Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.C(N(CC)CC)C.[CH3:40][CH:41]([CH3:47])[CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][NH:18][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:43]([CH2:42][CH:41]([CH3:47])[CH3:40])(=[O:45])=[O:44])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A solution of N-[2-(aminomethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-yl]-N-(2,2-diphenylethyl)amine (3.70 g, 8.63 mmol) (Preparation 6) and triethylamine (2.20 g, 21.78 mmol) in dry dichloromethane (20 ml) was treated with 2-methyl-1-propanesulfonyl chloride (1.48 g, 9.46 mmol) and the mixture was stirred at room temperature for 18 hours. TLC indicated that some starting material still remained and so further 2-methyl-1-propanesulfonyl chloride (0.2 g, 1.28 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) to afford the title compound as a foam (4.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[NH3:26]>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Methyl 2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate (130 mg, 0.24 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 110 mg 2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 88%. 1HNMR (400 MHz, DMSO-d6): δ7.52-7.54 (t, J=6.0 Hz, 1H), 7.56-7.59 (m, 1H), 7.77-7.80 (t, J=6.0 Hz, 1H), 7.86-7.88 (dd, J=6.4 Hz, 0.8 Hz, 1H), 7.92 (brs, 1H), 7.98 (brs, 1H), 8.00-8.03 (m, 2H), 8.22-8.24 (m, 1H), 8.36-8.38 (d, J=6.4 Hz, 1H), 8.61 (s, 1H), 8.65-8.67 (m, 1H), 9.03-9.04 (d, J=1.6 Hz, 1H). LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:7][N+:8]1[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:12]=2[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[N:9]=1)[CH2:18][CH2:17][CH2:16]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:23][CH2:22][CH2:21][C:10]2[N:9]=[N+:8]([O-:7])[C:13]3[CH:14]=[C:15]4[C:19]([CH2:18][CH2:17][CH2:16]4)=[CH:20][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Piperidine (3.0 g, 35 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 86 (1.33 g, 69%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.09-3.15 (m, 4H, H-6, H-8), 3.02-3.07 (m, 2H, CH2), 2.82-2.95 (m, 6H, 3×CH2), 2.27-2.38 (m, 2H, CH2), 2.17-2.26 (m, 2H, H-7), 1.76-1.87 (m, 4H, 2×CH2), 1.50-1.60 (m, 2H, CH2); 13C NMR δ 164.3, 155.0, 149.2, 147.4, 132.3, 122.7, 114.2, 57.1, 53.5 (2), 34.3, 33.2, 32.8, 25.7 (2), 23.7, 22.9, 22.6; HRMS (FAB+) calcd for C18H25N4O (MH+) m/z 313.2025, found 313.2025.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
A mixture of dimethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (3.0 g, 14 mmol) and 5% Pd—C (0.4 g) in ethyl acetate (70 mL) was hydrogenated under 50 psi hydrogen for 20 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacuo, providing 2.6 g, in quantitative yield; 1H NMR (CDCl3) δ 2.32 (s, 6H), 2.69 (t, J=5.8 Hz, 2H), 3.99 (t, J=5.8 Hz, 2H), 6.00-6.66 (m, 2H), 6.73-6.78 (m, 2H).
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][CH:13]([CH3:17])[C:14](=[O:16])C>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:14](=[O:16])[CH:13]([CH3:17])[CH3:12])[CH3:10]
Reactant: CC(=O)C(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
Sodium pellets (3.39 g, 148 mmol) were dissolved in ethanol (100 ml) under nitrogen at room temperature and a solution of diethyloxalate (20 ml, 147 mmol) in 3-methyl-2-butanone (18.9 ml, 177 mmol) was added dropwise at room temperature over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane:ethyl acetate (99:1 changing to 95:5, by volume) to give 4-methyl-3-oxo-pentanoic acid ethyl ester (23.8 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.80 (1H, brs), 6.40 (1H, s), 4.30-4.39 (2H, quart), 260-2.71 (1H, quin), 1.35-1.40 (3H, t), 1.15-1.20 (6H, d) ppm. LRMS (electrospray): m/z [M−H]+ 185.
