Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:28][CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][OH:39])[CH2:34][CH2:33]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:11]([O:28][CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[O:39])[CH2:34][CH2:33]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](OCCOC1CCC(CO)CC1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OCCOC1CCC(C=O)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
553.7 mg (4.36 mmol) of oxalyl chloride are dissolved in 25 ml of dichloromethane and cooled to −78° C. 681.6 mg (8.72 mmol) of dimethyl sulfoxide are added slowly. A solution of 1.20 g (2.91 mmol) of the compound from Example 4A in 10 ml of dichloromethane is then added dropwise. The mixture is stirred at −78° C. for 1 h. 2.0 ml (14.54 mmol) of triethylamine are then added, and the mixture is allowed to warm to RT over a period of 1 h. The mixture is then added to 20 ml of a 1:1 mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. After separation of the phases the aqueous phase is extracted two more times with in each case 10 ml of ethyl acetate. The combined organic phases are freed from the solvent on a rotary evaporator. The residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→5:1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:9]1[NH:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: Cc1cnc(-c2ccc[nH]2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(Br)[nH]2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Methyl-2-(1H-pyrrol-2-yl)-1,3-thiazole (100 mg, 0.61 mmol) synthesized in Example (3c) was dissolved in tetrahydrofuran (7 mL), and cooled to 0° C. N-Bromosuccinimide (108 mg, 0.61 mmol) was added, and stirring was carried out at room temperature for 18 hours under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used as it is in the next reaction.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]([C:24](=[O:26])[CH3:25])=[N:16][C:17]=2[CH:22]=1
Reactant: CC(=O)c1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1nc2cc(C)ccc2n1C1CCNCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(2-acetyl-5-methyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (107 mg, 0.30 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and CH2Cl2 (2 mL) at rt and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between dilute aqueous K2CO3 solution (20 mL) and CH2Cl2 (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(5-methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-ethanone as an oil (77 mg, 0.30 mmol, 100%) that was used without further purification or characterization.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C=O)C>[CH2:22]([NH:29][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Benzylamine (268 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2 and the combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (105 mg, 73%). NMR 1H (ppm, CDCl3): 8.01 (s, 1H), 7.72 (t, J3=7.89 Hz, 2H), 7.58 (d, J3=7.14 Hz, 2H), 7.49-7.24 (m, 9H), 6.57 (br. s., 1H), 4.64 (d, J3=5.29 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27]CCCCC)=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=3[OH:15])[N:8]=[C:4]2[CH:3]=1.S(=O)(=O)(O)O>C(O)C=C>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]=3[OH:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: C=CCO
Product: C=CCOC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 90 %

Procedure:
220 g (0.45 mol) of octyl 3-(5-chloro-2H-benzotriazole-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-benzene propanate manufactured by CIBA GEIGY INC. under the trade name of "TINUVIN 109" were dissolved in 500 ml of allyl alcohol, and was admixed with 5 ml of concentrated sulfuric acid. The resulting solution was refluxed for five hours. After cooling, a precipitated product was filtered off. The resulting solid substance was dissolved in 300 ml of methylene chloride, washed with a saturated aqueous solution of NaHCO3 and dried over magnesium sulfate. After filtration, the solvent was distilled off and the resulting solid substance was recrystallized from hexane to produce allyl 3-(5-chloro-2H-benzotriazole-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-benzene propanate, referred to hereinafter as a precursor (4) at a yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>CN(C)C(=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:21]
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (1.00 g, 3.92 mmol) was dissolved in 6 ml of N,N-dimethylacetamide giving a clear brown solution. After cooling to 5° C., neat 2-chlorobenzoyl chloride (0.80 g, 4.34 mmol) was added over 1 minute. The solution was warmed to room temperature and stirred for 4 hours. Addition of water (15 ml) caused white precipitate to come out of solution. The mixture was stirred for an additional 30 minutes at room temperature, then the precipitate was collected by vacuum filtration, rinsing with H2O and then hexanes. The solid was further dried under vacuum to give I-(4A-7)a as a colorless solid (1.27 g, 82%): +ACPI MS (M+1) 393.1; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.11 (s, 1H), 8.40 (s, 1H), 7.93 (dd, J=7.4, 1.6 Hz, 1H), 7.66–7.40 (m, 7H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Na+]>CO>[Br:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ncccc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
3-Bromo-pyridine-2-carboxylic acid methyl ester (12.8 g, 59.2 mmol) is dissolved in methanol (150 mL) and cooled to 0° C. To the mixture is added NaBH4 (11.2 g, 296 mmol) in 1.0 g portions. The mixture is warmed to room temperature and stirred for 3 h. The methanol is removed under reduced pressure, AcOEt is added and the solution is washed with saturated, aqueous ammonium chloride and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure to yield 6.8 g (62%) of the title compound as a white solid. GCMS m/e 187 [M−H]−.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([O:33]CC)=[O:32].Cl.[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O.C(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cc(C)nc2OC)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(=O)O)cnn2[C@H]2CCOC2)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 122.6 %

Procedure:
A 5 N aqueous sodium hydroxide solution (0.8 mL) was added to a solution of ethyl 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (397 mg) in ethanol (5 mL), and the reaction mixture was stirred at 70° C. for 1 hour. After cooling the reaction mixture to room temperature, chloroform and brine were added, and the mixture was adjusted to pH 6 with 5 N hydrochloric acid and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrates was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid (457 mg) as a crude. CDI (211 mg) was added to a solution of the carboxylic acid (457 mg) in DMF (6 mL), and the reaction mixture was stirred at room temperature. After 75 minutes, a 28% aqueous ammonia solution (0.88 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the precipitated solid was removed by filtration and washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/n-heptane, 60% to 80% to 85%) to give title compound (199 mg). This title compound was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:17])[CH3:16].NC1C=CC(C2C=CC=C(Cl)C=2)=CC=1[C:39](=[O:41])C.C([Mg]Br)C1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:18]([C:15]1([CH3:16])[O:17][C:39](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(O)(Cc1ccccc1)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: Br[Mg]Cc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure described previously, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry TRF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4 -dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H), MS (ESI) m/z 364 ([M+H]+,100%), Anal. Calc. For C22H18CINO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N,3.58.
Reaction SMILES: O=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.O.[CH3:24][NH:25][C:26](=[S:29])[NH:27][NH2:28]>CO>[CH3:24][NH:25][C:26]([NH:27][N:28]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])=[S:29]
Reactant: O=C(Nc1ccccc1)OCCCC(=O)c1ccccc1
Reactant: CNC(=S)NN
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=S)NN=C(CCCOC(=O)Nc1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 83.9 %

Procedure:
Phenyl-carbamic acid 4-oxo-4-phenyl-butyl ester (2.80 g, 9.88 mmol), prepared in the previous step, was suspended in 60 ml of methanol and the mixture warmed to dissolve the solid. While still warm 2.7 ml of 1 N HCl, 2.7 ml of water and 4-methyl-3-thiosemicarbazide (1.04 g, 9.92 mmol) were added and the reaction stirred under nitrogen for 21 hours. The solid formed was removed by filtration and dried under high vacuum to give the title compound (3.07 g, 84%) as a white solid, mp 155-157° C.
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:2][C:1]1[O:3][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCCCCC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCc1cc(C(=O)OCC)c(C)o1
Yield: 68.9 %

Procedure:
A mixture of 4.33 g (0.02 mole) ethyl 2-acetyl-2-nonenoate and 3.57 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 12 hours. After cooling, the succinimide was removed by filtration and the solution concentrated in vacuo. Distillation of the crude product gave 3.09 g (69%) of ethyl 2-methyl-5-pentyl-3-furoate, bp 115°-119° C. (1.3 mm).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2/[CH:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2/[CH:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(/C=C/c2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: Fc1ccc(C2CCNCC2/C=C/c2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), by cleaving off the BOC group using hydrogen chloride in methanol from tert-butyl (E)-(3RS,4SR)-4-(4-fluoro-phenyl)-3-(2-naphthalen-2-yl-vinyl)-piperidine-1-carboxylate there was obtained (E)-(3RS,4SR)-4-(4-fluoro-phenyl)-3-(2-naphthalen-2-yl-vinyl)-piperidine as a pale yellow oil; MS: 331 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([I:10])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:26](=[O:27])[C:25]2[CH:24]=[C:23]([C:22]([F:37])([F:36])[F:21])[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=2)=[C:4]([I:10])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1I
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (300 mg, 1.12 mmol, prepared according to WO2006013050) in THF (3 mL) was added dropwise at −78° C. lithium bis(trimethylsilyl)amide (1M solution in THF, 1.17 mL, 1.17 mmol). The reaction mixture was stirred at −78° C. for 30 minutes. Then, 3,5-bis(trifluoromethyl)benzoyl chloride (340 mg, 1.23 mmol, CAS RN 1271-19-8) was added at −78° C. and the reaction was stirred for 30 minutes at this temperature. The reaction mixture was allowed to warm to room temperature, stirred for another 1 hour and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless solid (328 mg, 57.7%). MS (TurboSpray): m/z=508.0 [M+H]+.
Reaction SMILES: [N:1]#[C:2]Cl.[CH:4]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]([N:9]1[C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH:12]=[CH:13][C:14]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]1=2)#[N:1]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: N#CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#CN1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6 g of cyanogen chloride are introduced within 1 hour into a solution, heated to 80°, of 9.64 g of 5H-dibenz[b,f]azepine and 1 g of benzyltriethylammonium chloride in 40 ml of toluene. The reaction mixture is stirred for a further 5 hours at 80°; it is then cooled to room temperature and washed with 40 ml of 2 N sodium hydroxide solution; the organic phase is separated, and is then evaporated to dryness in vacuo to obtain 5-cyano-5H-dibenz[b,f]azepine, which is identical to the product obtainable according to Example 1; m.p. 107°-108°; yield 6.2 g (56.9% of theory).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.CN1C(=O)CCC1.CCOCC>[CH2:23]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC[Mg]Br
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc2c(C(=O)OC)cccc2c1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In accordance with the procedure of Furstner (Angew. Chem. Int. Ed., 2002, 41, 609-612), a solution of methyl 6-(((trifluoromethyl)sulfonyl)oxy)-1-naphthoate (334 mg, 1.0 mmol) and Fe(acac)3 in THF (6 mL) and NMP (0.56 mL) was treated with n-hexylmagnesium bromide (1.2 mL of a 2.0 M solution in Et2O, 2.4 mmol) at room temperature. After 30 min, the mixture was diluted with Et2O (20 mL) and quenched with 1 N aqueous HCl (5 mL). The phases were separated and the organic phase was washed with water (2×15 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 40 g silica gel (100% hexanes→20% EtOAc/hexanes, gradient) to afford 206 mg (76%) of methyl 6-hexyl-1-naphthoate.
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.Cl.[NH2:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[C:21]([O:23][CH3:24])=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
4-Chlorobenzenesulfonylchloride (3.17 g, 15 mmol) was added to a mixture of cis-methyl 2-aminocycloheptanecarboxylate hydrochloride 2.08 g, 10 mmol) and triethylamine (4.2 mL, 30 mmol) and stirred at room temperature for 4 h. The reaction was partitioned between 100 mL diethyl ether and 100 mL water. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on 120 g silica gel with 0 to 30% ethyl acetate in hexane to yield cis-methyl 2-(4-chlorophenylsulfonamido)cycloheptanecarboxylate (3.15 g, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 7.78-7.81 (1H, m), 7.74-7.78 (1H, m), 7.46-7.48 (1H, m), 7.42-7.46 (1H, m), 5.33 (1H, d, J=9.57 Hz), 3.59 (3H, s), 3.53 (1H, tt, J=9.57, 4.03 Hz), 2.80 (1H, dt, J=8.06, 4.03 Hz), 1.76-1.92 (2H, m), 1.44-1.75 (6H, m), 1.25-1.41 (2H, m). LC/MS R.T.=2.65 min; [M+H]+=346.10; [M+Na]+=368.07; [M−H]−=344.04.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=O)=[C:8]([CH3:20])[C:7]([O:21][CH3:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O>N1C=CC=CC=1>[OH:3][C:1]1[C:4]2[C:9](=[C:8]([CH3:20])[C:7]([O:21][CH3:22])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:2]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1C
Temperature: 150 °C
Yield: 95 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)-amide (96) in pyridine (15 mL) was added 2.5 equivalent of freshly grounded KOH along with water (200 μL). The mixture was heated by microwave irradiation at 150° C. for 30 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give the title compound (1.8 g, 95%): m/z=299 (M+H)+.