Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(CC2CCNCC2)cc1
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3 mmol) in dichloromethane (20 mL) was cooled in an ice bath under nitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was added dropwise to the solution and stirred at ice bath temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The crude product was chromatographed on silica gel, eluting with 2% methanol/dichloromethane containing 0.01% ammonium hydroxide, to give 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g, 80%) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[S:15](=[O:19])(=[O:18])[NH:16][CH3:17].[C:20](Cl)(=O)C.C(O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:4][C:3]=1[S:15](=[O:19])(=[O:18])[NH:16][CH3:17]
Reactant: CC(=O)Cl
Reactant: CNS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Solvent: CCO
Solvent: CO
Product: CNS(=O)(=O)c1cc(C(=O)CCC(=O)OC)ccc1Cl

Procedure:
A mixture of 12 g of 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoic acid and 1.2 g of acetyl chloride in 120 ml of methanol is reacted for 48 hours and worked up, analogously to the instructions indicated in Example 2(a). Methyl 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoate of melting point 112°-114° C. (from ethanol) is obtained.
Reaction SMILES: [OH:1][CH:2]([CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH3:8])[CH2:3][C:4](=[O:6])[CH3:5].N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>C1C=CC=CC=1>[C:33]([O:1][CH:2]([CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH3:8])[CH2:3][C:4](=[O:6])[CH3:5])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (3.5 mmol) and pyridine (3.5 mmol) in benzene (20 ml) is added acetyl chloride (4.0 mmol). The mixture is stirred at RT overnight. The reaction mixture is diluted with benzene, washed with water, dried and the solvent is removed in vacuo to give 4-acetoxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (cpd. 10, Table B).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed solid-free with about 2 litres of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C(O)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:26])C(C)(C)C.[NH:28]1[CH2:33][CH:32]=[CH:31][CH2:30][CH2:29]1>ClCCl>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:21]([N:28]3[CH2:29][CH:30]=[CH:31][CH2:32][CH2:33]3)=[O:26])[C:6]=2[O:1][CH2:2][CH2:3]1
Reactant: C1=CCNCC1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc2c1OCCO2)N1CC=CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,4-benzodioxan-6-carboxylic acid (3.0 g; 16.7 mmol) was suspended in 40 mL of dichloromethane. The acid dissolved upon addition of 3.7 g (2.2 equivalents) of triethylamine. Addition of 2.0 g of pivaloyl chloride was exothermic, and produced a dense precipitate. The mixture was stirred at room temperature for about 20 minutes, then 1.52 g of 1,2,3,6-tetrahydropyridine was slowly added.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:43][CH:42]=3)=[O:27])[CH2:29][C:30]=12
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a stirred solution of 0.440 g of 3-chlorobenzo[b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220-222° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine (0.46 g, 1.51 mmol) in THF (5 ml) was added a solution of K2CO3 (0.419 g, 3.0 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.3 ml, 3.0 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (6.0 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (10 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.34 g (70%) of the title compound as a colorless oil. ES-MS m/e: 319.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:34][CH2:35][C:36]3[N:37]=[C:38]([C:42]4[O:43][CH:44]=[CH:45][CH:46]=4)[O:39][C:40]=3[CH3:41])=[C:28]([CH:33]=2)[C:29]([O:31]C)=[O:30])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:34][CH2:35][C:36]3[N:37]=[C:38]([C:42]4[O:43][CH:44]=[CH:45][CH:46]=4)[O:39][C:40]=3[CH3:41])=[C:28]([CH:33]=2)[C:29]([OH:31])=[O:30])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C(=O)OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C(=O)O)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of methyl 5-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (1 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration to give 5-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoic acid as colorless crystals (0.29 g, yield 74%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 169-170° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([CH2:13][S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[CH2:12][CH2:11]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: BrCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](CSCC1CC1)C(=O)O
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a suspension of L-cysteine (100 g) in ethanol (850 mL) under nitrogen was added over 40 min a solution of sodium hydroxide (2.0 eq., 64.6 g) in ethanol (650 mL) (the sodium hydroxide solution was maintained below 40° C. during its preparation, 3 hours for complete dissolution). After the addition, cyclopropylmethyl bromide (1.1 eq., 122.5 g) was added over 20 minutes while maintaining the temperature at 25–30° C. with a cold bath. The resulting white slurry was stirred for another 18 hours and then quenched by adding 2N HCl (0.73 eq., 300 mL) over 20 minutes. The thick suspension was concentrated (100 mbars, 52° C. bath) to about 400 mL (1.5 L ethanol/water distilled) and then water (750 mL) was added. The pH (9.6) was adjusted to pH 6.5 with 2N HCl and the mixture was stirred at 4° C. for 2 hours and then filtered. The cake was washed five times with water: (100 mL) and then dried in vacuum to afford S-cyclopropylmethyl-L-cysteine (128.2 g, 88.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]([C@H:9]2[CH2:11][O:10]2)[C:7]=1[F:8].[CH3:21][C:22]([NH2:33])([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:32][C:22]([NH:33][CH2:11][C@H:9]([C:6]1[CH:5]=[C:4]([CH:12]([CH2:19][CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:10])([CH3:21])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H]2CO2)c1
Reactant: CC(C)(N)CCCc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)CNC(C)(C)CCCc2ccccc2)c1
Yield: 68.6 %

Procedure:
Ethyl 3-{3,4-difluoro-5-[(2S)-2-oxiranyl]phenyl}pentanoate (8.56 g, 0.0301 mol) and (1,1-dimethyl-4-phenylbutyl)amine (5.39 g, 0.0304 mol) in ethanol (50 mL) was heated at 70° C. overnight. The reaction was concentrated and purified by column chromatography (0-40% ethyl acetate:hexane) yield the desired product (9.53 g, 69%). MS (m/z): 434.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: CCOC(=O)c1nc[nH]c1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]cnc1C(=O)NN
Yield: 86.6 %

Procedure:
To a hot solution of 154 g of 5-methyl-1H-imidazole-4-carboxylic acid, ethyl ester in 2 liters of absolute ethanol was added dropwise, but rapidly, 100 g of hydrazine hydrate. The solution was stirred at reflux temperature for 3 hours, then 150 ml of hydrazine hydrate was added and the solution was refluxed for 3 days. The mixture was partially evaporated, the solid collected, washed twice with absolute ethanol, then ether and dried, giving 121.3 g of 5-methyl-1H-imidazole-4-carboxylic acid hydrazide.
Reaction SMILES: [C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:22]([NH:26][OH:27])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=[N+:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[O-:27])=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NO
Reactant: CCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 50.2 %

Procedure:
To a solution of 4-n-butanoyl-3,5-di-tert-butylbenzaldehyde (9.63 g, 0.032 mol) in benzene (200 mL) was added tert-butylhydroxylamine (3.52 g, 0.040 mol) and p-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.30 for product and 0.91 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was crystallized from EtOAc and hexanes to afford the titled compound (50.2% yield) as a white solid, m.p. 216.9–236.5° C.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]([O-:6])=[O:5])=O.[C:8]([NH2:16])(=[S:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:17][CH2:18]O>>[CH2:17]([O:6][C:4]([C:3]1[S:15][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:16][CH:1]=1)=[O:5])[CH3:18]
Reactant: O=CC(Cl)C(=O)[O-]
Reactant: NC(=S)c1ccccc1
Reactant: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)s1
Yield: 15 %

Procedure:
A solution of α-formyl-α-chloroacetate (9.34 g, 49.5 mmol, 1 eq) and thiobenzamide (6.79 g, 49.5 mmol, 1 eq) in EtOH (37.0 mL) is refluxed for 1 hour. The solution changes from an orange/brown color to a deep green. This solution is washed with water and extracted with CH2Cl2. The organic fraction is dried over Na2SO4, filtered, and the solvent removed in vacuo. The product is purified by column chromatography using a Biotage Flash 40M column (20% hexanes/EtOAc) to give the product as a deep orange oil (1.82 g, 15%). MS (ESI) for C12H13NO3S m/z 252.1 (M+H)+.
Reaction SMILES: [K+].[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:32])/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O-:31])=O)=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].C1C=CC2[N:41]([OH:42])N=NC=2C=1.C(Cl)C[Cl:45].NOC1CCCCO1>C1COCC1.CN(C=O)C>[ClH:45].[OH:42][NH:41][C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]1[CH:25]=[CH:26][C:21](/[CH:20]=[CH:19]/[C:18]([C:15]2[CH:14]=[CH:13][C:12]([N:9]3[CH2:10][CH2:11][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)=[O:32])=[CH:22][CH:23]=1
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Reactant: CS(=O)(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)[O-])cc3)cc2)CC1
Agent: NOC1CCCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
(E)-3-(4-{(E)-3-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid potassium salt (190 mg, 0.398 mmol) was dissolved in THF (5 ml), DMF (5 ml) and TEA (0.111 ml, 0.796 mmol). HOBT (107.4 mg, 0.796 mmol), EDC (152 mg, 0.796 mmol) and NH2OTHP (56 mg, 0.477 mmol) were added to the resulting solution. The mixture was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH 98:2). The resulting product was dissolved in DCM and treated with HCl/Et2O for 2 h. The precipitate was filtered and washed with DCM to give 20 mg of (E)-N-hydroxy-3-(4-{(E)-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylamide hydrochloride.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=O)[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1.[CH2:19]([N:21]1[C:25]([OH:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([C:24]3[CH:23]=[N:22][N:21]([CH2:19][CH3:20])[C:25]=3[OH:26])=[O:15])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1
Reactant: CCn1nccc1O
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Yield: 68.3 %

Procedure:
A 50-ml eggplant type flask was charged with 0.76 g (2.8 mmol) of 4,5,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide, 0.35 g (2.1 mmol, 1.1 equivalents) of 1-ethyl-5-hydroxypyrazole and 5 ml of t-amyl alcohol, and a solution of 0.70 g (3.4 mmol, 1.2 equivalents) of N,N'-dicyclohexylcarbodiimide (DCC) in 5 ml of t-amyl alcohol was added at room temperature. The mixture was allowed to react at room temperature for 2 hours, then, 0.58 g (2.8 mmol, 1.5 equivalents) of potassium carbonate was added, and the mixture was allowed to react at 100° C. for 6 hours. The solvent was distilled off, the residue was distributed into 30 ml of water and 30 ml of ethyl acetate, and a DCC urea material as an insoluble material was separated by filtration. An organic layer was extracted with 10 ml of a 5% potassium carbonate aqueous solution twice. The aqueous layers were combined and acidified with concentrated hydrochloric acid and thereafter extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and the solvent was distilled off to give 0.77 g of a crude product. The crude product was recrystallized from ethanol to give 0.52 g (yield 51%) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 44).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1C
Yield: 97.9 %

Procedure:
2-Bromotoluene (87 mg, 0.51 mmol) reacted with 2-methylphenylboronic acid (88 mg, 0.65 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at room temperature to give the title compound (91 mg, 98%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.29-7.35 (m, 6H), 7.20 (d, 2H, J=6.3 Hz), 2.15 (s, 6H).). 13C{1H}-NMR (100 MHz, CDCl3): δ 141.56, 135.76, 129.77, 129.25, 127.12, 125.51, 19.81. GC/MS(EI): m/z 182 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C1COCC1>[NH2:1][C:2]1[C:3]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)nc1-c1ccco1
Temperature: 90 °C
Reaction time: 14 h
Yield: 0.1 %

Procedure:
3-Amino-6-chloro-2-iodopyridine (1.78 g), 2-furanboronic acid (1.17 g), and sodium carbonate (1.11 g) were suspended in a solvent mixture consistent of toluene (23 mL), THF (23 mL) and water (7 mL). The mixture was degassed using subsequent evaporation and flushing with nitrogen (5×) and tetrakis(triphenylphosphine)palladium(0) (808 mg) was added. The reaction mixture was stirred at 90° C. for 7 hours and 14 hours at room temperature. After addition of 2-furanboronic acid (783 mg), the mixture was stirred again for 4 hours at 90° C., then another portion of 2-furanboronic acid (390 mg) was added and the reaction mixture was stirred for 5.5 hours at 90° C. After 15 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.25) to afford 1.26 mg of the title compound of the formula
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[CH:6][C:5]=1[OH:21])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([N:10]3[C:11](=[O:20])[C:12]4[CH2:19][CH2:18][CH2:17][CH2:16][C:13]=4[C:14]3=[O:15])=[CH:6][C:5]=2[O:21]1
Reactant: C=CCc1ccc(N2C(=O)C3=C(CCCC3)C2=O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC1Cc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2O1

Procedure:
A mixture of 0.20 g of 1C, 100 mg of p-toluenesulfonic acid (PTSA), and 10 mL of xylene was refluxed for 24 hours, then cooled and poured into a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, and the extract was washed in succession with sodium bicarbonate solution, water and brine, dried (Na2SO4) and filtered. The solvent was evaporated and the residue was chromatographed on a Chromatotron™ plate, starting with a 3:17 v:v mixture of ethyl acetate and hexane as eluent and gradually increasing the ethyl acetate content in the eluent, to give the title compound, as yellow crystals, m.p.: 114°-118° C.