Reaction SMILES: [C:1]1([CH:7]([OH:12])[CH2:8][CH2:9][NH:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.CN1CCCC1=O.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:11][NH:10][CH2:9][CH2:8][CH:7]([O:12][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNCCC(O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Yield: 85 %

Procedure:
An improved process for the preparation in a superior yield of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of formula (I), ##STR5## or a pharmaceutically acceptable acid addition salt thereof, the said process comprising catalytically hydrogenating 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base of formula (II), ##STR6## to obtain 1-phenyl-3-(N-methylamino)-propan-1-ol of formula (III), ##STR7## and selectively etherifying the compound of formula (III) with 1-chloro-4-trifluoromethylbenzene of formula (IV), ##STR8## in a solvent selected from the group consisting of N-methylpyrrolidone and dimethylsulfoxide in the presence of a potassium t-butoxide, whereby N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine is formed in a yield greater than 85 percent of the theoretical value.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@H:11]([OH:29])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N+:25]([O-])=O)[CH:19]=3)[C:13]2=[O:28])=[CH:5][CH:4]=1)#[N:2]>C(O)(C)=O.O.[Fe]>[NH2:25][C:20]1[CH:19]=[C:18]([N:14]2[CH2:15][CH2:16][O:17][C@H:12]([C@@H:11]([OH:29])[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:30])[C:13]2=[O:28])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of compound 9-4 (70 mg) in AcOH—H2O (2 mL-0.1 mL), was added electrolytic iron powder (95.3 mg). The reaction mixture was stirred at room temperature for 1 hour then at 40° C. for 2 hours to complete the reaction. The reaction mixture was filtered with Celite® pad to remove iron powder. The filtrate was concentrated in vacuo. The resulting residue was purified by amino-silica gel flash column chromatography (eluent: CH2Cl2/MeOH=98/2-95/5) to obtain compound 9-5 (30 mg) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl methyl(piperidin-3-yl)carbamate (1.00 g, 4.67 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.03 g, 99%) as a yellow solid. ESI MS m/z 337 [C16H24N4O4+H]+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[K+].[Br-]>C(O)C>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][C:24]4[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=4[Cl:22])[CH2:31][CH2:30]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2c(F)cccc2Cl)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chloro-6-fluorobenzyl)piperazine. White crystals, m.p. 204–205° C. (from ethanol); HPLC-MS m/z=510 (M+H); IR (KBr): ν 1726 (C═O) cm−1;
Reaction SMILES: [N:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O.CO.Cl>[N:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate (2.5 g, 7.5 mmol) was added to a solution of sodium hydroxide (1.8 g, 45 mmol) in water (30 mL) and methanol (10 mL). The mixture was heated on a steam bath until all of the ester dissolved. Heating was continued for an additional 15 minutes and then the solution was diluted with an equal volume of water and neutralized with hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 1.9 g of crude product. This material was recrystallized from N,N-dimethylformamide to provide 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid. Analysis: Calculated for C19H19N3O2: % C, 71.01; % H, 5.96; % N, 13.07. Found: % C, 70.01; % H, 6.14; % N, 13.32.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC(OC2C=CC(OC(C)C(O)=O)=CC=2)=CC=1.S(Cl)(Cl)=O.[CH3:45][NH2:46]>C1C=CC=CC=1>[CH3:45][NH:46][C:13](=[O:14])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Reactant: CN
Agent: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
32 Grams of 4-(4-chlorophenoxy)-α-phenoxy-propionic acid chloride, prepared from 4-(4-chlorophenoxy)-α-phenoxypropionic acid (Example 5) and thionyl chloride, were dissolved in 150 ml of benzene and 7 grams of methyl amine were introduced at 15°C into the solution obtained. To complete the reaction the solution was stirred for 1 hour at 30°C, the precipitate formed was filtered off with suction, the benzenic solution was washed with water, dried over Na2SO4 and concentrated. The isolated crystals were recrystallized from petroleum ether. 28 Grams of 4-(4-chlorophenoxy)-α-phenoxypropionic acid methyl amide melting at 117° - 118°C were obtained. ##SPC6##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>C(#N)C>[CH2:34]([N:31]1[C:32]2[N:33]=[C:14]([CH2:13][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[N:8][CH:7]=3)[NH:26][C:27]=2[C:28](=[O:40])[N:29]([CH3:39])[C:30]1=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C

Procedure:
