Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[C:22]([C:25]#[N:26])[C:23]#[N:24])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:29][N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[C:22]([C:23]#[N:24])[C:25]#[N:26])[CH2:13][C:11]1[O:12][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: [BH3-]C#N
Reactant: N#CC(C#N)=C1NCCN1CCNCc1ccc(CN2CCCCC2)o1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CCN1CCNC1=C(C#N)C#N)Cc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
In 15 ml of acetonitrile were dissolved 904 mg (2.55 mmol) of Compound 28 and 1 ml (12.3 mmol) of 37% aqueous formalin followed by gradual addition of 271 mg (4.30 mmol) of sodium cyanoborohydride at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and, then, adjusted to pH 7.2 with acetic acid. The reaction mixture was further stirred at room temperature for 45 minutes, at the end of which time the solvent was distilled off under reduced pressure. The residue was diluted with 2N sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed with 0.1N sodium hydroxide solution once and, then, extracted with 1N hydrochloric acid twice. The aqueous layer was adjusted to pH 7.8 with 1N sodium hydroxide solution and re-extracted with 4 portions of methylene chloride. The pooled organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Finally the residue was purified by silica gel column chromatography (chloroform-methanol=10:1) to give 244 mg (26.0%) of Compound 45 as colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:37][CH:36]=[C:35]([O:34][CH3:38])[CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: COc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.093 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 4.17 (s, 2 H) 6.84 (m, 1 H) 6.98 (m, 3 H) 7.22 (d, J=8.09 Hz, 1 H) 7.26 (d, J=5.15 Hz, 1 H) 7.56 (t, J=7.17 Hz, 1 H) 7.67 (d, J=8.09 Hz, 1 H) 7.79 (t, J=8.46 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.22 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.84 (s, 1 H). MS (ESI−) m/z 481 (M−H)−.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13]OS(C)(=O)=O)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[SH:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13][S:39][C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn([C@H](CCOS(C)(=O)=O)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn([C@H](CCSc2ccc3ccccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a mixture of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate (160 mg, 0.368 mmol) and 2-naphthalenethiol (118 mg, 0.736 mmol) in DMF (5 ml) was added potassium carbonate (102 mg, 0.736 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The resulting reaction mixture was poured into water (25 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (100:1 to 50:1) to give ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate (146 mg, 79.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:13]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Cc2ccc(F)cc2)cc1
Agent: Cl
Product: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 500 mg of 4-(4-fluorophenyl) methylaniline and 445 mg of bis(2-chloroethyl)amine hydrochloride was stirred at 100° C. for 2 hours, then gradually raised in temperature to 200° C. and then further stirred for 2 hours. This was then cooled to room temperature, then the product was purified by silica gel column chromatography (chloroform:methanol:water (2% acetic acid)=65:35:5) to obtain the above-referenced compound (5) in an amount of 503 mg (yield of 75%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][O:21][C:20]3([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]3)[O:19]2)(=O)=O)=CC=1>CC(C)=O>[C:1]([S:3][CH2:17][CH:18]1[CH2:22][O:21][C:20]2([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)[O:19]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)CC1CCC2(C1)OCC(COS(=O)(=O)c1ccc(C)cc1)O2
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC2(C1)OCC(CSC(C)=O)O2

Procedure:
A stirred slurry of potassium thioacetate (1.14 g, 10 mmol) in a solution of the tosylate of Example L (4.14 g, 10 mmol) in acetone (30 ml) is refluxed under nitrogen for 5 hrs. The reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent is filtered, the solvent is removed using the rotary evaporator and the residue is chromatrographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Temperature: 25 °C

