Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C)c3O2)cc1
Yield: 76.9 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-methylphenyl boronic acid (1.017 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 provided 1.58 g (77%) of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.47 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C22H19FO4S.0.2 C4H8O2: C, 66.46; H, 5.30. Found: C, 66.25; H, 4.98.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(OCC(F)(F)F)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Temperature: 95 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.1 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.071 g), potassium carbonate (0.08 g) and DMF (2 ml) was stirred and heated to 95° C. for 24 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was washed with water and with brine, dried over magnesium sulphate and evaporated The residue was purified by column chromatography on silica using a 45:46:4 mixture of methylene chloride, ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.058 g); NMR Spectrum: (CDCl3) 1.95-2.1 (m, 2H), 2.1-2.3 (m, 2H), 2.32 (s, 3H), 2.3-2.45 (m, 2H), 2.75 (m, 2H), 4.48 (m, 2H), 4.64 (m, 1H), 6.05 (s, 2H), 6.6 (d, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.28 (s, 1H); Mass Spectrum: M+H+ 511 and 513.
Reaction SMILES: [OH:1][C:2]1[CH2:3][CH:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6](=[O:16])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[CH:22]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:22][O:18][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[C:7]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([OH:16])[CH2:5]1)=[O:19]
Reactant: c1ccccc1
Reactant: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1

Procedure:
60 G. of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid, 200 ml. of methanol, 1200 ml. of benzene and 5 g. of p-toluenesulfonic acid were heated together at reflux for 18 hours on a water separator. After cooling, the solution was washed with 500 ml. of a 5% sodium bicarbonate solution, washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column (500 g., activity stage I). After evaporation of the ethyl acetate, there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid methyl ester of melting point 144° C. (from benzene/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)c(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 36.9 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.34042 mmol), 3-Chloro-4-morpholin-4-yl-benzaldehyde (84.5 mg, 0.374 mmol), and Ammonium acetate (52.5 mg, 0.681 mmol) were reacted to produce 62.66 mg (37%) of the title compound. (300 MHz, DMSO-d6) 13.35 (s, 1H), 8.28 (d, J=5 Hz, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.52 (m, 1H), 7.38 (m, 2H), 7.25 (s, 1H), 6.38 (m, 2H), 5.14 (t, J=16 Hz, 8 Hz, 1H), 3.76 (m, 4H), 3.54 (s, 4H), 2.91 (s, 1H), 2.81 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.22 (d, J=9 Hz, 1H), 1.39 (d, J=9 Hz, 1H). MS=466 (M-Cl+), HPLC: 1.76 min. (G Method)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]CC4C=CC=CC=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1CC=CCC=1>CCO.[Pd]>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Reaction time: 3.5 h
Yield: 96.9 %

Procedure:
To a refluxing mixture of cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until the reaction was complete. The mixture was cooled to it, filtered through celite, and washed with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHCl3 (200 mL). The resulting suspension was stirred for 15 min at rt. The solid was filtered, and dried in the air to give cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (34.4 g, 95%, yield).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6].C[S-].[Na+]>CN(C)C(=O)C.O>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1C=O
Agent: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])c(O)cc1O
Temperature: 80 °C

Procedure:
2,4-dimethoxy-5-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N,N-dimethylacetamide and heated at 80° C. for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then acidified with 5% HCl and extracted again with dichloromethane. All of the organic layers are dried over Na2SO4, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-5-nitro-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:7]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(4-chlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (400 mg, 0.86 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (57 mg, 2.59 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 12 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate to give the title compound (250 mg, 0.60 mmol, 69%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (60 grams), the dimethyl acetal of 2-chloroacetaldehyde (25 grams) and sodium carbonate (21.2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150° C. for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 105° C. at 1 mm of Hg pressure.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+]>CN(C=O)C.O>[CH3:22][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Reaction time: 18 h

Procedure:
3-Trifluoromethylbenzyl bromide (50 mmole) and sodium p-toluenesulfinate (65 mmole) were dissolved in 100 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The compound was purified by recrystallization (EtOH). Colorless plates, mp 139°-140°: IR (KBr) 2954, 1614, 1598, 1450, 1332, 1312, 1288, 1164, 1142, 1116, 1074 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.34 (s, 2H), 7.16 (s, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.42 (m, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H); MS m/e 315 (MH+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=C([CH:23]=[CH:24][CH:25]=2)C(O)=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8]>CN(C=O)C.C(Cl)Cl>[CH:7]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[C:1]([CH:23]=[CH:24][CH:25]=2)[C:2]([Cl:4])=[O:3])[CH2:14][CH2:15]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2cccc(C(=O)Cl)c2)CC1

Procedure:
Oxalyl chloride (0.34 ml) was added to a stirred mixture of 3-(N-isopropylpiperidin-4-yloxy)benzoic acid (0.782 g), DMF (2 drops) and methylene chloride (20 ml) which had been cooled in an ice bath. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the 3-(N-isopropylpiperidin-4-yloxy)benzoyl chloride so obtained was dissolved in methylene chloride (20 ml).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:31][CH3:32])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Reaction time: 96 h

Procedure:
12.4 g 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-6-carboxylic acid are suspended in 80 ml of ethanol and 1.6 ml conc. Sulphuric acid are added. The reaction mixture is stirred for 96 hours at reflux temperature. The solid is suction filtered, dissolved in ethanol and made basic with sodium hydroxide solution. 5.3 g product are obtained as a solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:11])[C:8](=[O:10])[CH3:9].[Br:13]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:13][CH2:9][C:8](=[O:10])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])=[O:11]
Reactant: CC(=O)C(=O)c1ccccc1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)C(=O)CBr
Temperature: 70 °C
Yield: 97.6 %

Procedure:
A mixture of 3 g (18.49 mmol) 1-o-Tolyl-propane-1,2-dione and 1.05 ml (20.34 mmol) bromine in 30 ml CHCl3 and 0.53 ml acetic acid was heated to 70° C. for 16 h. The mixture was evaporated under reduced pressure to yield 4.35 g (98%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:22]1([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:14][CH2:13][N:12]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Yield: 74.7 %

Procedure:
5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (375 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol) and Pd(0) (35 mg) were mixed together in toluene (2 mL), and the mixture was heated at reflux for 16 hours. NaHCO3 solution (2%, mL) was added, and the mixture was extracted with CHCl3. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with EtOAc/hexane 1:1 to afford the title compound (280 mg). MS (CI/NH3) m/z 375 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.40 (s, 9H), 2.33-2.43 (m, 2H), 3.29 (t, J=7.5 Hz, 2H), 4.15 (dd, J=2.5, 7.5 Hz, 1H), 4.32-4.42 (m, 1H), 4.48-4.57 (m, 1H), 7.25-7.29 (m, 4H), 7.28 (d, J=2 Hz, 1H), 7.42-7.48 (m, 5H), 8.12 (d, J=3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[C:10]=1[C:11]#[N:12].O>O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: COCCO
Reactant: COc1cc(F)c(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(OC)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to 2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.38 g, 20 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the solution was extracted with dichloromethane (3×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 3:97) to give the title compound (3.8 g).
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH:29]=O)[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[F:9][C:8]1[C:3]([F:2])=[C:4]([CH:29]=[CH:28][CH2:27][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([CH2:11][CH2:12][CH3:13])[CH2:19][CH2:18]3)[CH2:21][CH2:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3cccc(F)c3F)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under nitrogen gas stream, 8.05 g (331 mmol) of magnesium was added to 20.0 ml of THF, and a solution of 58.1 g (301 mmol) of 2,3-difluoro-1-bromobenzene in 600 ml of THF was added by drops thereto so that the reaction temperature was maintained at about 50° C. and then stirred at room temperature for 1 hour. To the reaction solution was added by drops a solution of 70.0 g (251 mmol) of the crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the same manner as in the fifth step of Example 1 in 700 ml of THF, stirred at 50 to 60° C. for 2 hours, and then 200 ml of saturated aqueous ammonium chloride solution was added thereto to terminate the reaction. The reaction mixture was filtered with Celite, the solvent was distilled off under a reduced pressure, and then the residue was extracted with 700 ml of toluene. The organic layer was washed with 400 ml of water thrice and then dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was filtered off, 3.56 g of p-toluenesulfonic acid monohydrate was added to the filtrate, and heated to reflux for 4 hours. The organic layer was washed with 300 ml of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 63.5 g of a crude 2,3-difluoro-4-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butenyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](Cl)=[O:20])[CH:8]=2)[N:3]=1.[CH3:25][C:26]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:27]=1[CH2:28][NH2:29]>C(Cl)Cl.O>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:29][CH2:28][C:27]3[C:26]([CH3:25])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(C)c(CN)c(C)c1
Reactant: CCCN1Cc2cc(Oc3cccc(C(=O)Cl)c3)ccc2N=C1N
Solvent: ClCCl
Solvent: O
Product: CCCN1Cc2cc(Oc3cccc(C(=O)NCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 0 °C

Procedure:
A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoyl chloride (0.0008 mol) in DCM (20 mL) was stirred at 0° C. and 2,4,6-trimethylbenzylamine (0.0013 mol) was added. Then TEA (q.s.) was added, and the reaction mixture was stirred at room temperature. The mixture was stirred in H2O and the organic layer was separated. The remaining layer was washed again with H2O, then the organic layer was separated, dried, and filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected, and the solvent was evaporated. The residue was triturated under diisopropyl ether:CH3CN, and then the resulting solids were filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[C:24]3[C:23](=[CH:22][CH:21]=[C:20]([Br:19])[CH:25]=3)[NH:26][C:8]=2[CH2:7]1)([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:5]
Reactant: NNc1ccc(Br)cc1
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(C)(=O)=O
Agent: Cl
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Br)cc23)C1)S(C)(=O)=O

Procedure:
Analogously to example 1.2, from a racemic mixture of diastereomers of 2-methanesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride were prepared the following 2 racemic diastereomers which could be separated by column chromatography to yield (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester, MS: 414 (MH+,1Br), and (RR,SS)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester, MS: 414 (MH+,1Br).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17](=O)[C:18](=[CH:30]N(C)C)[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:30][C:18]2[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:36]=[CH:35][C:16]=3[C:17]=2[N:5]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
In two equal portions 28 g (150 mmole) of guanidine carbonate and 38 ml (150 mmole) of a 4.09M methanol solution of sodium methoxide was added over a 2 hr period to a solution of 7.0 g (20 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red solid. Recrystallization from a mixture of methanol and ethyl acetate gave the product as fine yellow needles, m.p. 320°-323° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).