Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH2:5])[CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1

Procedure:
Methanol (20 mL) was cooled to −10 degrees under an atmosphere of argon. To the solvent was added dropwise thionyl chloride (4.31 mL) and a solution of 3-aminophenylacetic acid (3.00 g) in methanol (25 mL) and the mixture was stirred at −10˜0 degrees for 1 hour. To the reaction mixture was added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the title compound (3.90 g) having the following physical data.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:35]1([C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:2][CH2:3]5)(=[O:5])=[O:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)=[O:33])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carboxylic acid (0.155 g) in N,N-dimethylformamide (5 mL) were added morpholine (0.056 mL), triethylamine (0.135 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (93 mg) and 1-hydroxybenzotriazole (74 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.106 g, yield 60%) as colorless crystals. MS: 550 (MH+). melting point 114-116° C.
Reaction SMILES: C([N:4]([C@@H:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[CH:16][CH:15]=[N:14][C:13]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=O)C.O.NN>CO.CCOC(C)=O>[N:17]1[C:18]2[CH2:19][CH2:20][CH2:21][C@@H:12]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])[C:13]=2[N:14]=[CH:15][CH:16]=1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CCCc2nccnc21
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2nccnc21
Yield: 94.9 %

Procedure:
A solution of (R)-tert-butyl acetyl(5,6,7,8-tetrahydroquinoxalin-5-yl)carbamate (293 mg) in methanol (10 mL) was treated with hydrazine hydrate (0.5 mL) for 1.5 h. The mixture was diluted with EtOAc and washed twice with saturated aqueous sodium chloride. The organic layer was separated, dried with sodium sulfate, and concentrated in vacuo to provide 238 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])=[C:11]([F:20])[CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:11]([F:20])[CH:10]=1
Reactant: CCCC(O)c1ccc(Br)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
Trifluoroacetic acid (366 mL, 3.21 mmol) was added dropwise to a 0° C. solution of 1-(4-bromo-2-fluorophenyl)butan-1-ol (440 mg, 1.8 mmol) in dichloromethane (10 mL). Added Dess-Martin periodinane (1.21 g, 2.85 mmol) and let reaction warm to room temperature and stir for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 1-(4-bromo-2-fluorophenyl)butan-1-one (330 mg, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.65-7.69 (m, 1H), 7.32-7.45 (m, 2H), 2.83-2.87 (m, 2H), 1.62-1.71 (m, 2H), 0.90 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH3:26])=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].O>C(Cl)(Cl)Cl>[C:34]([N:8]1[CH2:9][C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C@H:6]([CH2:5][C:4]2[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=2[O:25][CH3:26])[CH2:7]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2CNC[C@H]2Cc2cc(F)cc(F)c2OC)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc([C@@H]2CN(C(C)=O)C[C@H]2Cc2cc(F)cc(F)c2OC)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.17 g (6.17 mmol) of trans-3-(3,5-difluoro-2-methoxybenzyl)-4-(3,4-dimethoxyphenyl)pyrrolidine prepared in step (13) of Example 4 was dissolved in 30 ml of chloroform, and 0.75 g (7.4 mmol) of triethylamine was added thereto. 10 ml of a solution of 0.5 ml (7.0 mmol) of acetyl chloride in chloroform was dropwise added thereto under cooling with ice, and the mixture was stirred at room temperature for 3 hr. 1 ml of water was added thereto to stop the reaction. The reaction mixture was washed with water, a 2N hydrochloric acid solution, and a saturated aqueous sodium hydrogencarbonate solution sequentially, and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo, and the residue was subjected to silica gel column chromatography (methylene chloride:methanol=97:3) to prepare 2.5 g (quantitative) of the intended product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O>Br>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccccc3F)C2)o[nH]1
Yield: 124.1 %

