Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC1(CO)CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4-Chlorobenzenesulfonyl chloride (6.92 g, 32.8 mmol) was added to a solution of (1-aminocyclohexyl)methanol (prepared according to Helv. Chirp. Acta, 87:90-105 (2004)) (3.53 g, 27.3 mmol) and triethylamine (4.6 mL, 32.8 mmol) in 100 mL tetrahydrofuran at room temperature. The reaction was stirred overnight and concentrated. The residue was taken up in a mixture of 100 mL ethyl acetate and 100 mL brine. The organic layer was separated, dried over sodium sulfate, and purified by flash chromatography on 120 g silica gel with 20 to 100% ethyl acetate in hexane to yield 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (6.07 g, 73%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85-7.86 (1H, m), 7.81-7.84 (1H, m), 7.47-7.49 (1H, m), 7.44-7.46 (1H, m), 4.61 (1H, s), 3.60 (2H, d, J=5.54 Hz), 2.25 (1H, t, J=5.92 Hz), 1.57-1.69 (2H, m), 1.22-1.45 (8H, m). LC/MS R.T.=2.39 min; [M+H]+=304.03; [M+Na]+=326.05; [M−H]−=301.98.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H]>[Pd]>[O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12
Reactant: C1=CCCC2OC2CCC=CCC1
Reactant: [H][H]
Agent: [Pd]
Product: C1CCCCCC2OC2CCCC1

Procedure:
As a process for producing cyclododecanone and cyclododecanol by a catalytic reaction of epoxycyclododecane compounds with hydrogen, J. Mol. Catal., Vol 169, pp 95-103 (1991) discloses a catalytic hydrogenating reaction of 2-epoxy-5,9-cyclododecadiene with hydrogen. In this reaction of the reference, 1,2-epoxy-5,9-cyclododecadiene is brought into contact with hydrogen in the presence of a palladium-carrying catalyst at a reaction temperature of 90° C. under a hydrogen gas pressure of 1,275 kPa (13 kg/cm2) on gauge, and epoxycyclododecane is produced as a principal reaction product. Cyclododecanol is produced as a by-product in a yield of 4% and no cyclododecanone is produced. Also, the Draft of 24-th Symposium “Development of Reaction and Synthesis, Nov. 5-6, 1998, pp 68, discloses a process of catalytic reaction of 1,2-epoxy-5,9-cyclododecadiene with hydrogen in the presence of a palladium catalyst at room temperature under the ambient atmospheric pressure. In this process, epoxycyclododecane is produced as a principal product, cyclododecanol is produced, as a by-product, in a yield of 5%, and no cyclododecanone is produced.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:17][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:7][C:2]=1[Br:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(Br)c2)C1
Temperature: 150 °C
Yield: 100 %

