Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3](O)=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([Cl:23])=[O:4]
Reactant: CCCCCCCCCC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methylundecanoic acid (0.40 g, 2.0 mmol) in anhydrous dichloromethane (20 ml) and a catalytic amount of DMF (approximately 0.02 ml) was added oxalyl chloride (0.4 mL, 4.6 mmol). The resulting mixture was stirred vigorously for 2 hours at room temperature. The organic solvent was evaporated under reduced pressure and the residue (80) was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:19](=[O:21])[CH3:20]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:19](=[O:21])[CH3:20])=[N:3][CH:4]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1ccncn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Cc1ccncn1
Temperature: -78 °C

Procedure:
4-Methylpyrimidine (2 g) was stirred in dry tetrahydrofuran (65 ml) under argon and the solution was cooled to −78° C. Lithium diisopropylamide (13.8 ml, 2M solution) was added dropwise over 20 minutes and stirring was continued at −78° C. for 1.5 h before dropwise addition of N-methoxy-N-methylacetamide (2.49 ml). The reaction mixture was stirred at −78° C. for a further 40 minutes before allowing to warm to room temperature over 1.25 h, then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The layers were separated and the aqueous phase further extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel eluting with 40-50% ethyl acetate in hexane to give an oil which crystallised on standing (0.70 g, 24%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:17]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C:18]=1[CH2:19][CH2:20][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:25]([C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([OH:24])=[O:23])=[O:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 5-ethyl-2-imino-3-(4-iodobenzyl)-1,3,4-thiadiazoline (17.3 g) in chloroform (200 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (7.5 g), and they were stirred at room temperature for one hour. The reaction mixture was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in diethyl ether and collected by filtration, whereby 23.8 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15](C3C=CC=CC=3)[CH2:14]2)[N:10]=[C:9]1SCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:38].[I-].N.CO>CO.CCO>[NH2:38][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)[N:10]=1
Reactant: [NH4+]
Reactant: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: N
Agent: [I-]
Solvent: CCO
Solvent: CO
Product: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1:1, 2 mL) in a 10 mL CEM microwave test tube was added NH4I (50 mg, 0.34 mmol) and NH3/MeOH (7 N, 2 mL). The resulting mixture was heated in a CEM microwave reactor at 120° C. for 60 min. The cooled mixture was concentrated in vacuo and the residue was purified by reversed phase. HPLC to give 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])=[CH:10][CH:9]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 10 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 22.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:5]=1)=[C:2]=[S:3].[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH2:28])=[O:26])[N:19]=1>C(Cl)Cl>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH:28][C:2](=[S:3])[NH:1][C:4]2[CH:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:5]=2)=[O:26])[N:19]=1
Reactant: Cc1cc(C)n(C(C)C(=O)NN)n1
Reactant: Cc1cccc(Cn2ccc(N=C=S)n2)n1
Solvent: ClCCl
Product: Cc1cccc(Cn2ccc(NC(=S)NNC(=O)C(C)n3nc(C)cc3C)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Intermediate 74 2[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]-6-methylpyridine (101 mg, 0.439 mmol) was dissolved in 4 mL of DCM, and then Intermediate 102 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanohydrazide (80 mg, 0.439 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was evaporated under vacuum to give 2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl]-N-{1-[(6-methyl-2-pyridinyl)methyl]-1H-pyrazol-3-yl}hydrazinecarbothioamide (181 mg, 0.439 mmol, 100% yield) as yellow solid. [ES+MS] m/z 413 (MH+)]. Solid was dissolved in 5 mL of POCl3 and the mixture was stirred at 100° C., until no starting material was detected (1 h 30 minutes). Crude of reaction was partitioned between DCM and distilled water. Organic layer was dried over MgSO4 (anh), filtered and concentrated to give a light yellow solid. This solid was purified by HPLC preparative using X-Terra chromatography column (30 mm×150 mm), gradient 0% to 40% ACN/H2O, in neutral conditions to yield the title compound as a white solid (22 mg, 12.7%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s, 1H), 7.77 (d, 1H), 7.59-7.65 (m, 1H), 7.15-7.17 (m, 1H), 6.77-6.80 (m, 1H), 6.01 (d, 1H), 5.83 (br s, 1H), 5.77 (q, 1H), 5.26 (s, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.78 (d, 3H). [ES+MS] m/z 395 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][NH:22][CH3:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:22]([CH3:23])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CNC
Product: CN(C)C(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and dimethylamine (4.5 mg, 0.12 mmol). The title compound was obtained as a solid (5.8 mg, 16.0% yield). MS m/z: 378.90, 380.80 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(C(=O)CCc3ccc4c(c3)OCO4)sc3ncccc23)c1Cl
Yield: 94.3 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[3-(3,4-methylenedioxyphenyl)propionyl]thieno[2,3-b]pyridine-3-sulfonamide (0.26 g, 0.44 mmoles), methanol (7 ml) and 4N HCl (1.5 ml), giving 0.21 g (97%) of the title compound as a yellow foamy solid, m.p. 40-45° C.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([O:4][CH2:3][CH2:2][S:1][CH2:5][CH2:6][OH:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCSCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCCSCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 59 %

