Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)[CH3:2].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[CH2:17]([C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)[CH3:18]
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of methyl [(3S)-6-({2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.521 g, 0.919 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was diluted with water, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.413 g, yield 81%) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:14])[NH:12][NH2:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:15][O:16][C:17]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:17]=2[O:16][CH3:15])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COc1c(C=O)cccc1-c1ccc(C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Product: COc1c(C=NNC(=S)Nc2ccc(C(=O)O)cc2)cccc1-c1ccc(C)cc1
Reaction time: 24 h
Yield: 14.3 %

Procedure:
A solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (11 mg, 0.05 mmol) and 2-methoxy-3-(4-methylphenyl)benzaldehyde (14 mg, 0.06 mmol) in dimethylformamide (1 mL) was shaken with 4 Å molecular sieves for 40 h. PS-TsNHNH2 resin (17 mg, 0.05 mmol) was added and shaking continued for 24 h, then the resin was filtered off. The solvent was removed under vacuum and the residue chromatographed by reverse phase HPLC (CombiPrep ODS-A, 10–90% acetonitrile/water+0.1% trifluoroacetic acid) to give the title compound (3 mg, 14%) as a solid. MS (ES−) m/e 418 [M−H]−.
Reaction SMILES: [NH2:1][Cu:2].C(=O)([O-])[O-].[Na+].[Na+].[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11]>>[Cl:17][C:16]1[N:9]=[C:10]([Cl:11])[N:12]=[C:13]([NH:1][Cu:2])[N:15]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1nc(Cl)nc(N[Cu])n1

Procedure:
The preferred starting point for the further reaction of the amino copper complex formazan compound is the synthesis solution of (b), which is at pH 4, by reacting the solution with thorough stirring at a temperature of 0° to 5° C. and at a pH between 3 and 4, which is maintained by means of an aqueous sodium carbonate solution, with 16.6 parts of cyanuric chloride to give the 2,4-dichloro-s-triazin-6-ylamino copper complex formazan compound in the course of 3 to 4 hours.
Reaction SMILES: [CH2:1]([C:8]1([CH2:19][N:20]([CH3:22])[CH3:21])[CH2:13][CH2:12][C:11]([N:16]([CH3:18])[CH3:17])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Cl)[CH:28]=[CH:27]C=[CH:25][CH:24]=1.[NH4+].[Cl-].O>C1COCC1>[CH2:1]([C:8]1([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:13][CH2:12][C:11]([N:16]([CH3:17])[CH3:18])([C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)CC1(Cc2ccccc2)CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1(Cc2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 8 h

Procedure:
The title compound of step 1 (0.88 g, 2.94 mmol) was dissolved in THF (35 mL) and mixed in drops with 2M phenylmagnesium chloride solution (5.1 mL, 10.2 mmol) with ice cooling. The reaction solution was heated to boiling for 8 h. For work up the solution was mixed with 20% NH4Cl solution (0.6 mL) and water (0.4 mL) with ice cooling, extracted with ether (3×25 mL), the ether solution was washed with water, dried (Na2SO4) and concentrated to low volume in a vacuum. The residue was purified by column chromatography with EtOH/EE (1:20). 2 fractions were obtained, wherein according to LCMS, inter alia, the more polar fraction (300 mg) contained the desired substance.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C([C:17]([O-:19])=[O:18])C.[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Cl:20][S:21]([C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[C:11]3[NH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[C:10]=3[C:9]=2[CH:8]=1)(=[O:23])=[O:22]
Reactant: CCC(=O)[O-]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
85 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate as prepared in the preceding synthesis 1 is added in the space of 90 minutes to 106 μL (1.65 mmol) of chlorosulfonic acid cooled to 0° C. on an ice bath. On completion of addition, the solution is stirred for 1 hour at room temperature then 3 hours at 70° C. The reaction mixture is cooled to room temperature then poured into ice water (20 mL). The mixture is stirred for 15 minutes then the solid is filtered, and taken up in methanol/toluene mixture. The solvents are evaporated to give 64 mg (60%) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11](O)[CH2:12][NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:25])=O>[N+](C1C=CC=CC=1)([O-])=O>[ClH:9].[Cl:25][CH:11]1[CH2:12][N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=2[N:2]([CH3:1])[CH2:10]1
Reactant: CN(CC(O)CNC(=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1CC(Cl)CN=C(c2ccccc2)c2cc(Cl)ccc21
Product: Cl
Temperature: 95 °C