Procedure:
To the phenol from example 30 (117.5 mg, 0.39 mmol) in dry DMF (10 ml), under an atmosphere of nitrogen, was added potassium carbonate (75 mg, 0.54 mmol) and benzyl bromide (0.07 ml, 0.54 mmol). The reaction mixture was heated to 150° C. for 48 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was then re-extracted with ethyl acetate (2×20 ml). The combined organic extracts were then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude product as a brown oil. This was purified by column chromatography on silica eluting with dichloromethane:methanol (98:2) to give the title compound as a colourless oil (153 mg, 0.39 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.56 (q, 2H), 2.05 (t, 1H), 2.25 (t, 1H), 2.37 (t, 2H), 2.82 (d, 1H), 2.92 (d, 1H), 3.85 (t, 1H), 4.02 (d, 1H), 4.52 (d, 1H), 5.15 (s, 2H), 6.87 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.37 (t, 2H), 7.45 (d, 2H), 7.58 (s, 1H). LRMS: m/z 392 (M−H+).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11]>C1COCC1>[F:5][C:6]([F:15])([F:16])[C:7]1[CH:8]=[C:9]([C:10]([OH:11])=[CH:1][CH3:2])[CH:12]=[CH:13][CH:14]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC=C(O)c1cccc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Vinylmagnesium bromide (40 mL of a 1.0 M THF solution, 40 mmol) was added to a dry round bottom flask under nitrogen. The solution was cooled to −10° C. and charged with meta-trifluoromethylbenzaldehyde (5.0 g, 29 mmol). The reaction was stirred for 1 h, warmed to RT and quenched with sat. NH4Cl. The mixture was extracted with EtOAC three times, and the organic extracts were dried (MgSO4) and concentrated in vacuo. The crude material was purified via flash chromatography to give 1-(3-trifluoromethylphenyl)propen-1-ol as an oil (5.0 g, 87% yield). A portion of 1-(3-trifluoromethylphenyl)propen-1-ol (0.5 g, 2.5 mmol) was dissolved in acetone (20 mL). The resultant solution was cooled to 0° C., treated with Jones reagent (1.14 mL of a 2.6 M solution, 2.96 mmol), and stirred for 10 minutes before being quenched with the addition of isopropyl alcohol (1.5 mL). The mixture was stirred for 5 min at rt, diluted with Et2O, filtered through Celite, washed with 10% Na2SO3. The material was purified via filtration through a plug of silica gel (1:1 Et2O:hexanes as eluant) to provide the 1-(3-trifluoromethylphenyl)propenone as an oil (320 mg, 65% yield), which solidified upon standing in the freezer. 1H-NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.13 (d, 1H, J=7.7 Hz), 7.84 (d, 1H, J=9.0 Hz),7.64 (t, 1H, J=7.7 Hz), 7.16 (dd, 1H, J=17.2, 10.6 Hz), 6.49 (dd, 1H, J=17.2, 1.5 Hz), 6.03 (dd, 1H, J=10.6, 1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9](/[CH:16]=[C:23](/[C:22]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=2)\[C:24]#[N:25])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2c3ccccc3c(Cl)c3ccccc23)cc1OC
Yield: 56.1 %

Procedure:
10-Chloro-9-anthraldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (368 mg) through Method A (production step 2), to thereby yield the target product (yield: 466 mg, 56%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)=[CH:14][C:15](O)=[O:16]>C(OCC)C>[CH:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:14][C:15](=[O:16])[C:3]=2[CH:4]=1
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)=CC(=O)O
Solvent: CCOCC
Product: O=C1CCOc2ccccc21
Reaction time: 1 h
Yield: 168.3 %

Procedure:
The amount of 10 g of 3,4-dimethoxyphenol and 7.8 g of 3,3-dimethyl acrylic acid were combined in a 125 ml. erlenmeyer flask and dissolved with the addition of 40 ml anhydrous ethyl ether. The ether was removed in vacuo and while the contents of the flask remained liquid, 50 gm of polyphosphoric acid was added. The flask and contents were placed on a steam bath and heated with stirring for 1 hour. At the end of 1 hour, 75 ml. of water was added and the contents stirred into solution for 5 minutes. The solution was allowed to cool and a substantial sticky precipitate formed. The aqueous layer was decanted and extracted with 100 ml. of ether. The ether extract was washed successively with 150 ml. of water, 100 ml. of 5% sodium carbonate and 100 ml. of saturated NaCl solution. The ether extract was dried over anhydrous sodium sulfate. The sticky residue formed on cooling was dissolved in 300 ml. of chloroform and washed successively with 150 ml. of water, two 150 ml. portions of 5% sodium carbonate solution and 150 ml. of saturated NaCl solution. The chloroform solution was dried over anhydrous sodium sulfate. The ethereal and chloroform extracts were combined and the solvents removed in vacuo leaving 16.17 gm of off-white crystalline chromanone.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][CH3:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:17][C:15]1[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=1)[CH3:9]
Reactant: CCc1ncsc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ncsc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A mixture of 5-(bromomethyl)-4-ethyl-1,3-thiazole (7.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 4.9 mmol), and triethylamine (3.0 mL, 21.5 mmol) in absolute ethanol (70 mL) was stirred at room temperature overnight. The mixture was evaporated, and the residue was treated with 50% diethyl ether/acetone (100 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2). The column was repeated 4 times, affording the title compound (132 mg, 10% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 2H, J=7.5 Hz), 2.801 (m, 2H, J=7.5 Hz), 4.55 (s, 2H), 6.05 (s, 1H), 8.85 (s, 1H); M+268.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH2:12][CH2:13][C:14](O)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:14](=[O:15])[CH2:13][CH2:12][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCS
Reactant: OCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OCCCc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 3-mercaptopropionic acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours with stirring. At the end of the 10 hour period, the reaction mass is cooled to room temperature and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR70## (as confirmed by GLC, NMR, mass spectral and IR analyses).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][OH:14]>C(O)C>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4](/[C:8](=[N:13]\[OH:14])/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1C
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C/C(=N/O)c1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
1-(3-Chloro-2-methyl-phenyl)-ethanone (390 mg, 2.3 mmol) was dissolved in ethanol (6 ml) and hydroxylamine hydrochloride (433 μL, 10.4 mmol) was added. The mixture was stirred at 80° C. for 1.5 hours. Reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give (1Z)-1-(3-chloro-2-methylphenyl)ethanone oxime as a yellow oil (383 mg, 2.08 mmol, 90% yield). 1H NMR (400 MHz, CDCl3): 6.95-7.37 (m, 3H), 2.36 (s, 3H), 2.26 (s, 1H), 2.21 (s, 3H); MS (EI) for C9H10ClNO: 184 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>COCCOC>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Yield: 87.2 %