Procedure:
A solution of 8.5 ml of 2,2'-thiodiethanol (thiodiethyleneglycol) in 100 ml of pyridine is placed at -5° C. under argon gasification and treated dropwise within 10 minutes with 9.5 ml of benzoyl chloride. Thereby, the resulting mixture warms to about +8° C. and towards the end of the addition white crystals begin to precipitate. Subsequently, the mixture is stirred at room temperature for a further 36 hours and then the majority of the pyridine is distilled off on a rotary evaporator. The semicrystalline residue is added to 100 ml of ice-cold 2N hydrochloric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases are washed twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (about 14 g) on silica gel with the use of toluene/ethyl acetate (3:1) as the elution agent gives in succession 1.5 g (5.5 percent) of crystalline dibenzoate and 11 g (59 percent) of 2-[(2-hydroxyethyl)thio]ethyl benzoate as a colorless, viscous oil. After bulb-tube distillation (160°-170° C./0.20-0.16 mm Hg) of the latter, there are obtained 9.7 g (52.4 percent) of 2-[(2-hydroxyethyl)thio]ethyl benzoate in 99.4 percent purity; nD23 =1.5566.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25]O)=[CH:22][CH:21]=1.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1>[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:17])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: OCc1ccc(C(F)F)o1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)nc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To the solution of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.35 g, 1.37 mmol) and (5-(difluoromethyl)furan-2-yl)methanol (0.20 g, 1.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise tributhylphosphine (0.51 mL, 2.06 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and followed by the addition of 1,1′-azobis(N,N-dimethylformamide) (0.35 g, 2.06 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (4×20 mL). The organic solutions were combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (¼) to afford the title compound as a white solid in 53% yield (0.25 g): 1H NMR (300 MHz, CDCl3) δ 6.60-6.50 (m, 1H), 6.52 (t, JH-F=54.2 Hz, 1H), 6.37-6.29 (m, 1H), 4.45 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.09-3.98 (m, 2H), 3.60-3.49 (m, 2H), 2.54 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[F-:19].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][F:19])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: [F-]
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)CF)cn2)cc1
Yield: 43.1 %

Procedure:
According to Scheme 6 Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (8.39 mmol, 3.00 g), KF (33.6 mmol, 1.97 g) and 18-crown-6 (4.20 mmol, 1.12 g) in acetonitrile (25 mL) was stirred under reflux for 3 hours. After the evaporation of solvent, the crude residue was dissolved in AcOEt. The organic phase was washed with water, was dried over Na2SO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 95:5) as eluent to yield 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-fluoroethanone (3.62 mmol, 900 mg, 78%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 70.8 %

Procedure:
Using 4-bromobenzoic acid (1.01 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.03 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.38 g) was obtained.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+]>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:11]
Reactant: N#CCC(=O)O
Reactant: O=CC1CC2C=CC1C2
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: N#CCC=C1CC2C=CC1C2
Yield: 72.1 %

Procedure:
A stirred solution of 100 g (0.82 mol) of 2-formyl-5-norbornene (Aldrich Chemical Co.), 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58% ), 132 ml of diemthylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 79.6 g (68% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]hept-5-ene: b.p. 76-78° C/1 mm; ir 3060, 2260, 1420, 1330, 915, 840, 755, 720; nmr 1.3-2.5 (4H, m), 2.9-3.4 (4H, m), 5.0-5.5 (1H, m), 5.9-6.2 (2H, m); ms 145.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+]>CO.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)Cc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12C
Yield: 59.7 %

Procedure:
A solution of 10.2 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene in 205 ml of methanol is stirred with 33.7 ml of sodium hydroxide solution for 45 minutes at 15° C. Then, it is diluted with diethyl ether, washed with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 5.6 g of 17β-acetoxy-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained. [α]D22 =+32.2° (c=0.505% in chloroform)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)=[O:17])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 85.6 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-glutamine (8.0 g) and 1-benzylpiperazine (5.7 g) were condensed to obtain a colorless crystal 1-(N-tert-butoxycarbonyl-L-glutaminyl)-4-benzylpiperazine (11.2 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([Br:20])=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:34]S(C1C=CC(CN)=CC=1)(=O)=O.BrBr>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([Br:20])=[C:16]([CH3:21])[N:15]([CH:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[CH3:34])[CH:14]=2)=[O:12])=[CH:31][CH:32]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Agent: BrBr
Agent: Cl
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)c1ccc(C#N)cc1

Procedure:
5-Bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide can be prepared as described for preparation 9, substituting methylamine with 4-methylsulfonylbenzylamine hydrochloride; ESI mass spectrum: [M+H]+=528 (bromine isotope pattern); Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:6]2[NH:5][C:4](=[O:7])[NH:3][C:2]=2[CH3:1])=[O:18])=[CH:15][CH:14]=1
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of 98.1 g (1 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 moles) of anhydrous aluminum chloride and 500 ml of nitrobenzene there is added dropwise over 10 minutes, 158.6 g (1 mole) of p-fluorobenzoyl chloride. The mixture is stirred at 60°-65° C. for 6 hours, then poured onto 2 kg of ice. The precipitate which forms is separated by filtration, washed with diethyl ether and water and recrystallized from dimethylformamide to give 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one melting at about 289°-292° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:9]=2)=[O:5]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Yield: 62.1 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carboxylic acid ethyl ester (2 g, 4.85 mmol) obtained in Example 7 was dissolved in methanol, p-toluenesulfonic acid (92 mg, 0.49 mmol) was added thereto, and refluxed for 24 hrs. The resulting mixture washed with sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. Then, the resulting residue was purified by flash chromatography to obtain 1.2 g of the titled compound (yield: 62%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a cooled solution of 1 g (4.1 mmol) of (R)-2,2,2-trifluoro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide in acetone (30 mL) at 0° C., was added a solution of 2.03 g (8.2 mmol) MgSO4.7H2O in 15 mL of water. After 5 min of stirring, 1.95 g (12.3 mmol) of KMnO4 was added in small portions over 1 hr. The mixture was then stirred overnight, slowly warming to room temp. The mixture was filtered. The filtrate was treated with saturated sodium metabisulfite and filtered. The filtrate was extracted with DCM several times. The combined organic extracts were washed with distilled water and brine, dried over MgSO4 and concentrated in vacuo to afford 0.96 g (91%) of the title compound, whose purity was good enough to use crude.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:33]([F:41])=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[C:35]#[N:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:39]([F:40])=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=3[F:41])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(CCl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 56 mg (0.27 mmol) of 3-(chloromethyl)-2,4-difluorobenzonitrile from Example 135A in 3 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h and then diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude product that contained the target compound in a multicomponent mixture (20% pure). This crude material was used in the next step without further purification.