A suspension of (6-methoxy-isoquinolin4-yl)-acetic acid (3.5 g, 13.82 mmol) in acetonitrile (70 ml) is treated sequentially with Hunig's base (6.15 ml, 36 mmol), O-(7-benzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.29 g, 16.6 mmol) and 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (3.22 g, 15.2 at mmol) while the solution is stirred at room temperature. The reaction is stirred at ambient temperature for 2 h, prior to evaporation of the solvent. The residue is tritruated with ethyl acetate (50 ml) filtered and washed with ethyl acetate and then dried at 50° C. under reduced pressure. The resulting intermediate is suspended in a mixture of methanol (30 ml) and 4M aqueous sodium hydroxide (60 ml) and heated at 80° C. for 45 minutes. This suspension is neutralized with acetic acid and cooled to 0-5° C. overnight. The resultant solid is collected by filtration, and washed with methanol/water 1:9 (30 ml) followed by methanol (30 ml). Drying under high vacuum at 50° C. affords 3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 394.5.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[OH-].[K+].[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1)[CH3:23]
Reactant: CCO
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of benzyl bromide 4 (0.05 g, 0.159 mmole) in 5 mL ethanol was added potassium hydroxide (0.350 g, 0.627 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed on silica gel (hexanes:ethyl acetate, 9:1) to afford 0.039 g (51%) of ethyl ether 7 as a tan solid: Mp=166–168° C.; 1H NMR (DMSO-d6) δ 9.82 (br s, 1 H), 9.12 (bs, 1 H), 7.70 (d, 2 H, J=8.6 Hz), 7.02 (s, 1 H), 6.86 (d, 2 H, J=8.6 Hz), 6.81 (d, 1 H, J=2.1 Hz), 6.69 (d, 1 H, J=2.2 Hz), 4.71 (s, 2 H), 3.56 (q, 2 H, J=7.2 Hz), 1.18 (t, 3 H, J=7.2 Hz); MS 283 (M−H)−
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](O)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:23])=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Yield: 70.4 %

Procedure:
A solution of 8 g (28.7 mmol) of 7-(2-Chloro-ethoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 18.2 g (143.5 mmol) of oxalyl chloride in 80 ml of methylene chloride containing 0.26 g of dimethylformamide was stirred at reflux for 2.5 hr. The solvent was removed. The residue was mixed with cold dilute sodium hydroxide and extracted several time with ethyl acetate and tetrahydrofuran. The combined extracts were dried over magnesium sulfate and the solution was passed through a short silica gel column. The solvents were removed giving 6.0 g of the title compound as an off-white solid that is used without additional purification.
Reaction SMILES: C([Mg]CCCC)CCC.C([Li])CCC.Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30].CN1CCOCC1.[CH:38]([CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:39]>O1CCCC1>[OH:39][CH:38]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]
Reactant: CC(C)C(C=O)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COCCCc1cn(C)c2ccc(Br)cc12
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCCc1cn(C)c2ccc(C(O)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 12.51 ml of dibutylmagnesium (1M in heptane) in 70 ml of tetrahydrofuran is cooled to 0° C. and admixed with 7.80 ml of n-butyllithium (1M in hexane). After 10 minutes, the mixture is admixed with a solution of 3.60 g of 5-bromo-3-(3-methoxypropyl)-1-methyl-1H-indole (residue 3) and 0.14 ml of N-methylmorpholine in 15 ml of tetrahydrofuran and stirred at 0° C. for 30 minutes. The reaction mixture is cooled to −78° C. and admixed with the solution of 3.02 g of tert-butyl 4-(2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine -3-carboxylate in 15 ml of tetrahydrofuran over 2 minutes. The resulting mixture is stirred at −78° C. for another 45 minutes and subsequently successively quenched with 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed successively with 0.5N HCl (cold)(2×), water and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound (diastereomer mixture) is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane). Rt=24.2/25.4 (gradient II).
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:32])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
1.02 g of ethyl (2E,4E,6E)-3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoate were placed in 8 ml of abs. THF/ethanol (1/1) and treated under argon with 3.9 ml of 3N NaOH. The mixture was stirred at room temperature for 2 days and at 40° for 3 h. Then, the mixture was poured on to ice/HCl, extracted with diethyl ether, washed with water, dried and evaporated. Crystallization from diethyl ether yielded 644 mg of (2E,4E,6E)-3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 208-209°.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19].CCO>C1(C)C=CC=CC=1>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1cc(C)c(C(=O)CCl)c(C)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.2 %

Procedure:
A solution of compound N-(4-(2-chloroacetyl)-3,5-dimethylphenyl)acetamide (3.4 g, 14.2 mmol), thiourea (1.79 g, 23.6 mmol) and KI (150 mg) in toluene (50 mL) and 95% EtOH (50 mL) was refluxed overnight. After the solvent was distilled off, the residue was dissolved in EtOAc (600 mL) and washed with saturated Na2CO3 solution and brine successively, and dried over Na2SO4. After removal of solvent, the residue was subjected to column chromatography (silica gel, EtOAc:NH4OH=100:0.5) to furnish N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (3.2 g, 86.1% yield).