Procedure:
A solution of chloride 206 (100 mg, 0.45 mmol) and N1,N1-dimethylethane-1,2-diamine (0.2 mL, 1.8 mmol) in DME (10 mL) was stirred at reflux temperature for 1 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-8%) of MeOH/DCM to give the 1-oxide 207 (108 mg, 88%) as a yellow solid, mp 163-165° C.; 1H NMR δ 8.09 (t, J=1.4 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 5.83 (br s, 1H, NH), 4.72 (t, J=8.3 Hz, 2H, H-7), 3.52-3.56 (m, 2H, CH2N), 3.31 (dt, J=8.3, 1.4 Hz, 2H, H-8), 2.57 (t, J=8.3 Hz, 2H, CH2N), 2.29 [s, 6H, N(CH3)2]; 13C NMR δ 166.5, 159.3, 151.8, 129.3, 126.4, 116.6, 102.0, 72.9, 57.6, 45.0 (2), 38.6, 28.6. HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461, found 276.1461.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:21]3)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:29][CH2:30][N:31]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:32][CH2:33]2)=[N:21]3)=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
To a solution of N-{2-chloro-5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.23 mmol), triethylamine (0.92 mmol), in dichloromethane (5 ml) was added methanesulfonyl chloride (0.25 mmol), which stirred at 50° C. for 18 hours. The reaction was cooled to ambient temperature, concentrated, redissolved in methanol and purified on reverse phase HPLC (0.1% ammonium hydroxide/water in acetonitrile). The desired fractions were combined and concentrated to give the title compound (7.8 mg, 2%) as a white solid. MS(ES)+ m/e 560.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:22]([CH3:28])([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][Si:22]([CH3:28])([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
8-Acetoxy-2,6-dimethyl-2,6-octadien-1-ol in dimethylformamide (4 ml) was stirred on an ice bath. To the solution were added imidazole (338 mg, 4.96 mmol) and chlorodimethyl t-butylsilane (410 mg, 2.73 mmol), and the mixture was stirred at room temperature for one hour. After addition of water (30 ml) to the reaction mixture, the product was extracted with hexane (20 m1×2). The extract was dried over MgSO4 and evaporated in vacuo to remove the solvent to give a residue, which was subjected to silica gel column chromatography to obtain 1-acetoxy-8-(dimethyl t-butylsilyl)oxy-3,7-dimethyl-2,6-octadiene (606 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nnc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3ccccc3)c2c1
Yield: 46.9 %

Procedure:
Operating as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (0.45 g, 2.81 mmoles) in dry DMF (10 ml), 60% NaH (67 mg, 2.81 mmoles) and 1-chloro-6-methoxy-4-phenyl-phthalazine (0.38 g, 1.4 mmoles), prepared as described in example 14, in DMF (10 ml), 0.26 g of the title compound were obtained (yield: 47.3%). m.p.: 206-208° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][NH:7][C:8]([NH2:10])=[S:9].C(O)C.[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[NH:17][N:16]=1>O>[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=[N:6][NH:7][C:8]([NH2:10])=[S:9])[CH:22]=2)[NH:17][N:16]=1
Reactant: Cc1n[nH]c2ncc(C=O)cc12
Reactant: NNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2ncc(C=NNC(N)=S)cc12
Temperature: 80 °C

