Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C.C1COCC1.O>[CH2:15]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[CH:14]=[CH2:13]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C=O)cc1Cl
Temperature: 65 °C
Yield: 85.6 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (5.0 g, 31.9 mmol) in DMF/THF 1:3 (120 mL) is added NaH (1.67 g of a 55% dispersion in mineral oil, 38.3 mmol) in four portions. The mixture is stirred at rt for 1 h before allylbromide (9.66 g, 79.8 mmol) is added. The reaction mixture is heated to 65° C. for 18 h, diluted with water (250 mL) and extracted with diethyl ether (3×250 mL). The organic extracts are washed with water (250 mL), combined and concentrated. The remaining oil is chromatographed on silic gel with heptane/EA 4:1 to afford 4-allyloxy-3-chlorobenzaldehyde (5.37 g) as an almost colourless oil. LC: tR=0.95 min.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5].[CH3:17][O-:18].[Na+].O.Cl>COCCOC>[CH3:17][O:18][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(-c2ccccc2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2-chloro4-methyl-6-phenyl-nicotinonitrile (455 mg, 1.99 mmol) was dissolved in 20 mL of DME, added with 95% sodium methoxide (1.13 g, 19.90 mmol) and then stirred at room temperature for about 1 hour. The mixture was added to cool water and was adjusted to have a pH of about 6 to 7 with 10% HCl and then extracted with ethyl acetate. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 370 mg (83%) of 2-methoxy-4-methyl-6-phenyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 1) and 3-chlorophenylboronic acid (110 mg, 0.68 mmol). Yield 100 mg (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]1([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)[CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:1].[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH:20]5[CH2:22][CH2:21]5)[CH2:28]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNC(C2CC2)CN1
Solvent: c1ccncc1
Product: Cl
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Temperature: 135 °C

Procedure:
A mixture of 1.405 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 4.34 g of 2-cyclopropylpiperazine and 15 ml of pyridine was heated in a pressure bottle at 135° C. for 24 hours, then cooled and the pyridine removed under reduced pressure. The residue was purified by chromatography on silica gel, with chloroform:methanol:water:triethylamine (9.5:0.5:0.01:0.01). The solid (base form) was redissolved in ethanol, a few drops of concentrated hydrochloric acid were added and the solid collected, washed with cold ethanol, ether and dried, giving the desired products.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:20]([C:24]1[NH:25][C:26]([CH:30]=[O:31])=[C:27]([Cl:29])[N:28]=1)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:20]([C:24]1[N:25]([CH2:2][C:3]2[C:11]3[N:10]=[CH:9][N:8]([C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[C:14]#[N:15])[C:7]=3[CH:6]=[CH:5][CH:4]=2)[C:26]([CH:30]=[O:31])=[C:27]([Cl:29])[N:28]=1)[CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1ccccc1-n1cnc2c(CBr)cccc21
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1cccc2c1ncn2-c1ccccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
2-[4-(Bromomethyl)-1H-benzimidazol-1-yl]-benzonitrile (0.65 g, 2.08 mmol, prepared as described in part C of Example 8) and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.409 g, 2.19 mmol, prepared as described in part C of Example 5) were placed in 20.8 mL anhydrous dimethylformamide. Freshly ground cesium carbonate (1.02 g, 3.12 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between ethyl acetate and water and the organic phase was washed with brine, dried and concentrated. The crude oil was purified by flash chromatography (SiO2, 80:20 hexane:acetone) to yield the title A compound (0.68 g) as a white solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:10]2[CH3:23])=[CH:5][C:4]=1[S:25](Cl)(=[O:27])=[O:26].[CH3:29][NH2:30]>CO>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:23])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:25](=[O:27])(=[O:26])[NH:30][CH3:29]
Reactant: COc1ccc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)Cl)c3)N2C)cc1
Reactant: CN
Agent: Br
Solvent: CO
Product: CNS(=O)(=O)c1cc(-c2csc(=Nc3ccc(OC)cc3)n2C)ccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.6 g (0.02 mole) of 4-(4-chloro-3-chlorosulfonylphenyl)-2-(4-methoxyphenyl-imino)-3-methylthiazolidin-4-ol hydrobromide are introduced into a mixture of 10 ml of 40% strength aqueous methylamine and 150 ml of methanol and the resulting mixture is stirred for 20 hours at room temperature. The solvent is distilled off, the residue is taken up in 100 ml of ethanol and this solution is acidified with methanolic or ethanolic hydrogen chloride solution and heated at the boil for 2 hours. The solvent is distilled off, the residue is crystallized under ether, ethyl acetate or diisopropyl ether and the crystals are filtered off. Melting point 257° C. (with decomposition) (from isopropanol).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1.ClCCl>[CH3:10][S:11]([O:5][CH2:4][C@@H:3]([OH:6])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CC(C)(CO)[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a 0° C. solution of 25.3 g (189 mmol) of (2S)-3,3-dimethyl-1,2,4butanetriol in 170 mL of pyridine was added dropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reaction mixture was allowed to slowly warm to room temperature, stirred for 18 h, and then diluted with dichloromethane. To the mixture was added 200 mL of 1N hydrochloric acid followed by concentrated hydrochloric acid until the pH of the aqueous phase was brought to a value of 2. The mixture was extracted with dichloromethane, and the combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% acetone in dichloromethane to afford 21.75 g (52.10%) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate. 1H NMR (300 MHz, DMSO-d6) δ 5.48 (d, J=6 Hz, 1H), 4.30 (dd, J=2 Hz, J=10 Hz, 1H), 3.91-4.05 (m, 3H), 3.16 (d, J=4 Hz, 6H), 0.90 (d, J=13 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:14][CH:13]=1)[CH3:2].[CH2:33]([I:35])[CH3:34].[CH2:36](O)[CH3:37]>>[I-:35].[I-:35].[CH2:29]([N+:26]([CH2:33][CH3:34])([CH2:27][CH3:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N+:3]([CH2:36][CH3:37])([CH2:1][CH3:2])[CH2:31][CH3:32])=[CH:17][CH:16]=1)[CH3:30]
Reactant: CCN(CC)CCCCCCCCc1ccc(CCCCCCCCN(CC)CC)cc1
Reactant: CCO
Reactant: CCI
Product: CC[N+](CC)(CC)CCCCCCCCc1ccc(CCCCCCCC[N+](CC)(CC)CC)cc1
Product: [I-]
Reaction time: 0.17 h

