Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:7]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6][S:5](=[O:16])[N:4]=1.[CH3:17][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH2:30])=[CH:23][CH:22]=1)[CH3:19]>CO>[CH3:19][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH:30][C:3]2[C:7]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:6][S:5](=[O:16])[N:4]=2)=[CH:23][CH:22]=1)[CH3:17]
Reactant: COC1=NS(=O)N=C1NCc1cccnc1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)N=C2NCc2cccnc2)o1
Reaction time: 18 h

Procedure:
To the methanol solution of 3-methoxy-4-(3-pyridyl)methylamino-1,2,5-thiadiazole 1-oxide produced in Step A was added a solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (4.0 g; 18.7 mmoles) in 30 ml of methanol. The reaction mixture was stirred at ambient temperatures for 18 hours and the solvent was removed in vacuo. The residue was placed on 500 g of silica gel (230-400 mesh) and purified by flash chromatography using a gradient elution of acetonitrile-methanol. After combining the appropriate fractions, the title compound was obtained as an amber oil (4.25 g) containing one mole of methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.30 g (1.6 mmol) of 2,6-dichlorobenzamide and 0.22 g (1.8 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-dichlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.3 g (1.6 mmol) of 2-chloro-4-fluoro-3-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.58 g (Yield 84%) of the title compound as a solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]([OH:15])[C:12]([CH3:17])([CH3:16])[C:11]=2[CH:18]=1)(=[O:5])=[O:4].[CH3:19]O>S(=O)(=O)(O)O.C(N(CC)CC)C>[CH3:1][NH:2][S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]([O:15][CH3:19])[C:12]([CH3:16])([CH3:17])[C:11]=2[CH:18]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(O)O2
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(OC)O2
Reaction time: 0.5 h

Procedure:
4 drops of concentrated sulfuric acid was added to a solution of 22.5 parts of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methylaminosulfonate in 200 parts of methanol. The mixture was subsequently boiled for 30 minutes under reflux, and then cooled. The mixture was neutralized with triethylamine and concentrated to dryness in vacuo. Treatment of the viscous residue with a mixture of ether and n-hexane gave crystals of 2,3-dihydro-3,3-dimethyl-2-methoxybenzofuran -5-yl methylaminosulfonate; melting point: 89° to 91°C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.[H][H]>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2c3ccccc3ccn2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2n(c1=O)CCc1ccccc1-2

Procedure:
A mixture of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (2.68 g., 0.010 mole) in acetic acid (200 ml.) containing 10% palladium on carbon (1.0 g.) was shaken with hydrogen at an initial pressure of about 4 kg. cm.-2 until the theoretical pressure drop was reached (3.3 hours). The mixture was filtered and the filtrate flash evaporated to dryness to leave an oil, which upon dilution with toluene and reconcentration to dryness gave colorless crystalline material, m.p. 117°-125°. Two recrystallizations from ethanol raised the m.p. to 139°-141°. This material was combined with product of similar purity which separated from the first ethanolic mother liquor, and the lot recrystallized from cyclohexane to give the analytical sample, m.p. 138.5°-140°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.Cl[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=3)[CH:8]=2)[S:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)S3)nc1
Temperature: 55 °C
Reaction time: 60 h

Procedure:
A solution of 232 mg (1.01 mmol) of 2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 190 mg (1.03 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml of triethylamine was placed in a heavy-walled glass tube, degassed, placed under argon and then treated with a powdered mixture of 53 mg (0.28 mmol) of cuprous iodide and 84 mg (0.12 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was degassed again, placed under argon and the tube was sealed. The reaction mixture was heated at 55 degrees C. for 60 h and then cooled to room temperature. The mixture was treated with water and ether and the organic layer was separated. The aqueous layer was extracted with ether, the organic layers were then combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the resultant residue was purified by flash chromatograhy (silica; 10% ethyl acetate in hexanes) to give the title compound as a dark yellow oil. PMR (CDCl3): & 1.32-1.43 (15H, m), 1.92 (2H, s), 4.38 (2H, q, J-7.1 Hz), 7.28 (1H, dd, J-8.3 Hz, 1.8 Hz), 7.32-7.38 (2H, m), 7.53 (1H, d, J-8.3 Hz), 8.24 (1H, dd, J-8.2 Hz, 2.2 Hz), 9.16 (1H, d, J-2.2 Hz). MS exact mass, m/e 379.1594 (calcd. for C23H25NO2S, 379.1606).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2
Reactant: O=C(C=NO)Nc1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Temperature: 90 °C
Yield: 81 %

Procedure:
The N-(3,5-dichlorophenyl)-2-hydroxyiminoacetamide just prepared (12.1 g, 0.052 mol) was added to 96 per cent strength sulfuric acid (56 ml) at 50-75° C. in the course of 15 min. The reaction mixture was then heated at 90° C. for 15 min, while stirring. After cooling, the mixture was poured slowly on to ice (500 g). The solid formed was filtered off with suction after 30 min. The desired isatin was isolated in a yield of 81% (9.12 g) as an orange-coloured solid. It was not possible to determine a melting point.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1cccc(CF)n1
Product: CS(=O)(=O)OCCC#Cc1cccc(CF)n1
Yield: 75.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(B), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol (2.60 g, 15 mmol) and methanesulfonyl chloride (1.50 mL, 19 mmol) to afford 2.90 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 78%) as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[O:18][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=1[Cl:19])(=[O:17])[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccc(Br)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)cc1OC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Triethylamine (14.6 mL, 104.6 mmol) was added to a solution of 1-(4-Bromo-2-hydroxy-phenyl)-ethanone (15.0 g, 96.8 mmol) dissolved in dichloromethane (200 mL). The resulting solution was cooled to 0° C. at which time 2,4-dichloro-benzoyl chloride, dissolved in 50 mL dichloromethane was added dropwise over 30 minutes. The resulting mixture was allowed to warm to ambient temperature and stir at this temperature for an additional 16 hours. After this time, the reaction mixture was concentrated via rotary evaporation and then dissolved in EtOAc and washed twice with water and once with a saturated NaHCO3 solution. The organic portion was dried (MgSO4), filtered and concentrated to give the desired product (22.7 g, 84%) which was used without further purification. 1H-NMR (DMSO) δ 8.18 (d, 1H), 7.96 (d, 1H), 7.82 (s, 1H), 7.64 (m, 3H), 2.53 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13](N(CC)CC)C.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO.C(#N)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3.0 g, 17 mmol) and triethyl amine (3.14 mL, 22 mmol) in dichloromethane/methanol/acetonitrile (10:1:10, 168 mL) was treated with (trimethylsilyl)diazomethane (2M solution in hexanes, 10.25 mL, 20.5 mmol). It was stirred over night at room temperature, the solvent was removed under reduced pressure and chromatography on silica gel with hexanes/acetone (1:1) gave 2.2 g (67%) of the product as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:9][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: Clc1cc(Br)cc(CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)cc(Br)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
Step G3. A mixture of 1-bromo-3-(bromomethyl)-5-chlorobenzene (6 g, ˜21 mmol) and potassium phthalimide (3.15 g, 17 mmol) in DMF (50 ml) was heated at 120° C. for 2 hours. After cooled down, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 85%) was obtained as white solid. 1H NMR (DMSO-d6): δ3.72 (s, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 7.52 (s, 1H), 7.84,7.86 (d,2H), 8.05,8.07 (d,2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>CC(C)=O>[CH3:16][CH:15]1[CH2:17][N:3]2[N:4]=[CH:5][N:6]=[C:2]2[NH:1][C:14]1=[O:18]
Reactant: Nc1nc[nH]n1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1Cn2ncnc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
33.63 g (0.4 mol) 3-amino-1H-1,2,4-triazole was suspended in 300 ml acetone. 44.44 g (0.44 mol) triethyl amine was added and the mixture was cooled to 0° C. 33.63 g (0.44 mol) methacryloyl chloride was added dropwise over 45 minutes, while the temperature was kept at 0° C. The reaction was allowed to continue at 0° C. for one hour. The precipitated salts were removed by filtration and an additional 10 ml triethyl amine was added to the filtrate. The mixture was refluxed for 18 hours. The precipitated compounds were removed by filtration and the solvent was evaporated under reduced pressure. 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated by preparative column chromatography on a Prochrom LC 80 system, using Kromasil C18 100 Å 10 μm silica and MeOH and an aqueous solution of 0.2% (v/v) triethyl amine and 0.5% (v/v) acetic acid in a 42/58 ratio as eluent, at a flow rate of 150 ml/min. 770 mg of 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CN1CCN(CCCCCN)CC1
Solvent: O
Product: CN1CCN(CCCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 0.50 g (2.70 mmol) of 1-(5-aminopentyl)-4-methylpiperazine was heated with stirring in a 180° C. to 185° C. oil bath. After 2 minutes, solution was complete. After 0.5 hour, the solution was cooled to room temperature, and 5 mL of water was added to precipitate a taffy-like gum. Decanted and triturated gum again with 5 mL of water. Decanted and took up gum into 35 mL of ether. The ether solution was washed with 2×50 mL of water, dried (potassium carbonate), and concentrated to 5 mL volume. Petroleum ether was added to slight turbidity. The crystals that separated on inducement were filtered and washed with 80% ether/petroleum ether; wt 0.060 g; mp 110°-112° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[C:9]([CH3:12])[NH:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:7](=[O:13])[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH:10]=[C:9]1[CH3:12]
Reactant: CC1=COc2ccc(F)cc2C(=O)N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccc(F)cc2C(=O)N1CCCCBr
Reaction time: 0.5 h

Procedure:
416 mg of 4,5-dihydro-7-fluoro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 15 ml of dimethylformamide, then 113 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 1 ml (3.6 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.Cl>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:20]1[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Reactant: Nc1nccs1
Agent: Cl
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2nccs2)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (2.6 g) was dissolved in water (30 ml). To the solution was added 2-aminothiazole (1.0 g). The solution was adjusted at pH 5.0 with dilute hydrochloric acid and stirred at ambient temperature overnight. The precipitate was collected by filtration, washed with acetone and air-dried to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]hypoxanthine (2.2 g).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CC(C)=O>[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[C:41]([O:19][CH:4]([C:3]([CH2:21][F:22])([CH2:2][F:1])[CH3:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1ccnc1)C(C)(CF)CF
Temperature: 100 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
12.2 g (0.037 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butan-2-ol were dissolved in 70 ml of acetic anhydride. The solution was stirred at 100° C. for 16 hours, the excess acetic anhydride was distilled off in vacuo and the residue was taken up in 300 ml of methylene chloride. The organic phase was washed twice with 800 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of acetone, and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate which had formed was filtered off and dried. 13 g (68% of theory) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butane 1,5-naphthalenedisulphonate of melting point 221°-224° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9]1)=[C:17]1[C:19]([CH3:22])=[CH:20][S:21][C:16]1=[CH:15][CH:14]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:25]([N:12]1[C:13]2[C:18](=[C:17]3[C:19]([CH3:22])=[CH:20][S:21][C:16]3=[CH:15][CH:14]=2)[C:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:24][CH2:23][C:11]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1csc2ccc3c(c4c(n3Cc3ccccc3)CCN(Cc3ccccc3)C4)c12

Procedure:
The compound is formed analogously to that described in Example 28, from 3.3 g of 9-benzyl-1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole and 2 ml of benzyl bromide in 50 ml of hexamethylphosphoric acid triamide in the presence of NaH. Melting point: 206° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:3]1.C(O)(=O)C.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CSc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone (45 mg) in 20 ml carbon tetrachloride, were added acetic acid (0.5 ml) and bromine (0.1 ml). The reaction solution was stirred at room temperature for one hour. Then the reaction was quenched by adding 20 ml of saturated aqueous sodium thiosulfate solution to the reaction solution. After removing the carbon tetrachloride in vacuo, the resulting aqueous layer was extracted with dichloromethane (50 ml×3) and the organic layer was then washed with water (50 ml×1). The organic layer was concentrated in vacuo and the resulting residue was chromatographed (hexane/ethylacetate=2:1) to yield 69 mg of 4-bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone as a solid. NMR: δ1.52 (s, 6H), 2.55 (s, 3H), 7.33 (d, J=9.3 Hz, 2H), 8.15 (d, J=9.0 Hz, 2H); IR (cm−1): 1704, 1594, 1574, 1486, 1348, 1184, 1069.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[CH3:32].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1.O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=2[CH3:34])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C)c1N
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(C)ccc(O)c2C)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2,3-dimethyl-benzoic acid (intermediate III(m)) (0.4 g, 1.6 mmol, 1.0 eq) in CH2Cl2 (15 mL) was added (COCl)2 (0.62 g, 4.9 mmol, 3.0 eq) and DMF (0.01 mL). The reaction mixture was stirred at room temperature for 1.5 h, then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (260 mg, 1.9 mmol, 1.2 eq) and K2CO3 (0.9 g, 6.5 mmol, 4.0 eq) in THF (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h, then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 15:1 to 3:1) to give the title compound as a colorless oil (300 mg, 51%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])[C:11](=[O:24])[CH:10]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:23])[C:16]([OH:18])=[O:17])[C:11](=[O:24])[CH:10]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O

Procedure:
A solution of 2.3 g (6.2 mmol) of tert-butyl 2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) in a 4-molar hydrochloric acid/dioxane solution was stirred at RT for 7 h and then concentrated under reduced pressure. The residue was coevaporated three times with dichloromethane and dried under reduced pressure. Yield: 2.0 g (99% of theory)