Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 30.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.9 mg) was obtained.
Reaction SMILES: [F-].[K+].[CH2:3]([OH:5])[CH3:4].S(F)([O:9][C:10](F)(F)[C:11]([F:17])([I:16])[C:12]([F:15])([F:14])[F:13])(=O)=O>O>[I:16][C:11]([F:17])([C:12]([F:15])([F:14])[F:13])[C:10]([O:5][CH2:3][CH3:4])=[O:9]
Reactant: CCO
Reactant: O=S(=O)(F)OC(F)(F)C(F)(I)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(F)(I)C(F)(F)F
Temperature: 70 °C
Yield: 56 %

Procedure:
A 500 mL flask was charged with potassium fluoride (17.5 g, 0.31 mol) and absolute ethanol (110 mL), and was cooled in an ice-water bath. 2-iodo-hexafluoropropyl fluorosulfate (112.8 g, 0.3 mol) was added slowly. The reaction was exothermic and the reaction temperature was controlled at 20°-25° C. After addition was complete, the reaction mixture was heated at 70° C. for 4 hr and then poured into cold water. The bottom organic layer was separated, washed with saturated NaCl aqueous solution and dried over MgSO4. Evaporation of the solvent in vacuo followed by distillation gave 50 g (56% yield) of ethyl 2-iodotetrafluoropropionate product, formula above, having a boiling point of 60°-65° C. at 50 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[NH:10])=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:8]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[N:10]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A suspension of the product of Step D (0.4 g; 1.16 mmol) and 1M TBAF in THF (0.5 ml) in anhydrous toluene (10 ml) was refluxed for 3 h under N2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H2O (5 ml) and the solid was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.35 g; 92%) as colourless solid. 1H-NMR (CDCl3) 4.0 (s, 3H); 6.66 (m, 1H); 7.05 (d, 1H, J=8.7 Hz); 7.27 (m, 1H); 7.49 (d, 1H, J=8.7 Hz); 7.97-8.01 (m, 1H); 8.1-8.13 (m, 1H); 8.27 (d, 1H, J=2.1 Hz); 8.3 (broad s, 1H); 8.48 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:28]1[CH:36]=[CH:35][C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:33][N:32]([CH3:34])[C:31]1[CH:35]=[CH:36][C:28]([NH:1][C:2]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:29][CH:30]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.12 g and cesium carbonate 0.36 g were added 4-bromo-N,N-dimethylaniline 0.18 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.1 mg and palladium acetate 2.0 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.1 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((4-(dimethylamino)phenyl)amino)-4-phenylbenzoate.
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:18]([O:20]CC)=[O:19])([F:17])[F:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCOCC1.[OH-].[Na+:36]>O>[C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([F:16])([F:17])[C:18]([O-:20])=[O:19])=[O:12])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[Na+:36]
Reactant: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OC(c1ccccc1)C(F)(F)C(=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
A mixture of 6.6 g of 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate, prepared in Synthesis Example 1-5, 20 g of 1,4-dioxane, and 2.5 g of 25 wt % sodium hydroxide was stirred for 2 hours. Water, 30 g, was added to the reaction solution. The reaction solution was washed with n-hexane, obtaining an aqueous solution of sodium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate. To this solution, 32 g of an aqueous solution of triphenylsulfonium chloride and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 5.5 g of the target compound, triphenylsulfonium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate as white crystals (yield 58%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][OH:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][OH:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 2-bromoethanol (23.5 g), and the mixture was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 2-(4-bromophenoxy)-1-ethanol (15.9 g).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CN(C)C(Cl)=O.[N:13]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[N+:21]([O-])[CH:22]=1)=[N+:14]=[N-:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:13]([CH2:16][C:17]1[C:22]([C:5]#[N:6])=[N:21][C:20]([CH3:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15]
Reactant: Cc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(CN=[N+]=[N-])c(C#N)n1
Reaction time: 23 h
Yield: 77.4 %

Procedure:
Trimethylsilyl cyanide (6.4 ml, 48 mmol) and dimethylcarbamyl chloride (4.2 ml, 46 mmol) were added in that order to a solution of the 5-(azidomethyl)-2-methyl-1-pyridiniumolate (7.08 g, 43.2 mmol) in methylene chloride (80 ml) at room temperature and the mixture was stirred at the same temperature for 23 hours. After confirming completion of the reaction by thin layer chromatography, saturated aqueous sodium hydrogencarbonate (80 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate, the aqueous layer was separated and extraction was performed with ethyl acetate. The collected organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.79 g, 56%, two steps) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:31]>CO>[IH:31].[IH:31].[N:11]1([C:15]2[N:19]([CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1nc(Cn2c(N3CCCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)cs1
Agent: I
Solvent: CO
Product: Cc1nc(Cn2c(N3CCCNCC3)nc3ccccc32)cs1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Hydrolyze 4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.59 g, 1.38 mmol) by refluxing with hydriodic acid (57%, 3.04 mmol) in methanol (10 mL) for 10 hours. Concentrate to remove the methanol, add ether (70 mL) and allow the resultant slurry to stand for 1 hour. Decant the supernatant and dry the solid residue in vacuo at 60° C. to provide 0.78 g of 2-[1,4]diazepan-1-yl-1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazole dihydroiodide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A solution of 1-(4-hydroxyphenyl)ethanone (1.48 g, 10.9 mmol) and tributylphosphine (3.0 g, 14.9 mmol) in toluene (20 ml) was treated dropwise at 0° C. with a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2 g, 9.94 mmol) and 1,1′-(azodicarbonyl)dipiperidine (2.75 g, 10.9 mmol) in toluene (20 ml). The mixture was stirred at room temperature for 2 days then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol/dichloromethane (1:9) to afford the title compound (0.81 g, 23%); MS(ES−) m/e 318 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1)[CH3:17]>O1CCCC1>[Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([Cl:14])=[C:6]([C:7]([C:21]2[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=2)=[O:8])[CH:13]=1
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cc(Br)c(F)cc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 5-bromo-2-chloro-4-fluoro-N-methoxy-N-methylbenzamide (936 mg, 3.17 mmol) in tetrahydrofuran (15 mL) was added (4-ethylphenyl)magnesium bromide (9.5 mmol, 9.5 mL, 1 M in tetrahydrofuran) at 0° C. The mixture was stirred at 25° C. for 1 hour, then the reaction was quenched with saturated ammonium chloride, and most of the tetrahydrofuran was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic layer was separated, washed with water, then with brine, and dried over sodium sulfate. The sample was concentrated and then purified by preparative thin layer chromatography (petroleum ether:ethyl acetate, 4:1) to provide pure product 31a as a white solid (995 mg, 88% yield). 1H-NMR (CDCl3, 400 MHz): δ 7.71 (d, J=8.4 Hz, 2H), 7.58 (d, J=6.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.26 (d, J=6.8 Hz, 1H), 2.73 (q, J=8 Hz, 2H), 1.27 (t, J=8 Hz, 2H).
Reaction SMILES: [C:1]([S:5]([NH:8][S:9](F)(=[O:11])=[O:10])(=[O:7])=[O:6])([F:4])([F:3])[F:2].FC(F)(F)S(N)(=O)=O.S(Cl)([Cl:23])=O.ClS(O)(=O)=O>>[C:1]([S:5]([NH:8][S:9]([Cl:23])(=[O:11])=[O:10])(=[O:7])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Agent: NS(=O)(=O)C(F)(F)F
Agent: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)NS(=O)(=O)C(F)(F)F

Procedure:
This example illustrates synthesis of CF3SO2NHSO2F by the reaction of trifluoromethane sulfonamide (CF3SO2NH2), thionyl chloride (SOCl2), chlorosulfonic acid (ClSO3H) to produce CF3SO2NHSO2Cl intermediate, which is then fluorinated with anhydrous hydrogen fluoride (HF) to produce CF3SO2NHSO2F.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][N:15]1[CH2:16][CH2:17][CH:12]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH2:13][CH2:14]1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1ncnc2c1c(I)nn2C1CCN(Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.45 mmol), 1H-2-imidazolecarbaldehyde (0.42 g, 4.34 mmol), sodium triacetoxyborohydride (0.61 g, 2.90 mmol) and glacial acetic acid (0.26 g, 4.36 mmol) were mixed with 1,2-dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.57 g, 92%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.17 (m, 4H), 2.92 (m, 2H), 3.55 (s, 2H), 4.57 (m, 1H), 6.92 (s, 2H), 8.14 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>CN(C)C=O>[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(O)c2)CC1
Temperature: 20 °C
Yield: 27.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11.2 g), triethylamine (16.8 cc) and 4- (3-hydroxyphenyl)piperazine dihydrobromide (13.6 g) in dimethylformamide (250 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 6 hours at this temperature. After purification by crystallization from isopropyl oxide (30 cc), then recrystallization from boiling acetonitrile (125 cc), 2-{3-[4-(3-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 175° C.