Procedure:
6-Bromo-3-pyridinecarbaldehyde (500 mg, 2.7 mmol) and 1,2-ethanediol (200 mg, 3.2 mmol) are dissolved in toluene (50 ml) together with Amberlyst 15 (100 mg) in a round bottom flask equipped with a reflux condenser and a Dean-Stark trap. The solution is stirred at reflux overnight, then cooled to room temperature, filtered and concentrated in vacuo. The crude product is chromatographed over silica gel with cyclohexane and ethyl acetate as the eluent to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C=O)C.O>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:20]([C:21]4[O:23][N:43]=[C:41]([CH3:42])[N:40]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acid from Step 2 (1.0 eq.) in DMF (0.1M) was added CDI (2.0 eq.) and N-hydroxy-acetamidine (2.0 eq.). The mixture was stirred for 1 h at rt then 12 h at 120° C. The mixture was cooled, poured in water and extracted with EtOAc. The organic extract was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.52 (m, 3H), 8.38 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.64 (dd, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.05 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[N:3]=1.S(=O)(=O)(O)[OH:21]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cccc(C#Cc2cccc(Br)n2)c1
Product: COC(=O)c1cccc(C(=O)Cc2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.2 g of 2-bromo-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine in 30 ml of 60% sulfuric acid is heated to 140° C. with stirring for 1.5 hours. After cooling to room temperature, the reaction mixture is poured on ice water, the precipitate is suctioned off, and washed neutral with water. After drying at 50° C. in a vacuum, the crude product is dissolved in 35 ml of methanol, mixed with 3 drops of concentrated sulfuric acid and refluxed for 8 hours. Then, the reaction mixture is concentrated by evaporation, distributed between water and ethyl acetate, the organic phase is washed with 10% sodium bicarbonate and water, dried on sodium sulfate and concentrated by evaporation. 3.5 g of 2-bromo-6-[(3-methoxycarbonylbenzoyl)-methyl]-pyridine of melting point 84°-86° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)c1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 91%). MS (ESI) m/z 458 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([O:13]C)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1>>[O:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([N:15]3[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Reactant: C1=CCNCC1
Product: O=C(C1CC2(CCN1)OCCO2)N1CC=CCC1
Temperature: 150 °C

Procedure:
A mixture of the product of Example 1 stage (iv) (1 g) and 1,2,3,6-tetrahydropyridine (2.8 ml) was heated at 150° C. in a reactivial for 2 h. After cooling the mixture was evaporated in vacuo and the solid residue (800 mg) was purified by flash chromatography eluting with dichloromethane/methanol/ammonia (200:10:1) to give the title compound as an oil (260 mg). T.l.c. Silica, dichloromethane/methanol/ammonia (150:8:1) Rf 0.25.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=O)[C:36]([F:39])([F:38])[F:37])=[CH:30][C:29]=1[I:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[CH:44](OC)[CH2:45][NH2:46]>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:44]=[CH:45][N:46]=[C:35]2[C:36]([F:39])([F:38])[F:37])=[CH:30][C:29]=1[I:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(CN)OC
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(I)c1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1nccn1-c1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Triphenylphosphine (3.11 g, 11.88 mmol) was added to a suspension of N-(4-benzyloxy-3-iodophenyl)trifluoroacetamide (Description 15; 2.5 g, 5.94 mmol) in carbon tetrachloride (35 ml) and the mixture was heated under reflux for 24 hours. The mixture was then allowed to cool and the solvent was evaporated under reduced pressure. Hexane was then added and the mixture was heated under reflux for 1 hour. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (20 ml), aminoacetaldehyde dimethyl acetal (2.5 ml, 22.9 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and acetic acid was added. The mixture was heated under reflux for 3 hours, cooled and diluted with water. The mixture was basified and extracted with ethyl acetate. The organic extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (75:25) to give the title compound as a pale yellow oil (900 mg, 34%). 1H NMR (360 MHz, CDCl3) δ 7.80 (1H, d, J 2.5 Hz), 7.50 (2H, m), 7.44−7.43 (3H, m), 7.30 (1H, dd, J 2.5, 8.7 Hz), 7.20 (1H, s), 7.10 (1H, s), 6.91 (1H, d, J 8.7 Hz), and 5.22 (2H, s). m/z (ES+) 445 (M+1).
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH2:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:26]([CH3:32])[C:27](OCC)=[O:28])=[O:18])[CH2:13][CH2:14][CH3:15]>CN(C)C=O>[CH2:12]([N:16]1[C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:25]1[CH:26]([CH3:32])[C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:28])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2ccccc2C1C(C)C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
N-[2-(2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine is prepared as described in Example 30, starting with 3.63 g (38.0 mmol) of guanidinium chloride in 20 cm3 of dimethylformamide and 3.84 g (34.2 mmol) of potassium tert-butoxide. The mixture is stirred for 45 minutes at a temperature in the region of 20° C., followed by dropwise addition of a solution of 1.10 g (3.80 mmol) of ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate in 15 cm3 of dimethylformamide, and the mixture is stirred for 3 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed and the residue is dissolved in aqueous 2N hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is then taken up in aqueous 2N hydrochloric acid solution, filtered and then freeze dried. 1.07 g of N-[2-(2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine are thus obtained in the form of a mixture of the diastereomers. The pH of the aqueous phase is adjusted to a value of 12 with potassium hydroxide and the precipitate thus obtained is filtered off*. The solid thus obtained is taken up in aqueous 2N hydrochloric acid solution and, after filtration and a freeze drying procedure, about 106 mg of one of the two diastereomers produced (diastereomer A) are obtained in the form of the hydrochloride enriched in a ratio of 5:1 (MS(ES): M+H: 303.1).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[C:1]1([CH2:7][CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10]C23C=CC=CC2C(NC3=O)=O)=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27].O.[NH2:32]N.O>C(O)C>[CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][NH2:32])=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1c(OCCC23C=CC=CC2C(=O)NC3=O)ccc(C(OC)OC)c1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1c(OCCN)ccc(C(OC)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 116.4 %

