Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>CN(C=O)C>[CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=[CH:27][C:28]2[CH:31]=[CH:31][C:28]([CH:27]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:29]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(=CC=O)c2ccc(N(CC)CC)cc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CC)CC)cc3)c3ccc(N(CC)CC)cc3)cc2)c2ccc(N(CC)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
In 100 ml of DMF were dissolved 2.5 g of 3,3-bis(p-diethylaminophenyl)acrolein and 1.5 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and then 0.9 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent:benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.74 g (yield 63.0%) of red crystals having a melting point of 201.5° C. to 204.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
125 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(3,4-dichlorophenyl)piperazine (60 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.Cl[S:24]([OH:27])(=O)=[O:25].[CH3:28][NH:29][CH3:30]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:24](=[O:27])(=[O:25])[N:29]([CH3:30])[CH3:28])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1
Reactant: CNC
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In dichloromethane (10 ml) was dissolved methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g). Under ice-cooling, to the solution was added dropwise chlorosulfonic acid (0.74 ml). The mixture was stirred at room temperature for 30 minutes and, to the mixture was additionally added chlorosulfonic acid (0.37 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added dropwise to 2M dimethylamine solution in methanol (35 ml) under ice-cooling, and the mixture was stirred overnight. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:27][CH2:28][CH3:29])(=[O:26])[C:17]1[CH:25]=[CH:24][C:22](O)=[C:19]([O:20][CH3:21])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:16]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.94 mL) was added to an ice-cooled mixture of ethyl vanillate (1.0 g) and pyridine (0.45 mL) in methylene chloride (5 mL) with stirring. The mixture was stirred for 10 min, and poured into a mixture of 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to afford ethyl 3-methoxy-4-trifluoromethanesulfonyloxybenzoate (1.47 g).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>C(Cl)Cl>[C:9]([NH:16][C@H:17]([C:25]([CH:37]1[CH:38]2[CH2:39][CH:40]3[CH2:41][CH:42]([CH2:43][C:36]1([NH2:35])[CH2:45]3)[CH2:44]2)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere 6.5 ml of isobutylchloroformate is added to 100 ml of a stirred methylene chloride solution containing 2 g of 5A sieves, 13.26 g Boc-phenylalanine, and 5.5 ml of N-methylmorpholine at -50° C. Over a 30 minute period the reaction mixture is warmed to -10° C. and then recooled to -40° C., and 7.94 g of 1-aminoadamantane is added. The cooling bath is removed, and the reaction mixture is stirred at room temperature overnight. The solution is filtered and washed with 50 ml of cold 1 M potassium bisulfate solution followed by washes with 20 ml portions of 2 M potassium carbonate solution and saturated sodium chloride solution. The solution is then dried over sodium sulfate, filtered and concentrated to dryness to give Boc-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR32##
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:55])[CH2:53][NH2:54])([CH3:50])([CH3:49])[CH3:48].O>CN(C)C=O.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>[C:47]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (200 mg) and glycine t-butyl ester hydrochloride (60 mg) in dimethylformamide (3 ml), triethylamine (0.099 ml) and diethyl cyanophosphate (72 ml) were added, followed by stirring at room temperature for 17 hours. After addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium. hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to yield the title compound (206 mg, yield 90%) as a wax-like substance.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([Cl:29])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoic acid (700 mg, 1.99 mmol, 1.00 equiv) in anhydrous DCM (30.0 mL), then oxalyl dichloride (0.7 mL) was added dropwise at room temperature. Two drops of anhydrous DMF were then added. The resulting solution was heated to reflux for 40 min. The solvent was removed under vacuum to yield 750 mg of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoyl chloride as pale yellow oil, which was used directly for the next reaction step without further purification.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([OH:22])(=[O:21])[CH3:19].[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1