Procedure:
A mixture of 32 grams of N-methyl-N-(2-hydroxy-3-benzoylaminopropyl)-4-chloroaniline and 50 milliliters of phosphorus oxychloride and 100 milliliters of nitrobenzene was heated at a temperature of 95° C. during the course of 22 hours. The excess phosphorus oxychloride and the nitrobenzene were then distilled therefrom at a subatmospheric pressure. The residue was then extracted with chloroform and treated with ice water and dilute sodium hydroxide as described hereinbefore in Example 1. The chloroform extract was then concentrated by evaporation at a subatmospheric pressure. The residue was dissolved in diethyl ether and an isopropanol solution of hydrogen chloride was then added thereto. After recrystallization from a mixture of ethanol and diethyl ether there was obtained 3,8-dichloro-1-methyl-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine hydrochloride having a melting point of 195°-196° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=O.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([Cl:25])=[CH:27][CH:28]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2cc(CC(Cl)C(=O)Nc3ccc(Cl)cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.16 g (0.0013 mole) of 4-chloroaniline, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold reaction mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.28 g of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-N-(4-chlorophenyl)propionamide as an oil, Compound A23 of Table 1A.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.II.[I:21](O)(=O)=O>CO>[I:21][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: [O-][I+2]([O-])O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: CO
Product: Ic1ccc2c(c1)Cc1ccccc1-2

Procedure:
56.8 parts of fluorene, 200 parts of methanol, 37 parts of 63% sulfuric acid aqueous solution, 31 parts of iodine, and 34 parts of 34% iodic acid aqueous solution were stirred at 60° C. for 5 hours. After completion of the stirring, the resultant was filtrated, and it was then washed with 100 parts of water twice. Thereafter, the resultant was dried at 70° C. overnight. After completion of the drying, the resultant was recrystallized in methanol to obtain 60 parts of 2-iodofluorene in the form of white powders.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[OH-].[Na+]>C(O)C>[C:11]1([CH:21]=[C:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Yield: 55.7 %