Procedure:
A solution of 2-[2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethyl]phtalimide (0.05 g, 0.12 mmol) obtained in Step 2 in ethanol (1.0 mL) was added with hydrazine monohydrate (6.4 μL, 0.13 mmol) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and added with water, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethylamine (0.04 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4](=[CH:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19].ClC1C=CC=C(C(OO)=[O:28])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3([O:28][CH:5]3[CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19]
Reactant: CN1C(=O)CC2(c3ccccc3)CCCC=C2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC2(c3ccccc3)CCCC3OC32C1=O
Yield: 65.8 %

Procedure:
A solution of 1.0 g (3.92 mmoles) of N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline in 10 ml of chloroform was treated with a solution of 746 mg of 85% m-chloroperbenzoic acid in 12 ml of chloroform. The reaction mixture was refluxed for 36 hours, after which it was poured into 5 N sodium hydroxide. The aqueous phase was extracted twice with chloroform and the combined organic layers were washed well with water, then brine. Drying with sodium sulfate and evaporation of the solvent gave 0.7 g of white solid N-methyl-4a-phenyl-1,3-diketo-8,8a-epoxy-decahydroisoquinoline, mp 135°-140° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH:7]([OH:9])[CH3:8])[CH3:2].C[O:23][C:24]([CH:26](C(CC(OC)=O)CC(OC)=O)CC([O-])=O)=O.C1OC2C=CC(CC(=O)C)=CC=2O1.C(OC(OCC)CI)C>C(OC=C)(=O)C.C(N(CC)CC)C>[C:24]([O:9][C@@H:7]([C@H:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:5][CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH3:8])(=[O:23])[CH3:26]
Reactant: CCOC(CC(c1ccc2c(c1)OCO2)C(C)O)OCC
Reactant: COC(=O)CC(CC(=O)OC)C(CC(=O)[O-])C(=O)OC
Agent: CC(=O)Cc1ccc2c(c1)OCO2
Agent: CCOC(CI)OCC
Solvent: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(C[C@@H](c1ccc2c(c1)OCO2)[C@@H](C)OC(C)=O)OCC
Temperature: 30 °C
Reaction time: 16 h

Procedure:
31.98 g of (2RS,3RS)-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentan-2-ol [synthesized by the same method as Reference Example 1(1) and (2) using 3,4-methylenedioxyphenylacetone and iodoacetaldehyde diethyl acetal as the starting materials] was dissolved in 320 ml of vinyl acetate, and 15.1 ml of triethylamine was added thereto. Then, 1.0 g of immobilized lipase (Toyothium LIP) was added thereto, followed by stirring at 30° C. for 16 hours. Further, 0.9 g of immobilized lipase was added thereto, followed by stirring at the same temperature for 46 hours. Then, insoluble matters were filtered off. The filtrate was diluted with ethyl acetate, then sequentially washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→1/1) to obtain 16.05 g of the above-identified compound, [α]D20 -31.8° (c 1.0, methanol) as colorless oily substance and 18.40 g of (2R,3S)-2-acetoxy-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentane as colorless oily substance. Further, the absolute configuration of the above-identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:5]3[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:29][CH:28]=2)=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 23.5 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (107 mg) was obtained.