Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23]C=1>>[CH:24]1([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([N:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:25][CH2:26][CH2:21][CH2:27]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Reactant: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(ccn3CC3CCCC3)c2)CC1
Temperature: 110 °C

Procedure:
A mixture of 21.7 mg (0.08 mmol) (1H-indol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone (intermediate 1), 16 mg (0.16 mmol) cyclopentylmethynol (commercially available), 38.6 mg (0.16 mmol) cyanomethylenetri-n-butylphospborane in toluene was heated to 110° C. for an extended period of time. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 5.4 mg of the title compound. MS (m/e): 354.4 (MH+).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1>C(Cl)(Cl)(Cl)Cl>[Br:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[CH:28]=[O:7]
Reactant: Cc1ccc(-c2cnco2)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cnco2)c(Br)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 10.9 %

Procedure:
N-Bromosuccinimide (2.36 g) and 2,2′-azobis(2-methylpropionitrile) (164 mg) were added to a solution (100 mL) of 5-(2-bromo-4-methylphenyl)-1,3-oxazole (2.6 g) in carbon tetrachloride, and the mixture was refluxed under heating for 2.5 hours. Insoluble matter was removed through filtration, followed by purification, to thereby yield 5-[2-bromo-4-(bromomethyl)phenyl]-1,3-oxazole (3.2 g). Acetic acid (190 mg) and sodium hydrogencarbonate (336 mg) were added to a solution (50 mL) of the thus-obtained 5-[2-bromo-4-(bromomethyl)phenyl]-1,3-oxazole (500 mg) in anhydrous N,N-dimethylformamide, and the mixture was stirred at room temperature for 23 hours. The solvent was evaporated, and the residue was purified, to thereby yield 3-bromo-4-(1,3-oxazol-5-yl)benzyl acetate (300 mg). This procedure was repeated. 2N Aqueous sodium hydroxide solution (5 mL) was added to a solution (50 mL) of the thus-obtained 3-bromo-4-(1,3-oxazol-5-yl)benzyl acetate (490 mg) in methanol, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified, to thereby yield [3-bromo-4-(1,3-oxazol-5-yl)phenyl]methanol (350 mg). Manganese dioxide (672 mg) was added to a solution (50 mL) of the thus-obtained [3-bromo-4-(1,3-oxazol-5-yl)phenyl]methanol (350 mg) in chloroform, and the mixture was refluxed under heating for 20 hours. Insoluble matter was removed through filtration by use of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (dichloromethane), followed by concentration, to thereby yield the title compound (300 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:14](Br)[CH2:15][CH:16]=[CH2:17].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:17]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[CH2:16][CH:15]=[CH2:14]
Reactant: O=C1CCCCC1
Reactant: C=CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCC1CCCCC1=O
Temperature: 0 °C

Procedure:
EX-18a) A suspension of potassium t-butoxide in toluene cooled to 0° C. in an ice bath under N2 is treated with cyclohexanone. To the reaction mixture is slowly added 3-butenyl bromide. The reaction is warmed to room temperature. The reaction is then poured into EtOAc and washed once with 10% potassium hydrogen sulfate. The organic solution is then washed with brine, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to afford 2-(3-butenyl) cyclohexanone.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>[N+](C1C=CC=CC=1)([O-])=O>[C:18]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Into a 250 ml round-bottom flask equipped with magnetic stirrer, condenser, heating mantle and nitrogen blanket, were placed 10.0 g of 1-aminoanthraquinone, 80 ml of nitrobenzene and 6.5 g of n-heptanoyl chloride. The solution was refluxed for 2.5 hours and cooled. Crude product was precipitated with methanol, filtered and dried. Chromatography on silica gel with toluene eluent afforded yellow 1-n-heptanoylaminoanthraquinone, melting at 133° C.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH2:7](Br)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO.[Na+].[I-]>[CH2:7]([N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1cn[nH]c1
Reactant: BrCCc1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: c1ccc(CCn2cccn2)cc1
Temperature: 50 °C
Yield: 24.7 %

Procedure:
To a solution prepared by dissolving sodium (1.01 g, 44.07 mmol) in absolute EtOH (25 mL), was added 1H-pyrazole (2.5 g, 36.72 mmol). The solution was heated to gentle reflux, then allowed to cool to about 50° C. and treated with a catalytic amount of NaI (25 mg) followed by a slow addition of phenethyl bromide (6.0 mL, 44.07 mmol). The reaction was returned to reflux and after a few min, a white solid precipitated out of solution. After refluxing for 16 h, the solvent was removed by evaporation and the residue dissolved in water (30 mL) and extracted with EtOAc (4×50 mL). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (Isco CombiFlash) 0-20% EtOAc/heptane to afford 1-phenethyl-1H-pyrazole (1.56 g, 25%). 1H NMR (400 MHz, CDCl3) δ ppm 3.18 (t, J=7.28 Hz, 2H), 4.34-4.39 (m, 2H), 6.18 (t, J=2.06 Hz, 1H), 7.07-7.11 (m, 2H), 7.17 (d, J=2.20 Hz, 1H), 7.20-7.31 (m, 3H), 7.55 (d, J=1.74 Hz, 1H); LCMS-MS (ESI+) 172.86 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=439.2, tR (minutes, Method D)=0.84
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[N:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]1[O:21][CH2:20][CH:19]([C@H:28]3[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]3)[NH:18][C:17]2=1>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[N:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]1[O:21][CH2:20][CH:19]([C@H:28]3[CH2:33][CH2:32][C@H:31]([N:34]4[C:1](=[O:11])[C:2]5[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:4]4=[O:6])[CH2:30][CH2:29]3)[NH:18][C:17]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3