Reactant: CCOC(=O)COCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)COCC1CCNCC1
Yield: 201.7 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (1.4 g), ethanol (100 ml), glacial acetic acid (0.25 g), 10% Pd on C (140 mg) and hydrogen gas were reacted to give ethyl piperidin-4-ylmethoxyacetate, acetate salt (1.1 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.12 (2H, m), 1.20 (3H, t), 1.62 (3H, m), 1.84 (3H, s), 2.48 (2H, m), 2.96 (2H, m), 3.29 (2H, d), 4.05 (2H, s), 4.12 (2H, q).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][C@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[Cl:17])[CH:3]=2)[CH2:28][C@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Yield: 22.9 %

Procedure:
Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1,200 mg, 0.756 mmol) and (2R)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 μl, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45° C. for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%–75% ethyl acetate/hexane) to yield 80 mg (23%) of the title compound: mass spectrum (ion spray): m/z=462.4 (M+1); 1H NMR: δ (CDCl3, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[N:15]([CH2:16]C(OCC)=O)[C:14]2[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:13]=2[N:12]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[CH2:32][O:31]CC1.[CH3:33][Mg]Br>O>[Cl:26][C:24]1[C:23]([Cl:27])=[CH:22][C:14]2[N:15]([CH2:16][C:32]([OH:31])([CH3:28])[CH3:33])[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:12][C:13]=2[CH:25]=1
Reactant: CCOC(=O)Cn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Cl)c(Cl)cc21
Reactant: C1CCOC1
Reactant: C[Mg]Br
Solvent: O
Product: CN(Cc1nc2cc(Cl)c(Cl)cc2n1CC(C)(C)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl (2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-5,6-dichloro-1H-benzimidazol-1-yl)acetate (390 mg) and THF (8 mL) was added dropwise methylmagnesium bromide (3 M THF solution, 0.94 mL) at room temperature, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=70/30-40/60) to obtain tert-butyl {[5,6-dichloro-1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate (70 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O=[C:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])=[CH:6]1.C(O)C.[H][H]>[Pd].O>[CH3:1][N:2]([CH:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH3:13])[CH2:6]1)[CH3:3]
Reactant: CNC
Reactant: [H][H]
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC1CC(N(C)C)CC(C)(C)C1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 15.8g of dimethylamine, 32g of isophorone, 2g of 5% Palladium on charcoal and 150cc of ethanol was placed in an autoclave. Hydrogen gas was added to increase the pressure to 500 psi. The reaction mixture was heated to 95° C. and kept with stirring at 95° C. for 1 hr. Hydrogen gas was added during the reaction, to maintain a pressure of 330-500 psi. After the mixture was allowed to cool to ambient temperature, the solvent and the water produced were removed under diminished pressure. Distillation yielded 35g of N,N-dimethyl-3,5,5-trimethylcyclohexylamine; b760 196°-198° C.; nuclear magnetic resonance spectrum, δ in ppm, 2.18 s, 6H; 2.15-1.00 m's, 8H; 1.17 s, 3H; 0.90 s and 0.88 d, 6H.
Reaction SMILES: [O:1]([CH3:3])[Na].C[O:5][C:6](=[O:36])[CH2:7][C@H:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C@H:18]3[C:26]4[C:21](=[C:22]([O:28][C:29]5[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=5)[CH:23]=[CH:24][C:25]=4[F:27])[CH2:20][CH2:19]3)=[CH:16][C:11]=2[O:10][CH2:9]1.[OH-].[Na+]>O1CCCC1.CO>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][C:29]2[N:30]=[N:31][C:32]([O:1][CH3:3])=[CH:33][CH:34]=2)=[C:21]2[C:26]=1[C@H:18]([O:17][C:15]1[CH:14]=[CH:13][C:12]3[C@H:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:9][O:10][C:11]=3[CH:16]=1)[CH2:19][CH2:20]2