Procedure:
To a solution of 32.3 g of ethyl succinate and 29.0 g of 1-naphthaldehyde in 320 ml of absolute ethyl alcohol was added 10.7 g of a 50% sodium hydride (dispersion in mineral oil) with stirring under ice-cooling, and then the mixture was reflux for 0.5 hours. To the reaction mixture was added 230 ml of a 1N-aqueous sodium hydroxide solution, and the mixture was reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral substances. An aqueous layer was acidified by the addition of concentrated hydrochloric acid, and the acid solution was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. Benzene was added to the residue, and precipitated crystals were collected by filtration to obtain 26.5 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals.
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14](=[NH:2])[NH2:15])[CH:11]=[CH:10][N:9]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a suspension of ammonium chloride (10.7 g, 200 mmol) in 250 mL of dry toluene. was added a 2 M solution of Al(CH3)3 (100 mL, 200 mmol) in toluene dropwise under nitrogen at 0° C. The resulting reaction mixture was stirred at rt until no more evolution of gas was observed and then 2-chloropyridine-4-carbonitrile (13.86 g, 100 mmol) was added. The mixture was stirred at 90° C. overnight. It was then cooled down to 0° C. and 300 mL of methanol were added with subsequent stirring for 1 h at rt. After filtration, the solid was washed with methanol for several times, the solution was evaporated to dryness under vacuum. The residue was washed with methanol to give 2-chloropyridine-4-carboximidamide. (18.3 g, 95%). 1HNMR δ (400 MHz, d6-DMSO): 8.70 (dd, J=4.8, 0.4 Hz, 1H), 8.00 (dd, 0.4 Hz, 1H), 7.84 (dd, J=5.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.53 (t, J=8.1 Hz, 1H); MS (ESI) m/z (M+H)+ 156.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([C:15]#[C:16][CH3:17])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:23]I>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([N:12]([CH3:23])[C:13]([CH3:14])([C:15]#[C:16][CH3:17])[CH3:18])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(C)(C)N(C)C(=O)C(CC)Oc1cncc(Cl)c1
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-chloro-3-pyridyloxy)-N-(2-methylpent-3-yn-2-yl)butyramide (0.10 g; prepared as described in Example 1) in dry tetrahydrofuran (9 ml) was added sodium hydride (0.011 g) at ambient temperature under an atmosphere of nitrogen. The mixture was stirred for 0.75 hours, a solution of methyl iodide (0.023 ml) in dry tetrahydrofuran was added then the reaction mixture stirred for a further 0.5 hours at ambient temperature. The reaction was diluted with water, extracted with ethyl acetate (three times) and the extracts were combined, washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was fractionated by chromatography (silica:hexane/ethyl acetate, 3:1 by volume) to give the required product as a beige solid, 0.075 g. m.p. 67–68° C. 1H NMR (CDCl3) δ: 1.14 (3H, t); 1.68 (3H, s); 1.69 (3H, s); 1.85 (3H, s); 2.02 (2H, m); 3.20 (3H, s); 4.70 (1H, t); 7.18 (1H, m); 8.18 (1H, m); 8.20 (1H, m).
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CCN(CC)CC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:16]/[CH:1]=[CH:2]\[CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCC/C=C\CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC=CC/C=C\OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A 10 mL round bottom flask was charged with 21 (0.48 g, 2.12 mmol), Et3N (590 μL, 4.24 mmol), 4-dimethylaminopyridine (0.03 g, 0.21 mmol), and CH2Cl2 (5 mL) under an argon atmosphere. The solution was cooled to 0° C., and a solution of 4-toluenesulfonyl chloride (0.61 g, 3.18 mmol) in CH2Cl2 (1 mL) was added drop wise. The mixture was stirred vigourously for 4 hours at room temperature. The reaction mixture was treated with saturated aqueous NaHCO3 (10 mL). After stirring at room temperature for 20 minutes, ethyl acetate (20 mL) was added. The organic layer was separated and washed with water (3×100 mL) and brine (50 mL), and dried over MgSO4. The solution was filtered and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of 2:1 hexanes/CH2Cl2 to 1:1 hexanes/CH2Cl2) provided 22 (0.68 g, 84% yield, 84% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 7.79 (2H, d, J=8.3 Hz), 7.33 (2H, d, J=8.9 Hz), 5.19-5.40 (2H, m), 4.02 2H, t, J=6.4 Hz), 2.44 (3H, s), 1.91-2.08 (4H, m), 1.66-1.71 (2H, m), 1.25 (16H, m), 0.88 (3H, t, J=7.0 Hz); 13C NMR (100 Hz, CDCl3): δ 144.8, 144.7, 133.3, 131.8, 129.9, 128.0, 127.8, 127.4, 70.2, 32.6, 32.0, 29.7 (2C), 29.6 (2C), 29.5, 29.4, 29.0, 27.3, 23.1, 22.8, 14.3; HRMS (FAB): 381.2477, [C22H36O3S+H]+ requires 381.2458.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:20])[CH2:18]C.Cl>CN(C)P(N(C)C)(N(C)C)=O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([CH:11]([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][O:20][CH2:17][CH3:18]
Reactant: CC(=O)c1cc(C(C)CO)ccc1O
Reactant: CCOC(=O)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCC(=O)c1cc(C(C)CO)ccc1O
Reaction time: 2 h