Procedure:
To a solution of 223 mg of 1,4-bis(8-diethylaminooctyl)benzene in 1 ml of ethanol was added 0.40 ml of ethyl iodide, and the mixture was refluxed for 2 hours, concentrated under a reduced pressure and further dried under reduced pressure. To the residue was added 3 ml of ethyl acetate to solidify the residue. To the solid was added 3 ml of acetone and the whole was stirred for 10 minutes and filtered. The resulting crystal was washed with ethyl acetate and n-hexane, and dried under a reduced pressure to obtain 315 mg of the title compound as a yellow crystal.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane (4.5 L) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (235 g, 0.54 mol) was added triethylamine (85 mL, 0.59 mol), followed by a dichloromethane (800 mL) solution of trityl chloride (159 g, 0.56 mol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Chromatography over silica eluting with 20-80% acetone/heptane afforded the title compound as an orange solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[C:25]([O:35][CH:36]2[O:38][C@H:37]2[CH3:39])=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:10][N:11]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:12]1)[CH2:39][C@H:37]([OH:38])[CH2:36][O:35][C:25]1[C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:33][C:34]=2[CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(NCc3ccccc3)C2)cc1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3cccc4[nH]c5ccccc5c34)C2)cc1

Procedure:
Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine (which was obtained in Example 398) (1.95 g, 6.87 mmol) and (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (Berridge et al., Int. J. RadiaL Appl. Instrum., 1992, 563) (1.64 g, 6.87 mmol) was stirred at reflux in anhydrous methanol for 24 hours. Methanol was removed in vacuo and the desired product was isolated using silica gel flash chromatography to give 3.01 g of product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ2.90 (m, 2H), 3.04 (s, 1H), 3.85 (m, 3H), 3.98 (m, 3H), 4.23 (m, 3H), 6.01 (d, 2H, J=7.26Hz), 6.61 (d, 1H, J=8.10 Hz), 7.06 (d, 1H, J=8.04 Hz), 7.17 (t, 1H, J=2.14 Hz), 7.34 (m, 7H), 7.97 (d, 2H, J=9.12 Hz), 8.14 (t, 2H, J=8.79 Hz); MS (ES) m/z: 522.9 (MH+); Anal. Calcd. for C31H30N4O4: C, 71.25; H, 5.79; N, 10.72. Found: C, 70.77; H, 6.17; N, 9.61.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19]>C(O)C>[ClH:19].[ClH:19].[ClH:19].[ClH:19].[C:1]1([CH:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][N:12]3[CH2:13][CH2:14][N:9]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[CH2:10][CH2:11]3)[CH2:13][CH2:14]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: ClCCCBr
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(CCCN2CCN(C(C)c3ccccc3)CC2)CC1
Product: Cl
Yield: 211.9 %