Reactant: CO[Na]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(Cl)nn5)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaOCH3 (0.5 mol/L in methanol; 1.3 mL) is added to a solution of {(S)-6-[(R)-4-(6-chloro-pyridazin-3-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester in tetrahydrofuran (3 mL) and methanol (0.1 mL) at room temperature. The solution is stirred at room temperature for 1 h, and then 4 M aqueous NaOH solution (0.21 mL) is added. The solution is stirred for 1 h and is then concentrated. The residue is purified by HPLC (acetonitrile/water/ammonia) to give the title compound. LC (method 2): tR=1.02 min; Mass spectrum (ESI−): m/z=451 [M−H]−.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]=2[CH:18]=1.[CH:19](N1CCOCC1)=[O:20]>CCCCC.C1COCC1.C(OCC)C>[CH:19]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]=2[CH:18]=1)=[O:20]
Reactant: OC1CCCOc2ccc(Br)cc21
Reactant: O=CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1ccc2c(c1)C(O)CCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
254 ml (0.6 mole) of a 1.7 molar solution of tert.-butyllithium in n-pentane is slowly added dropwise under argon to a stirred solution of 48.6 g (0.2 mole) of 7-bromo-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin in 550 ml of absolute THF at -90° C. to -100° C. The mixture is subsequently stirred at -78° C. for 1 hour and then, at this temperature, a solution of 24 ml (0.24 mole) of N-formylmorpholine in 180 ml of absolute THF is added dropwise while stirring vigorously. The mixture is stirred at -78° C. for 1 hour and subsequently allowed to warm to 0° C., and is diluted with diethyl ether and hydrolyzed with ice-water. After extraction several times with diethyl ether, the combined organic extracts are washed with water and saturated brine and dried over sodium sulfate, and the solvent is stripped off in vacuo. 40.7 g of yellowish oil are obtained and reacted further without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[O:8])=[CH:17][CH:16]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N4CCOCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Morpholinocarbonylbenzoic acid (130 mg, 0.54 mmol; described in: J. Med Chem. 1994, 37(26), 4538-4554) was dissolved in thionyl chloride (5 mL). When the acid was dissolved, the excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 160 mg (72%) of the title compound as white crystals: mp 124-127° C.; [α]21D −40° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 462 (2, M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:27][C:28]([NH2:30])=[O:29].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:30][C:28](=[O:29])[NH:27]2)[CH:7]=[C:8]([F:11])[C:9]=1[OH:10]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(O)c(Br)c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(F)c(O)c(Br)c2)N1
Temperature: 95 °C
Yield: 33.7 %

Procedure:
To a mixture of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (Intermediate 77) (600 mg, 2.7 mmol), 1,2-diphenylethanone (538 mg, 2.7 mmol), urea (493 mg, 8.2 mmol) and conc HCl (1 mL) in ethanol (4 mL) was heated at 95° C. for 50 hours. The mixture was evaporated under reduced pressure and was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to give product (400 mg, yield 33%) as yellow solid. 1H NMR (DMSO 300 MHz): δ 10.41 (brs, 1H), 8.66 (s, 1H), 7.45 (s, 1H), 7.24-6.95 (m, 10H), 6.75 (d, J=7.8 Hz, 2H), 5.07 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34]([Cl:37])(=[O:36])[CH3:35].CCOCC>C(Cl)(Cl)Cl>[ClH:37].[C:34]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]2[CH3:24])=[CH:25][CH:26]=1)(=[O:36])[CH3:35]
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(NC(C)=O)cc1)CC2
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A stirred suspension of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride (11.9 g, 0.03 m) in chloroform (300 ml) under nitrogen at 0° C. was treated with triethylamine (3.5 g, 0.035 m) and then after 5 minutes with acetyl chloride (2.75 g, 0.035 m). The mixture was stirred for 1 hour, retreated with 3.5 g triethylamine and 2.75 g acetyl chloride and stirred an additional hour at 0°. Chloroform (50 ml) and then ether (100 ml) were added and the white solid precipitate collected by filtration, 13.9 g. The solid was dissolved in chloroform (250 ml), filtered to remove insoluble salts and the filtrate washed with cold 10% NaOH (200 ml) and cold water (2×200 ml) and dried over MgSO4. The solvent was carefully evaporated under vacuum at 20°. The residue was dissolved in 200 ml CHCl3 /100 ml ether, cooled in an ice-salt bath and slowly acidified with HCl gas. The precipitated solid was collected by filtration and recrystallized as above, filtering under nitrogen to protect the solid product from moisture and vacuum dried at 85° to give 3.8 g of N-(4-acetamidophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride, m.p. 150°-154°.