CN=[N+]=[N-]
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
To a solution of the compound 7 (240 mg) in cyclohexanol (0.4 mL), 1-(2-chloro-4-pyrimidinyl)azepane (210 mg) was added. The reaction mixture was stirred at 120° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was added tert-butyl methyl ether, washed with aqueous 2N sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol:27% aqueous ammonia=100:0:0→90:10:0→90:10:1) to obtain the title compound (190 mg) having the following physical properties.
Reaction SMILES: O[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].C(#N)C.C[Si](Cl)(C)C.[I-].[Na+]>CCCCCC>[F:22][C:21]([F:23])([F:24])[C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:10]=[C:9]([CH:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:14]=[CH:13][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC(O)(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCCC
Product: CC(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 4.8 grams (0.014 mole) of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile in 40 mL (0.760 mole) of acetonitrile was cooled to 0° C., and 9.4 grams (0.086 mole) of trimethyl-silyl chloride was added slowly. Upon completion of addition, the reaction mixture was stirred for about 15 minutes, and then 40 mL of hexane was added. After this time the reaction mixture was again stirred for 15 minutes, and 13.0 grams (0.086 mole) of sodium iodide was added. The reaction mixture was then stirred as it was allowed to warm to ambient temperature. Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was not complete. The reaction mixture was then warmed to reflux where it stirred for two hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated and washed with an aqueous dilute solution of sodium metabisulfite to remove iodine. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 25% ethyl acetate in hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 3.2 grams of 5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CO[C:10]1[CH:16]=CC(O)=C[CH:11]=1.CO>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4].C(O)CCC>[C:1]([O:6][CH2:7][CH2:11][CH2:10][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CO
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
An 74.1 g (1.0 mole) amount of n-butanol, 250.2 g (2.5 moles) of methyl methacrylate, 0.488 g (0.001 mole) of zirconium acetylacetonate and 0.28 g of hydroquinone monomethyl ether were added to a one liter flask fitted with an agitator, thermometer and fractionating tower and were heated and agitated. An azeotropic mixture of methyl methacrylate and methanol from the upper part (top) of the fractionating tower was removed at a reflux ratio of 5 to 10:1 to continuously advance the reaction. The reaction was conducted for 1.5 hours while the temperature at the top was 65° to 70° C. and the flask temperature was 104° to 130° C. The reaction showed a 99.5% conversion of n-butanol and a 99.2% yield of n-butyl methacrylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([NH:22][OH:23])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15].Cl>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:22]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[O-:23])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)NO
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=[N+]([O-])C(C)(C)CC(C)(C)C)ccc1OC
Yield: 60 %

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde, N-tert-octylhydroxylamine and catalytic amount of HCl in methanol was refluxed for 90 hrs with molecular sieves in a soxhlet for waster removal. The title compound was obtained in 60.0% yield as white powder, m.p. 77.5° C. (Rf=0.40 on a silica gel plate using hexanes:EtOAc, 3:2. v:v, as an eluant).
Reaction SMILES: [CH3:1][S:2]([C:4]1[C:5](=[O:29])[C:6](=[CH:20]/[CH:21]=[CH:22]\[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][OH:27])[C:7](=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)=[O:3].ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:4]1[C:5](=[O:29])[C:6](=[CH:20]/[CH:21]=[CH:22]\[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][OH:27])[C:7](=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1)(=[O:38])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)C1=CC(=CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C1=CC(=CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a solution of 6.5 mg of 2-methylsulfinyl-5-[(Z)-4,7-dihydroxy-2-heptenylidene]-4-(4-phenoxybutylidene)-2-cyclopentenone obtained in Example 573 or Example 574 dissolved in 1.5 ml of dichloromethane was added 3 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 4 hours. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 3.9 mg (yield 60%) of 2-methylsulfonyl-5-[(Z)-4,7-dihydroxy-2-heptenylidene]-4-(4-phenoxybutylidene)-2-cyclopentenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:18]([O:17][C:11](=[O:16])/[CH:12]=[C:13](\[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)/[CH3:15])[CH3:19]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(=O)/C=C(/C)Nc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
7.66 g (37.9 mmol) of 4-bromo-3-methoxy-phenylamine (preparation described in Tetrahedron Lett., 1995, 7583) were dissolved in 80 ml of cyclohexane at 70° C. and subsequently treated under stirring with 72 mg (0.38 mmol) of p-toluenesulfonic acid monohydrate and 4.93 g (37.9 mmol) of ethyl acetoacetate. The solution was then heated at reflux for 3.5 h with a water separator funnel connected. It was then cooled to RT and concentrated in vacuo. The residue was applied to a silica gel column with hexane/diethyl ether (3:1) as eluent. Combinations of the purified fractions and concentration in vacuo gave 8.2 g (68.8%) of the (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester, as a yellow solid. ISP mass spectrum, m/e: 316.2(M+1 calculated for C13H16BrNO3: 316).
Reaction SMILES: CS(O[CH2:6][C:7]#[CH:8])(=O)=O.[Cl:9][C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Cl:9][C:10]1[C:15]([O:16][CH2:8][C:7]#[CH:6])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: C#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C#CCOc1cc(-c2c(Cl)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 39.9 %

Procedure:
2-propinyl methanesulfonate (0.35 g; 2.6 mmoles) is added to a mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl) -2,4-dichloro-1-methyl-5-trifluoromethyl pyrrole (0.9 g; 2.5 mmoles) and potassium carbonate (0.33 g; 2.39 mmoles) in methylisobutylketone (10 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (1.0 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 90:10. 0.40 g of solid white product are obtained.
Reaction SMILES: NC1C=CC=CC=1.O=[S:9](Cl)Cl.[NH2:12][C:13]1[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=1[NH2:19]>C1(C)C=CC=CC=1>[N:19]1[S:9][N:12]=[C:13]2[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=12
Reactant: CCC(=O)c1ccc(N)c(N)c1
Reactant: O=S(Cl)Cl
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc2nsnc2c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To a solution of aniline (1.86 g, 20 mmol) in 50 mL of toluene was added SOCl2 (2.6 g, 22 mmol) dropwise at 0° C. and the mixture was then refluxed for 2 h. After cooling to rt, 1-(3,4-diaminophenyl)propan-1-one (1.65 g, 10 mmol) was added. The mixture was refluxed for 2 h, cooled, concentrated, and purified by flash chromatography to give the desired product (960 mg, 50%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.15 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 of 1-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.