Procedure:
(2R,4S)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (492 mg, 1.47 mmol) was stirred in hydrogen bromide (33% in AcOH) overnight (19 h). Evaporation of solvents and purification by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) yielded 5-((2R,4S)-2-(2-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (504 mg, 124%). The sample contained DMSO and acetic acid. 1H NMR (400 MHz, cd3od) δ 1.50-1.65 (m, 1H), 1.69-1.84 (m, 1H), 2.08-2.22 (m, 2H), 2.89-3.18 (m, 4H), 3.38-3.51 (m, 2H), 5.66 (s, 1H), 7.11-7.23 (m, 2H), 7.28-7.41 (m, 2H). HRMS Calcd for [C15H17FN2O2+H]+: 277.1352. Found: 277.1344.
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:13][C:12]=2[CH:25]=1)([O-])=O>CO.[C].[Pd]>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[NH:13][C:12]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
To 10% palladium-carbon (50 mg) and ammonium formate (228 mg), a solution of tert-butyl ((6-nitro-1H-benzo[d]imidazol-2-yl)methyl)carbamate (C19, 106 mg) in methanol (4 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl ((6-amino-1H-benzo[d]imidazol-2-yl)methyl)carbamate (C20, 100 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][N:11]([CH3:29])[C:12]([C:14]1[S:18][C:17](CNC(=O)OC(C)(C)C)=[CH:16][C:15]=1[CH3:28])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:33](CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH3:30][N:8]([CH2:9][CH2:10][N:11]([CH3:29])[C:12]([C:14]1[S:18][C:17]([NH:33][CH3:31])=[CH:16][C:15]=1[CH3:28])=[O:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CNc1cc(C)c(C(=O)N(C)CCN(C)C(=O)OC(C)(C)C)s1
Yield: 98.6 %

Procedure:
The compound (418 mg, 0.947 mmol) obtained in Example 90a, triethylamine (0.658 mL, 4.74 mmol) and di-tert-butyl dicarbonate (248 mg, 1.14 mmol) were used to give the title compound (319 mg; yield, 99%) as a yellow oily substance according to the method described in Example 89c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15](O)=O)=[C:7]2[C:11]=1[O:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8]2.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][N:20]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:6]([C:15]2[NH:25][C:24]3[C:19]([N:18]=2)=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2cc(C(C)C)oc12
Reactant: Nc1cccnc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3ncccc3[nH]2)c2cc(C(C)C)oc12

Procedure:
4.6 g of 7-methoxy-2-(1-methylethyl)benzofuran-4-carboxylic acid and 2.2 g of 2,3-diaminopyridine are boiled under reflux for 4 h in 80 ml of phosphorus oxychloride. The mixture is largely evaporated in vacuo, the residue is partitioned between 100 ml of ice water and 500 ml of ethyl acetate and the aqueous phase is rendered alkaline with 50 percent sodium hydroxide solution. The organic phase is separated off, the aqueous phase is extracted a further two times by shaking with ethyl acetate, and the organic phases are combined, dried over ignited calcium carbonate and concentrated in vacuo. The residue is chromatographed on silica gel using a 1:1 mixture of toluene and ethyl acetate. After the evaporation of appropriate fractions, 1.7 g (28.3% of theory) of title compound having the m.p. 242° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[CH:11]=[CH:10][S:9]1)=[O:4].S(Cl)([Cl:17])(=O)=O>>[Cl:17][C:10]1[S:9][N:8]([CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:12](=[O:13])[CH:11]=1
Reactant: COC(=O)CCCn1sccc1=O
Reactant: O=S(=O)(Cl)Cl
Product: COC(=O)CCCn1sc(Cl)cc1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To prepare 2-(3-methoxycarbonylpropyl)-3-isothiazolone, Compound I (1.02 g, 2.5 mmol) was dissolved in25 ml distilled ethyl acetate and cooled to 0° C. Sulfuryl chloride (1.04 g, 7.75 mmol) was added slowly dropwise and the yellow solution stirred at 0° C. for 1 hr. During this time a white precipitate formed (5-chloro-2-(3-methoxycarbonylpropyl)-3-isothiazolone (200 mg)) which was removed by filtration. The resulting filtrate was concentrated and the residue flash-chromatographed (10% acetone-chloroform) to yield 2-(3-methoxycarbonylpropyl)-3-isothiazolone (120 mg) as a clear oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]([N+:33]([O-])=O)=[CH:22][N:21]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:33][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][C:20]([O:19][C:15]2[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:21][CH:22]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc(Oc2cccc(S(=O)(=O)NCCN3CCOCC3)c2)cc1Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(Oc2cccc(S(=O)(=O)NCCN3CCOCC3)c2)cc1Nc1ccccc1

Procedure:
The product of Step 3 (3.3 g, 6.6 mmol) was hydrogenated overnight with a balloon of hydrogen gas in MeOH (50 mL) in the presence of 5% Pd/C (300 mg). The reaction mixture was filtered through Celite and concentrated to give the title compound as a dark oil which was used directly in the next step (˜3.1 g, quant.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[CH3:19][O:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][O:20][C:21]([NH:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]1)=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCC(C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (commercially available) in CH2Cl2 was added Et3N (2 eq.) and methyl-chloroformate (1.05 eq.). Stirring was continued overnight at RT. The reaction was quenched by addition of H2O, the product was extracted with CH2Cl2 and the organic phase washed with aq. HCl 1M. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The residue was dissolved in MeOH and a 2M KOH aq. solution was added. The reaction was stirred at RT 4 hours, aq. HCl was added until ph=6, and then the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to afford the title product as a white foam which was used in the next step without further purification.
Reaction SMILES: C[C@@H]1[C@H](C2C=CC=CC=2)OC(=O)N1.C(Cl)(=O)CCCC.[O:21]=[C:22]([N:27]1[C@@H:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][O:29][C:28]1=[O:39])[CH2:23][CH2:24][CH2:25][CH3:26]>>[O:21]=[C:22]([N:27]1[C@H:31]([CH3:30])[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:29][C:28]1=[O:39])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCC(=O)Cl
Agent: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 84 %

Procedure:
(4R,5S)-3-(1′-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone was synthesized from (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and valeroyl chloride by the same procedure as (4S)-3-(1′-oxopentyl)-4-benzyl-2-oxazolidinone. The product (29.55 g) was obtained in 84% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:24])=[CH:15]/[C:16]3[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2>CCOCC.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:24])=[CH:15]/[C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: C/C(=C\c1ccc(C=O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzyl alcohol (prepared as described in Example 12) dissolved in 100 ml of absolute ether are added dropwise within 10 minutes to a stirred suspension, cooled to 0°-5° C., of manganese dioxide in 100 ml of absolute ether. The mixture is stirred at room temperature overnight and then filtered through Celite. The filtrate is concentrated to dryness on a rotary evaporator. The yellowish oil crystallizes. Recrystallisation from ether yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzaldehyde in the form of colourless crystals of melting point 140°-141° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]4=[O:25])=[CH:14][CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:4]=1.Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1>>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([N:19]4[CH2:24][CH2:23][N:22]([C:34]5[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=5)[CH2:21][C:20]4=[O:25])=[CH:14][CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)[N:4]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCNCC5=O)cc4C3)nc(N)n2)CC1
Agent: Cl
Product: CCOC(=O)c1ccc(N2CCN(c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)C(=O)C2)nc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 2 starting from 1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperazin-2-one hydrochloride and ethyl 6-chloronicotinate (Aldrich, Cat. No. 531197). LCMS (M+H)+: m/z=572.3.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:25]([F:37])[CH:24]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:18][CH2:19]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[C:25]([F:37])[CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (1.0 g) and rhodium acetate (dimer, 0.044 g) in toluene (10 mL) was added dropwise ethyl diazoacetate (0.83 mL) at 100° C., and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.47 g, 42%).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15]1([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]1([CH2:7][C:8]([C:18]2[CH:19]=[CH:20][C:15]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylacetyl chloride (3.4 ml) is added to a solution of anhydrous aluminum chloride (4.27 g) in 1,2-dichloroethane (35 ml) under ice cooling, and then a solution of ethyl 3-phenylpropionate (5.1 g) in anhydrous 1,2-dichloroethane (5 ml) is added dropwise thereto. The mixture is stirred under ice cooling for 20 minutes and at room temperature overnight. The reaction mixture is added little by little to a saturated aqueous sodium hydrogencarbonate solution (150 ml) containing ice (100 g). The resulting precipitates are filtered out. Ether is added to the filtrate. The organic layer is washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give ethyl 3-[4-(phenylacetyl)phenyl]propionate as crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:12]>>[Br:12][CH2:11][C:10]1[CH:9]=[C:8]([O:7][C:6]([F:5])([F:16])[F:17])[CH:15]=[CH:14][C:13]=1[N+:1]([O-:4])=[O:2]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1CBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Fuming nitric acid (5 mL) was cooled to 0° C. and 3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added. After 15 minutes, the reaction was poured into ice water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water, saturated NaHCO3, and brine (75 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene Rf=0.54 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.14 (d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.31 (m, 1H), 4.82 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2ccsc2)=C1c1ccc(Cl)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 3.77 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-furanone, 0.73 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 0.5 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 1.49 g of 5-(4-chlorophenyl)-6-methyl-4-(3-thienyl)-2H-pyridazin-3-one.