Procedure:
Phthalic anhydride (200 mg, 1.34 mmol, 2.53 eq) is added at room temperature to a stirred solution of trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine (200 mg, 0.53 mmol, 1.0 eq) in pyridine (4 mL). The reaction mixture is heated to reflux for 3 hours, pyridine is then removed and acetic anhydride (1 mL) is added. The resulting mixture is heated to reflux for 2 hours, then extracted with ethyl acetate (3×10 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 2-[trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as a light brown semisolid (190 mg, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].Cl>C1(C)C=CC=CC=1.O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CNCCO1
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCO[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a mixture of (2R)-2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (25 g, 90.3 mmol) and acetonitrile (125 ml), triethylamine (27.4 g, 271 mmol) was added under a nitrogen stream, the resulting mixture was cooled to 0-5° C., then a solution of 3,4,5-trimethoxybenzoyl chloride (21.24 g, 92.1 mmol) in toluene (100 ml) was further added dropwise at below 10° C., and then the mixture was stirred at 0-5° C. for one hour. After completion of the reaction, toluene (150 ml), water (125 ml) and concentrated hydrochloric acid (25 ml) were added to the reaction mixture, and the resulting mixture was partitioned. The separated organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and concentrated to afford (2R)-2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol (44.4 g) as an oil.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](I)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH:26]1[CH2:30][CH2:29][CH2:28][CH:27]=1.C([O-])(=O)C.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O.CC(O)=O.[Pd].CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:26]3[CH2:30][CH2:29][CH2:28][CH:27]=3)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: C1=CCCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Temperature: 62.5 °C
Yield: 81.2 %

Procedure:
Add to a 2-L 3-neck round bottom flask equipped with overhead stirrer, N2 line, and temperature probe 4-(3-Iodo-indole-1-sulfonyl)-benzoic acid methyl ester (69.0 g, 0.156 mol) and anhydrous DMF (700 mL). Add to the stirring solution at room temperature cyclopentene (138.0 mL, 1.57 mol), palladium II acetate (1.8 g, 8.0 mmol), tetrabutylammonium chloride (43.5 g, 0.156 mol), and potassium acetate (46.0 g, 0.469 mol). Warm the resulting dark mixture at 60-65° C. for 16 h. Cool the reaction mixture filter through celite, and back-wash with ethyl acetate (1 L). Partition the solution with 2×1 L of brine, dry the organic layer over sodium sulfate, and chromatograph over flash silica gel (10% ethyl acetate in hexanes gradually increasing to 20% ethyl acetate in hexanes) to provide pure title compound (48.3 g, 81%); MS(ESI) m/z 382 (m+H); 1H NMR (DMSO-d6) reveals the material to actually be a mixture of olefinic 3-substituted cyclopentene indoles (approx. 1:1, with olefinic H's at 5.8, 5.9, and 6.0 ppm integrating to 1H each), suitable as such for subsequent hydrogenation.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C@H:24]([C:32]([NH:34][CH2:35][C:36]([NH:38][C@H:39]([C:41]([OH:43])=O)[CH3:40])=[O:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:44][C@H:45]([CH2:50][OH:51])[CH2:46][CH:47]([CH3:49])[CH3:48].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:23][C@H:24]([C:32]([NH:34][CH2:35][C:36]([NH:38][C@H:39]([C:41]([NH:44][C@H:45]([CH:50]=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:40])=[O:37])=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H](NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
29.9 g (70.7 mol) of Dess-Martin periodinane was suspended in 500 ml CH2Cl2 and stirred for 10 min. Moc-Phe-Gly-Ala-Leucinol (10.6 g, 23.5 mol) was dissolved in 100 ml CH2Cl2 and added at a moderate rate to the periodinane slurry. The mixture was stirred for 1h and poured into 150 ml NaHCO3 containing 123 g Na2S2 O3. The mixture was allowed to stir for 15 min and extracted with EtOAc. The organic phase was dried and filtered followed by removal of solvent. Chromatography (3.5% MeOH/CH2Cl2) on silica gave 5.1 g of pure white solid that is a mixture of the methoxy hemiacetal and aldehyde. 13C NMR (CDCl3,CD3OD) 17.62, 17.94, 21.53, 21.71, 22.99, 23.30, 23.39, 24.54, 37.05, 37.70, 37.92, 38.24, 42.87, 49.83, 51.79, 52.14, 52.40, 56.75, 57.19, 98.40, 99.18, 127.00, 128.60, 129.06, 136.44, 157.27, 169.19, 169.67, 172.73, 173.40, 200.43.
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:6]([CH3:13])(=[O:12])[O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:5])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]([P:6]([CH3:13])(=[O:12])[O:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)C(C)CC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)C(C)CCN