Procedure:
2-(3-Acetyl-4-hydroxyphenyl)propan-1-ol (15.0 g; 0.077 mol) was dissolved in hexamethylphosphoramide (150 ml) and slowly added to a stirred slurry of sodium hydride (10.0 g; 0.417 mol) in hexamethylphosphoramide (40 ml) at a rate sufficient to maintain the temperature below 25° C. Ethyl propionate (20.0 g; 0.2 mol) was added and the mixture stirred for 2 hours before pouring into 2N hydrochloric acid (600 ml). The solution was extracted with ether (2×300 ml) and the extracts evaporated to give 2-[4-hydroxy-3-(3-oxapentanoyl)phenyl]propan-1-ol as a yellow oil. This was dissolved in ethanol (100 ml) containing concentrated hydrochloric acid (20 ml) and the solution was refluxed for 30 mins. The ethanol was removed in vacuo and the aqueous phase extracted with chloroform (2×150 ml). The combined extracts were washed with saturated sodium bicarbonate solution and dried over magnesium sulphate. The solvent was removed and the resulting oil was chromatographed on a silica gel column using ether as eluent. Recrystallisation of the product using hexane/ether (2:1) furnished a white microcrystalline solid (5.0 g) mp 59.5°-60.5° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]>C1COCC1.CC(OC)(C)C>[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[C:19]([I:1])[C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(Cl)c2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
N-Iodosuccinimide (2.09 g, 9.29 mmol) was added portionwise to a stirred solution of 2-butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.69 g, 8.06 mmol) in THF (35 mL). The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with TBME (50 mL) then washed with aqueous sodium thiosulphate solution (50 mL) then saturated aqueous sodium chloride solution (20 mL). The organic phase was dried (Na2SO4), filtered and evaporated. The sample was dissolved in dichloromethane and purified by chromatography on silica using a gradient of 0-100% dichloromethane-cyclohexane over 30 minutes followed by a gradient of 0-100% TBME-cyclohexane followed by 0-20% methanol over 15 minutes. The appropriate fractions were identified by LC-MS then combined and evaporated in vacuo to give the title compound as a yellow solid (2.2 g).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].IC.[CH2:10](N(CC)CC)C.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>CC(C)=O.C(Cl)Cl>[CH:1]([N:4]1[C:18](=[O:19])[C:17](=[O:21])[N:7]=[C:5]1[S:6][CH3:10])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)NC(N)=S
Reactant: O=C(Cl)C(=O)Cl
Solvent: CI
Solvent: CC(C)=O
Solvent: ClCCl
Product: CSC1=NC(=O)C(=O)N1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl thiourea 9 (8.0 g, 67.7 mmol) in 100 ml of dry acetone was added iodomethane (6.3 ml, 101 mmol) dropwise at room temperature. After the addition was completed, the mixture was refluxed for 1 hour, and the solvent was evaporated to dryness under the reduced pressure to give a gum. The gummy hydroiodide salt was suspended in 200 ml of dry methylene chloride and to the suspension was added triethylamine (37.7 ml, 270 mmol). The mixture was stirred for 30 minutes at room temperature, cooled down to −78° C. with a dry ice/acetone bath. To the mixture was added dropwise oxalyl chloride (40.6 ml of 2M solution, 81.2 mmol) and stirred at −78° C. for 1 hour. The reaction was quenched by addition of water to decompose the excess oxalyl chloride, the solvent was dried over Na2SO4 and evaporated to dryness in vacuo.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][C:7]1[CH:21]=[CH:20][C:10]2[O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.C(C1C=CC2OC(C3C=CC=CC=3)OC=2C=1)(OC)=O>>[Cl:3][CH2:6][C:7]1[CH:21]=[CH:20][C:10]2[O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OC(c1ccccc1)O2
Agent: COC(=O)c1ccc2c(c1)OC(c1ccccc1)O2
Product: ClCc1ccc2c(c1)OC(c1ccccc1)O2

Procedure:
The starting compound, 5-chloromethyl-2-phenyl benzo [d]-1,3-dioxole (nD25 = 1.597) was prepared by chlorination, with SOCl2, of 5-hydroxymethyl-2-phenyl benzo [d]-1,3-dioxole melting (K) at 75° C, itself prepared by reduction, with Li Al H4, of 5-carbomethoxy-2-phenyl benzo [d]-1,3-dioxole, B.P./0.05 mm = 155° to 157° C, nD25 = 1.583.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:4]=1[CH3:21].C[OH:23]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[O:23])[C:4]=1[CH3:21]
Reactant: COc1c(C)cnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: CO
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reaction time: 1 h

Procedure:
53.5 g of 2-[[(4-methoxy-3,5-dimethyl-2 -pyridyl)methyl]thio]benzimidazole are dissolved in 1.2 l of methylene chloride and 100 ml of methanol and then cooled to -20°. 33.4 g of m-chloroperbenzoic acid, recrystallized from methylene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred for a further 60 minutes at -20° and then poured into a mixture of 250 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphinyl]benzimidazole of melting point 157°-159°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28]>>[OH:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: CC(C)(O)CN
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(C)(C)O)n(C)n1
Yield: 28 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-2-methylpropylamine instead of isopropylamine, to the title compound (9.4 mg, 28%) which was obtained as a white solid. MS: m/e=399.2 [M+H]+.