Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:19])[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)OC(C)(C)C)c(C)c1
Yield: 84 %

Procedure:
4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester from Example E30.1 (4.00 g, 14.5 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (480 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (3.41 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(O)(C)C>[C:21]([NH:20][C:19](=[N:11][C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:10])[O:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)#[N:22]
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: COc1ccc([C@H](C)N=C(NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
(S)-(−)-1-(4-methoxyphenyl)ethylamine (321 mg) was dissolved in isopropanol (6 ml). Thereafter, diphenyl N-cyanocarbonimidate (508 mg) was added to the solution, and the obtained mixture was stirred at a room temperature for 2 hours. The precipitated crystals were collected by filtration, and the collected crystals were then washed with isopropyl ether to obtain (S)-1-cyano-3-[1-(4-methoxyphenyl)ethyl]-2-phenyl isourea (339 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC3)c(F)c2)c1
Yield: 38.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:23][Si:24]([CH3:27])([CH3:26])[O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O

Procedure:
A mixture of 9.0 gm (0.03 mole) of 19-hydroxy-4-androstene-3,17-dione, 4.3 gm (0.04 mole) of trimethylchlorosilane and 3.2 gm (0.04 mole) of pyridine is refluxed in 100 ml of benzene for a period of 18 hours. The resulting suspension is filtered, the volatiles removed in vacuo and concentrated to a yellow oil. The oil is placed upon a silica gel chromatographic column packed in chloroform and eluted with chloroform. The chloroform eluate is evaporated to dryness in vacuo and the residue is recrystallized twice from hexane to yield the desired 19-(trimethylsiloxy)-4-androstene-3,17-dione having a m.p. of 87°-9° C., uv max (MeOH) 242 nm (ε14,700).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][N:31]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CO.[Pd]>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N)cn2)cc1
Yield: 14.4 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (149 mg; 1.73 mmol) in 10 ml of MeOH was treated with 10% Pd/C (60 mg) and hydrogenated under balloon pressure for 2 hr. The catalyst was filtered off and washed with chloroform/methanol. The filtrate was concentrated and the residue purified by radial chromatography using a methanol-dichloromethane gradient (1–10%) to afford the title compound as a dark-colored oil (125 mg; 89% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=C=O>>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:18]1([C:11]([NH2:10])=[O:13])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C=NC1CCCCC1
Agent: O=C1CN(Cc2ccccc2)C(=O)N1
Product: NC(=O)C1CCCCC1

Procedure:
1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and isocyanatocyclohexane (79 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 22 mg (13%), M+H+: 316.18.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.[ClH:22]>CO.CCOC(C)=O>[ClH:22].[ClH:22].[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (5.0 g) in DMF (50 ml) was added 4-fluorobenzoylchloride (3.38 ml) and N,N-diisopropylethylamine (9.35 ml), the mixture was stirred at 70° C. for 2 hours. The mixed solution was poured into a mixture of water (300 ml) and AcOEt (300 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g) in MeOH(34 ml) was treated with 4N HCl in AcOEt (29 ml) and was stirred at 25° C. for 12 hours. The solvent was removed under reduced pressure. Recrystallization (acetonitrile-MeOH) provided (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride as white solid (3.77 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([NH2:12])[CH2:7]1)=[O:5].C(N(C(C)C)C(C)C)C.[Cl:22][C:23]1[S:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([NH:12][C:28]([C:26]2[S:27][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:29])[CH2:7]1)=[O:5]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reaction time: 18 h

Procedure:
A solution of (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester hydrochloride (160 mg) in THF (5 ml) was treated under an argon atmosphere with N-ethyldiisopropylamine (0.56 ml), 5-chloro-2-thiophenecarboxylic acid (160 mg) and BOP (434 mg). The mixture soon turned to a clear light yellow solution and was then stirred for 18 h. The reaction mixture was concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:7) to give (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester as colorless gum. MS: 304.0 ([M+H]+).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN
Reactant: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.7 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoic acid (140 mg) synthesized above, ethyl β-alaninate hydrochloride (62.5 mg), 1-hydroxybenzotriazole monohydrate (62.3 mg) and triethylamine (57 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.0 mg), and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane), and then purified by NH-silica gel column chromatography (ethyl acetate) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (116 mg, 70%) as a white solid.
Reaction SMILES: C([CH:3]1[CH2:6][CH2:5][C:4]1([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])C.Cl>C(O)(=O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:4]2([C:7]([OH:9])=[O:8])[CH2:5][CH2:6][CH2:3]2)=[CH:16][CH:15]=1
Reactant: CCC1CCC1(Oc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1(Oc2ccc(Cl)cc2)CCC1
Yield: 87.5 %