Procedure:
A solution of 29.8 g of isobutyl P-(3-cyanoprop-2-yl)-P-methyl-phosphinate in 200 ml of ethanol is added to 310.0 g of an 8% solution of ammonia in ethanol. To this are added 20 ml of Raney nickel slurry, and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is distilled under reduced pressure to give isobutyl P-(4-aminobut-2-yl)-P-methyl-phosphinate, b.p. 100°/0.1 mbar, 31P-NMR spectrum: δ=+58.9 and +58.4 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15](C(OCC(Cl)(Cl)Cl)=O)[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C2CC3CCC(N3)C2OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A suspension of 1.14 g (2.06 mmol) of 2,2,2-trichloroethyl (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate and 400 mg of zinc in 10 ml of acetic acid was stirred at room temperature for 12 hours. The reaction solution was diluted with 50 ml of water and extracted four times with 40 ml of methylene chloride. The organic phase was washed twice with 50 ml of 1N sodium hydroxide solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent. There was obtained 0.480 g (61% of theory) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane of m.p. 184-185°; MS: 379 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]#[N:15])[CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, (cis-3-cyanomethyl-cyclopentyl)-carbamic acid tert-butyl ester (188 mg, 0.84 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (2.0 ml, 26.0 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to afford (cis-3-amino-cyclopentyl)-acetonitrile trifluoroacetate as a yellow oil which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:22]>>[BrH:22].[OH:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C2CNCc3c(C)cccc32)cc1OC
Agent: Br
Product: Cc1cccc2c1CNCC2c1ccc(O)c(O)c1
Reaction time: 0.17 h

Procedure:
To 420 mg of 4-(3,4-dimethoxyphenyl)-8-methyl-1,-2,3,4-tetrahydroisoquinoline, was added 48% hydrobromic acid, and the mixture was heated under reflux for 3 hours. After about 10 minutes, the crystals become separated out. The reaction mixture was cooled, and the crystals were collected by filtration, giving 420 mg of 4-(3,4-dihydroxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[ClH:31].[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:40]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCN(C)C)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.2 %

Procedure:
Tolvaptan (1.0 g, 2.2 mmol), 4-dimethylamino-butyric acid hydrochloride (0.48 g, 2.9 mmol), and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were suspended in dichloromethane (5 ml). Triethylamine (0.4 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.55 g, 2.9 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=50:50→0:100). The purified product was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate, a 4N hydrogen chloride ethyl acetate solution was added thereto, and the resultant mixture was concentrated under reduced pressure. To the residue was added water (10 ml). After filtration, the filtrate was freeze-dried to obtain 0.91 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-dimethylaminobutyrate hydrochloride as white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1.O=O.O.C([O:25]C)(C)(C)C>C(O)(=O)C>[CH3:17][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[C:4](=[O:25])[CH2:3]1
Reactant: CCCCOc1cc2c(cc1C)CCC2(C)C
Reactant: COC(C)(C)C
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1cc2c(cc1C)C(=O)CC2(C)C
Temperature: 40 °C
Yield: 75.5 %

Procedure:
100 g 3,3,6-trimethyl-5-butoxy-indane are dissolved in 400 g acetic acid and 1 g Co-II acetate is added. The reaction mixture is heated to 40° C., with stirring, and oxygen is passed through this solution for 10 hours. After cooling to room temperature, 500 g water and 500 g methyl tert.-butyl ether are added. After phase separation, the organic phase is rinsed with a further 200 g water and distilled in a 30 cm packed column. 80 g 3,3,6-trimethyl-5-butoxy-indan-1-one is obtained, which corresponds to a yield of 75% of theory. The compound can be recrystallised from heptane and a white solid is obtained, melting point: 59° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[Li].[CH:11](=[N:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:11]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [Li]c1nc2ccccc2s1
Reactant: C(=Nc1ccncc1)c1ccccc1
Product: c1ccc(C(Nc2ccncc2)c2nc3ccccc3s2)cc1

Procedure:
The title compound is prepared in a manner similar to Examples 5, 6 and 7 by reacting 2-benzthiazolyl lithium (formed by treating benzothiazole with butyl lithium) and 4-benzylideneaminopyridine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:23]1([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1>CN(C)C=O.O>[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:32](=[O:34])[CH2:31][CH2:30][CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1
Reactant: O=C(O)CCCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and 1-hydroxybenzotriazole (0.13 g) in N,N-dimethylformamide (5 mL) was added 0.12 g of 4-phenylbutyric acid at 0° C. and the mixture was stirred at that temperature for 5 minutes and further at room temperature for 2 hours. This reaction mixture was added to a solution of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine (0.20 g) in N,N-dimethylformamide (2 mL) at 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:2) to provide 0.22 g of the title compound. Yield 74%.