Procedure:
Sodium acetate (166 mg, 2.02 mmol), thiosemicarbazide (333 mg, 3.66 mmol), 100 ml ethanol and 2 ml distilled water were charged into a 250 ml round bottom flask. The resulting suspension was heated to 80° C. until it becomes a clear solution. The reaction was then cooled down to room temperature and the resulting mixture was added into a 250 ml round bottom flask containing 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (333 mg, 2.1 mmol). After the addition, the resulting mixture was heated to 80° C. for 16 hours. The mixture was cooled to room temperature and solid was precipitated out. The solid was filtered off and washed with ether (50 ml). The product (500 mg, y=95%) was used directly for the next step without further purification.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.[OH-].[Na+].O>C(Cl)Cl>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:7][C:6]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=Cc2ccc(F)cc2)cc(OC)c1
Reaction time: 5 h

Procedure:
To a solution of (3,5-dimethoxybenzyl)triphenylphosphonium bromide (300 mg, 0.6 mM), 4-fluorobenzaldehyde (133 mg, 1.07 mM), catalytic amounts of 18 crown-6 in DCM was added 1.5 mL of 50% solution of NaOH. The reaction was stirred for 5 h and water was added. The water phase was extracted with ethyl acetate and the organic phase was combined. The crude product was purified through flash chromatography eluting with hexanes/ethyl acetate (98:2).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([OH:26])[CH2:23][NH:24][CH3:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([OH:26])[CH2:23][N:24]([CH3:25])[S:11]([C:10]2[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=3[S:8][CH:9]=2)(=[O:13])=[O:12])=[CH:20][CH:21]=1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: CNC[C@H](O)c1ccc(F)cc1
Product: CN(C[C@H](O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (286 mg) and (1R)-1-(4-fluorophenyl)-2-(methylamino)ethanol (the compound of Preparation Example 40) (212 mg), the title compound (356 mg) was obtained as a colorless solid, in the same way as Preparation Example 41. The NMR data matched the racemic mixture described in Preparation Example 48. The optical purity as measured by high performance liquid chromatography (ChiralPak AD-H, hexane:2-propanol=8:2) was >99% e.e.
Reaction SMILES: F[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Cl:10][C:9]1[C:2]2[S:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc(Cl)c2s1

Procedure:
Using 1.0 g (6.31 mmol) of 2-fluoro-3-chlorobenzaldehyde, 0.38 g (9.46 mmol) of sodium hydride (60% pure) and 0.74 g (6.94 mmol) of methyl mercaptoacetate, 1.04 g (72.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: OCCc1ccc2ccccc2c1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
2-(2-Naphthyl)ethanol (3.44 g., 0.02 mole), 4-benzamidopiperidine (4.08 g., 0.02 mole) and Raney Nickel (W7 ca. 5 g.) were suspended in xylene (200 ml.) and the stirred mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. The mixture was filtered hot and evaporated to ca. 100 ml. The resulting yellow solution was stored until crystallisation was complete. The title compound was obtained as off-white needles (3.30 g.), m.p. 189°-191° C.
Reaction SMILES: [I-].[Li+].COC([C:7]1([CH2:31][CH:32]=[CH2:33])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O>N1C=CC=CC=1.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH2:31][CH:32]=[CH2:33]
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: C=CCC1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Reaction time: 11 h
Yield: 69.9 %

Procedure:
Lithium iodide (11.98 g; 89.44 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-(2-propenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one (9.69 g; 22.36 mmole) in pyridine (40 ml) and water (a few drops). The mixture was refluxed with stirring for 11 hours. The pyridine was vacuum distilled off and the residue was dissolved into methanol and washed with 1N hydrochloric acid (three times), and saturated sodium chloride, and dried (magnesium sulfate). The concentrated residue was black indicating some decomposition occurred. The 9.67 g of this black residue was flash chromatographed (silica gel/3:1-hexane:ethyl acetate, followed by 1:1-hexane/ethyl acetate). Appropriate fractions were combined and concentrated giving 5.87 g of the title compound as a solid.