Procedure:
A mixture of 7.6 g of 1-(1-phenylethyl)piperazine, 3.2 g of 1-bromo-3-chloropropane and 50 ml of reagent ethanol was refluxed for 5 hours. The solvent was then removed under vacuum, 75 ml of water were added, and the mixture was extracted with ether (3×150 ml). The ether extract was evaporated to an oil and chromatographed on silica, the eluant being CH2Cl2 /CH3OH/ammonium hydroxide (45:5:1). The resulting yellow oil was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrogen chloride to yield 6.1 g (51% of theory) of 1,3-bis[4-(1-phenylethyl) -1-piperazinyl]propane tetrahydrochloride. The product was recrystallized from ethanol/water to yield a white crystalline solid (m.p. 236°-246° C., with decomp.).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([C:19](=[CH2:21])[CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:23])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([C:19](=[CH2:21])[CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:23])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:26])[CH3:25]
Reactant: C=C1C[C@]2(CC)C(=O)C[C@H](O)[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C1C[C@]2(CC)C(=O)C[C@H](OC(C)=O)[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Temperature: 0 °C

Procedure:
2.2 g of 15α-hydroxy-18-methyl-11-methylene-4-estrene-3,17-dione is reacted in 10 ml of pyridine with 2.5 ml of acetic anhydride under argon at room temperature within 2 hours. The solution is introduced into ice/water. The thus-precipitated crude product is vacuum-filtered, dissolved in ethyl acetate, and dried. Chromatography of the crude product on silica gel with 0-20% acetone/hexane yields 1.7 g of 15α-acetoxy-18-methyl-11-methylene-4-estrene-3,17-dione, mp 176.3° C.
Reaction SMILES: CC(OC([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)C.[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: Cc1cccc(N)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)[C@@H]2Cc3ccccc3CN2)c1C

Procedure:
N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 2,3-dimethyl aniline using standard peptide coupling procedures. The product was deprotected using TFA in CH2Cl2 to give the title compound.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[Br:49])[C:37]1=[O:50].O>CN(C=O)C.C(OCC)(=O)C>[Br:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[CH:38]1[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[C:37]1=[O:50]
Reactant: NN1CCCC(c2ccc(F)cc2Br)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(F)cc3Br)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
BOPCl (1.48 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1.0 g), 1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (1.15 g) and TEA (1.1 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 953 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH:12]([OH:15])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=[O:15])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of 5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-ol (455 mg, 1.88 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with pyridine (0.38 mL, 4.6 mmol), followed by Dess-Martin periodinane (1.95 g, 4.6 mmol) and warmed to ambient temperature. After 2 h, 3 drops of H2O were added. After 0.5 h, the reaction was quenched with saturated NaHCO3, saturated Na2SO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried and concentrated in vacuo. Purification by silica gel chromatography gave the target compound (200 mg, 44%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.50 (m, 1 H) 1.51-1.58 (m, 1 H) 2.11 (dd, 1 H) 2.21-2.37 (m, 3 H) 2.37-2.45 (m, 1 H) 7.04 (dd, 1H) 7.32 (d, 1 H) 7.37 (d, 1 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@@H:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: C[C@@H](N)c1ccnc2ccccc12
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccnc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(quinolin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 554 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[OH-].[CH2:17]([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CI>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:17]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6.0 g of 5-(tert-butyl)-2-hydroxybenzoic acid methyl ester in a round bottom flask was added tetrabutyl-ammoniumhydroxide 40% solution (7.45 g, 1 eq). The resulting solution was stirred at room temperature for 2 hr. All water was evaporated under reduced pressure and then in vacuo. To remove trace water, the salt was dried in a vacuum oven overnight and yielded 12.9 g (99%). To a solution of 12.9 g of tetra-butylammonium salt in 50 ml dry THF was slowly added methyliodide (3.61 mL, 2 eq). The resulting solution was stirred at room temperature for 2 hr. After the reaction was completed, the product was filtered out using ammonium iodide salt and washed with ethylacetate twice. The pH was adjusted to pH=2–3 using 1M HCl solution. This organic layer was collected by extraction with ethylacetate and water three times. The organic layer was dried over anhydrous magnesium sulfate (MgSO4). The organic layer was evaporated and the residue was purified by column chromatography (ethylacetate:hexane=1:5) (yield: 3.8 g, 60.0%) 1H NMR (CDCl3, 300 MHz): δ 1.30 (s, 9H), 3.86 (s, 3H), 3.90 (s, 3H), 6.90 (d, J=10.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.82 (s, 1H).
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#[N:38].[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([CH2:2][C:3]([NH2:38])([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[OH:4])[CH3:30])=[CH:20][CH:21]=1)=[O:27]
Reactant: [BH3-]C#N
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)CC(N)(O)c2ccc3ccccc3c2)cc1
Yield: 51.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(2-naphthyl)ethanol (prepared as described in Preparation 9), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.49 g of sodium cyanoborohydride, 3.23 g of the title compound were obtained having an Rf=0.15 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).