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH:37]([C:39]1[CH:51]=[CH:50][C:42]([CH:43]=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:41][CH:40]=1)=O>C1COCC1>[O:2]([CH2:9][CH2:10][CH2:11][CH:12]=[CH:37][C:39]1[CH:40]=[CH:41][C:42](/[CH:43]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:50][CH:51]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=Cc1ccc(C=O)cc1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(C=CCCCOc2ccccc2)cc1
Temperature: -40 °C
Yield: 65 %

Procedure:
3.16 g of (4-phenoxybutyl)(triphenyl)phosphonium bromide are suspended in 25 ml of THF under argon and cooled to −40° C. 2.36 ml of n-butyllithium (1.6 molar in hexane) are added dropwise, and the mixture is warmed to 0° C. after 5 minutes and cooled again to −40° C. after 15 minutes. A solution of 0.70 g of ethyl 4-formylcinnamate in THF is added dropwise and, after 5 minutes, the reaction mixture is warmed to room temperature. The solvent is removed in a rotary evaporator. 0.75 g of product is obtained as an E/Z mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH:20]([CH3:28])[CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH:20]([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Br)cn3n1)C(C)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
Reaction SMILES: O=O.[F:3][C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1.ClCCl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH2:9][OH:10])[CH:13]=1
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With exclusion of oxygen, 27.1 g (159.28 mmol) of methyl 5-fluoro-2-hydroxybenzoate are initially charged in 500 ml of dry THF and cooled to 0° C. With cooling, 238 ml (238 mmol) of a 1 M solution of lithium aluminum hydride in THF are then slowly added dropwise, and the mixture is stirred at 0° C. for 1 hour and then at RT overnight. After the reaction has gone to completion, saturated ammonium chloride solution is added, and the mixture is taken up in dichloromethane. The organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed under reduced pressure. The crude product is purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1). This gives 18.0 g (126.6 mmol, 79% of theory) of a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([O:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc(O)cc(CCCC2OCCCO2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCCC2OCCCO2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To all of 2-[3-(3-hydroxy-5-methoxyphenyl)propyl]-1,3-dioxane, as prepared in step d, in dichloromethane (2 mL) containing 500 μL of N,N-diisopropylethylamine was added 166 mg (0.79 mmol) of 2-chlorobenzenesulfonyl chloride. After stirring at ambient temperature for 30 min, 5 mg of N,N-dimethylaminopyridine was added and the reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with 10% aqueous citric acid, extracted into diethyl ether, dried (MgSO4), concentrated, and purified by flash chromatography (dichloromethane/diethyl ether (100:0 to 95:5)) to give 180 mg (77% yield from 2-[3-(3-hydroxy-5-methoxyphenyl)-3-propenyl]-1,3-dioxane) of the title compound. 1H-NMR (300 MHz, CDCl3) δ 7.84 (dd, 1 H, J 1.5, 8 Hz), 7.53-7.63 (m, 2 H), 7.33-7.39 (m, 1 H), 6.59 (t, 1 H, J =2 Hz), 6.50 (m, 2 H), 4.48 (t, 1 H, J=5 Hz), 4.06-4.11 (m, 2 H), 3.70 (s,3 H), 3.71-3.79(m,2 H), 2.49 (t, 2 H, J=5 Hz), 1.98-2.14 (m, 1 H), 1.25-1.6 (m, 5 H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C20H23ClO6S: 449.1 (M+Na). Found: 449.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:15])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-(4-Bromo-phenyl)-propan-1-ol (2.60 g, obtained in example 130, step 1) was dissolved in THF (35 mL). The mixture was cooled to 0° C. and sodium hydride (60% in mineral oil, 967 mg) was added in four portions to the cold mixture. Stirring was continued at 0° C. for 1 hour. Then, iodomethane (1.13 mL) was added dropwise over a period of 15 minutes to the reaction mixture. The mixture was warmed to room temperature over a period of 1 hour. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow liquid (2.61 g, 94%). MS (EI): 229.0 [M−].