Procedure:
To the product of Example 55A (320 mg, 1.26 mmol) was added glacial acetic acid (10 ml) followed by 5% aqueous hydrochloric acid (2.5 ml) and the mixture was heated to reflux for about 18 hours. The mixture was cooled and was evaporated to dryness. The residue was taken up in toluene and was evaporated to dryness two times to provide 250 mg (87%) of the title compound. MS (DCI): m/z 244 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: Cn1c(-c2ccc(C#N)cc2)nc(-c2ccccc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(CN)cc2)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of 2-(4-cyanophenyl)-1-methyl-4-phenyl-5-(4-pyridyl)imidazole (0.20 g, 0.6 mmol) [See Ex. 3 above] in THF (10 mL) was added LiAlH4 (0.60 mL of 1.0 M solution in THF, 0.6 mmol), and the resulting mixture was stirred at rt for 1 h. The mixture was then poured into 2.5 N NaOH and extracted with Et2O. The organic extract was evaporated, and the residue was purified by flash chromatography, eluting first with a solvent gradient of 0-10% MeOH/CHCl3, followed by 1:10:90 NH4OH/MeOH/CHCl3. Trituration with ether afforded the title compound as a white solid (66 mg, 32%): CIMS (NH3, m/z): 341 (M++H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=[C:2]2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1ccc2c(c1)c(C#C[Si](C)(C)C)nn2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a round bottom flask were introduced tert-butyl 3-iodo-5-methyl-1H-indazole-1-carboxylate (8.3 g; 23.2 mmol; 1.0 eq.), (trimethylsilyl)acetylene (6.8 mL; 48.8 mmol; 2.1 eq.), Pd(OAc)2 (521 mg; 2.3 mmol; 0.1 eq.), triphenylphosphine (1.22 g; 4.65 mmol; 0.2 eq.) and copper iodide (442 mg; 2.32 mmol; 0.1 eq.) in TEA (57 mL). The reaction mixture was degassed and stirred at 80° C. under N2 for 1 hour. Et2O was added and the reaction mixture was filtrated through a celite pad. The filtrate was then washed twice with an aqueous saturated solution of NH4Cl and brine, dried over magnesium sulfate, filtered and concentrated. This crude was purified by flash chromatography on silica (Heptane/EtOAc, gradient from 100:0 to 10:90) to afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.[O:27]=[C:28]1[NH:32][C@H:31]([CH2:33][O:34]C(=O)C2C=CC=CC=2)[CH2:30][O:29]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[C@H:31]([CH2:33][OH:34])[CH2:30][O:29][C:28]5=[O:27])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cc1cc(N2C(=O)OC[C@H]2CO)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 71.6 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (347 mg) described in Preparation Example 130 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (278 mg), the title compound (270 mg) was obtained.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.O.C(O)(=O)C.O1CCCC1>[Cl-].[Na+]>[OH:8][CH:9]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)COc3ccccc3)CCC2C1=O
Yield: 98 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (13 mg), prepared as described in Reference Example 51 and in the form of (±)-6β-[(E)-3α-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15R)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (0.53 ml; 7:13:2 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The extract was washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was subjected to medium pressure liquid chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (9:13 v/v), to give 6-[(E)-3-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (9.9 mg), in the form of (±)-6β-[(E)-3α-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15R)-6a-oxo-6,9-methano-15-hydroxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate [NMR (in deuterochloroform): multiplets at 6.8-7.3, 6.4-6.6, 5.6-5.8, 4.3-4.6, 3.8-4.0, 1.3- 2.8 p.p.m., singlet at 3.6 p.p.m⟧
Reaction SMILES: S(Br)([Br:3])=O.N1C=CC=CC=1.[C:11]1([C:17]2[C:18]([O:20][C:21](=[O:23])[CH:22]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:3][C:22]1[C:21](=[O:23])[O:20][C:18](=[O:19])[C:17]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: O=S(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Br
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 10° C., first 40.2 g (193 munol) of thionyl bromide and then 15.3 g (193 mmol) of pyridine were added dropwise with stirring to 16.8 g (97 mmol) of phenylmaleic anhydride in 200 ml of toluene. The mixture was stirred at 10° C. for 30 min, heated at 75° C. for 30 min using a preheated heating bath and allowed to cool, and excess thionyl bromide was removed at 65° C. under reduced pressure. The mixture was then stirred with 150 ml of toluene and filtered, and the residue was washed twice with in each case 200 ml of toluene, and the filtrate was concentrated under reduced pressure. The crude product (9.3 g) still contained 25% of unreacted starting material and was used without further purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.CI>O1CCCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of diisopropylamine (10.08 mL, 0.0738 mol) in tetrahydrofuran (80 mL), n-butyl lithium (46 mL, 0.0738 mol, 1.6M), was added at −78° C. and then it was warmed to 0° C. and stirred for 30 min, then it was cooled to −78° C. and the solution of 3-bromo-5-fluoro-pyridine (10.0 g, 0.056 mol) in tetrahydrofuran (10 mL) was added and stirred for 30 min. Methyl iodide (4 mL, 0.062 mol) was added to reaction mixture and allowed to room temperature for 2 h. Reaction mass was quenched with saturated ammonium chloride (100 mL) solution. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 3H). LCMS (M+3): 192.2.
Reaction SMILES: [CH2:1]1[C:18]2[CH:5]([CH2:6][CH:7]3[CH:16]([CH:17]=2)[C:15](=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]3)[CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=[O:21].[NH4+].[Ce]>CC(C)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[CH2:13]1[C:14]2[C:15](=[O:19])[C:16]3[C:7](=[CH:6][C:5]4[C:18]([CH:17]=3)=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:8](=[O:21])[C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1c2ccccc2CC2CC3CCCCC3=CC12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Ce]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)c2cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 147.4 %

Procedure:
A solution of 36 mg (0.075 mmol) of the octahydro-11-naphthacenone and 60 mg (0.675 mmol) of NaHCP3 in 10 mL of acetone was treated with a solution of 167 mg (3mmol) of cerium ammonium nitrate (CAN) and 1 mg of dichlorodicyanobenzoquinone (DDQ) in 2 mL of acetone added in one portion at 0 degrees centigrade. The reaction mixture was stirred at room temperature for 1.5 hours during which the color changed from shiny yellow to orange red, and then 25 mL of CH2Cl2 was added. The mixture was filtered through over Celite. The organic layer was washed with saturated NaCl solution (2×20 mL), dried over Na2SO4, and evaporated to give the tetrahydro-5,12-naphthacenedione as a red crystals (29 mg, 86 percent).mp greater than 258 degrees centigrade (decomp).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]Cl.[C:11](#[N:13])C>[C-]#N.C([N+](CC)(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][C:11]#[N:13])[CH:9]=1
Reactant: ClCc1cc(Br)ccc1Cl
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: N#CCc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification.