Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5](=[C:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:5](=[C:12]1[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]1=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NCCC1=Cc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: O=C(Cl)N1CCC(=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g (20.5 mmols) of phosgene are added to a suspension of 3.0 g (18.6 mmols) of 3-benzylidene-2-pyrrolidinone 50 ml in abs. ethyl acetate at -20°. A solution of 3.8 g (20.5 mmols) of tri-n-butylamine in 20 ml of abs. ethyl acetate is added dropwise to this mixture at 0° to 5°. After stirring for 4 hours at room temperature, dry nitrogen is passed through the mixture for 30 minutes and the mixture is then concentrated. Water is added to the oily residue, whereupon the acid chloride precipitates in the solid form. It is filtered off and dried over P2O5 and KOH is a desiccator. 3.5 g (84.5%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TFA (171 mL) was added to a solution of (S)-tert-butyl-1-hydroxy-3-(4-nitrophenyl)propan-2-ylcarbamate 20 (Erlanson et al., U.S. Pat. No. 7,214,487 B2; 13.9 g, 46.9 mmol) in DCM (272 mL) at 0° C. The reaction mixture was warmed to RT and reaction was allowed to proceed for 25 minutes. The solution was concentrated to afford 9.2 g of crude (S)-2-amino-3-(4-nitrophenyl)propan-1-ol as a white solid. To a solution of this crude product and sodium carbonate (12.4 g, 117.3 mmol) in THF (87 mL) and water (87 mL) was added N-carbethoxyphthalimide (“CEPT,” 12.3 g, 56.3 mmol). After the reaction mixture was stirred at RT for 4 h, EtOAc (150 mL) was added. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a crude residue which was purified by flash chromatography eluting from silica gel with a gradient of 0-100% EtOAc in hexanes to give 12.3 g of alcohol 30. MS: (+) m/z 327.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][C:6]2=[S:23])[CH2:3][CH2:2]1.[S]>ClC1C=CC=CC=1Cl>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:7][C:6]2=[S:23])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C(c1ccccc1)NC(=S)N2CC1CC1
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: COc1ccc2c(c1)c(-c1ccccc1)nc(=S)n2CC1CC1
Yield: 78.3 %

Procedure:
A mixture of 1.62 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinethione, 0.48 g of sulfur and 10 ml of o-dichlorobenzene was stirred under reflux for 5 hours. The solvent was then removed under reduced pressure and the residue was chromatographed on a silica gel column, eluting with chloroform to give 1.26 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(1H)-quinazolinethione, m.p. 180°-181° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](B(O)O)=[CH:20]1>>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([C:15]2[CH:16]=[C:17]3[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=[CH:11][C:12]3=[N:13][CH:14]=2)=[CH:20]1
Reactant: OB(O)c1csc2ccccc12
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
Product: c1ccc(COn2ccc3ncc(-c4csc5ccccc45)cc32)cc1

Procedure:
The entitled compound was prepared from 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and 1-benzothiophen-3-ylboronic acid according to the procedure described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Product: O=C(NCCO)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 72 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using ethanolamine instead of 4-aminotetrahydropyran to the title compound (82 mg, 72%) which was obtained as a white solid. MS: m/e=341.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12]O)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][N:27]([C@@H:35]([CH3:59])[C:36]([NH:38][C@H:39]1[C@H:45]([CH3:46])[N:44]([C:47](=[O:53])[CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[C:43]2[CH:54]=[CH:55][CH:56]=[CH:57][C:42]=2[NH:41][C:40]1=[O:58])=[O:37])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:26][N:27]([C@@H:35]([CH3:59])[C:36]([NH:38][C@H:39]1[C@H:45]([CH3:46])[N:44]([C:47](=[O:53])[CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])[C:43]2[CH:54]=[CH:55][CH:56]=[CH:57][C:42]=2[N:41]([CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[CH:3][C:2]=2[CH3:1])[C:40]1=[O:58])=[O:37])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cnc2ccccc2c1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a rt suspension of (3-methylquinolin-4-yl)methanol (90 mg, 520 μmol) in CH2Cl2 (5.2 ml) was added triethylamine (145 μl, 1.04 mmol), followed by methanesulfonyl chloride (48.4 μl, 624 μmol), dropwise. The reaction was stirred at rt for 2 h, then diluted with CH2Cl2, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. This material was mixed with tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (167 mg, 336 μmol), cesium carbonate (142 mg, 437 μmol), and sodium iodide (65.5 mg, 437 μmol) in DMF (841 μl). The reaction was stirred at rt for 3.5 days, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl methyl((S)-1-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (142 mg, 65%) as a white solid. MS m/z 652 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.O.O=P(Cl)(Cl)[Cl:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:28][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reaction time: 2 h
Yield: 96 %

Procedure:
A 100 mL round-bottomed flask was charged with ethyl-4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (6.49 g, 28.4 mmol) in 14 mL POCl3. To the solution was added N,N-diisopropylethylamine (1.2 mL), the reaction mixture was stirred at 80˜90° C. for 2 hours. The mixture was condensed under reduced pressure yielding the dark brown residue. To the residue was added iced water, then diluted with DCM, and saturated aqueous NaHCO3 solution. The separated organic layer was dried over MgSO4. The solvent was removed by a rotavapor providing dark brown oily product (6.76 g, 96%). MS m/z: 246.9 (M+H)+, 248.9 (isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:17](Br)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1

Procedure:
2-Nitrophenol (11.0 g, 79 mmole), anhydrous potassium carbonate (17.6 g, 127.4 mmole) and benzhydryl bromide (19.6 g, 79 mmol) in acetone (220 ml) were refluxed under nitrogen for 5 hours. The mixture was cooled, filtered and evaporated in vacuo. The residue was triturated with diethyl ether, filtered and evaporated. Trituration with 60°-80° C. petroleum ether yielded a brown solid.
Reaction SMILES: [CH2:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])[C:2]#[CH:3].[Li]CCCC.[Al](Cl)(C)C.[CH2:17]([C@@H:19]1[O:21][CH2:20]1)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][CH2:17][C@H:19]([OH:21])[CH2:20][C:3]#[C:2][CH2:1][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CC[Si](C)(C)C
Reactant: ClC[C@H]1CO1
Agent: C[Al](C)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CC#CC[C@@H](O)CCl
Reaction time: 24 h
Yield: 66.6 %

Procedure:
14.11 g (126 mmol) of propargyltrimethylsilane was dissolved in 125 ml of abs. toluene and cooled to -17°. 81.1 ml of nBuLi (1.55M, hexane) was slowly added while keeping the temperature below -5°. 5 Minutes later, 126 ml of Me2AlCl (1M, hexane) was added to this solution of the Li-acetylide. The temperature was then lowered to -45° and 6.90 ml of (R)-epichlorohydrine (88 mmol), dissolved in 50 ml of toluene, was added. The cooling bath was then removed and the reaction mixture allowed to reach ambient temperature during 24 h. After careful quenching with icecold water and filtration, the product was extracted with ether, washed with NH4Cl, dried over sodium sulfate and the solvents removed i. V. Flash chromatography (SiO2, hexane/AcOEt=86/14) yielded 12.01 g of (R)-1-chloro-6-trimethylsilanyl-hex-4-yn-2-ol as colorless oil, 97% pure according to GC.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].Cl[C:26]([O:28][CH2:29][CH2:30]Br)=[O:27].[OH-].[Na+].C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:1]([C:3](=[C:26]1[O:28][CH2:29][CH2:30][O:27]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:13])[F:11])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1CC(C)C
Reactant: O=C(Cl)OCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCO2)c1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of 5.0 g (14.3 mmol) of 5-(cyanomethyl)-4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 8.02 g 2-bromoethyl chloroformate, and 0.3 g benzyltriethylammonium chloride in 125 mL dichloromethane was added 82 mL 50% NaOH. The solution was stirred at room temperature for one hour. The mixture was then poured into ice water and extracted twice with ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered through silica gel, and concentrated to give 3.2 g of crude dark yellow oil. Chromatography using 50% ethyl acetate in hexanes yielded 2.0 g of the desired product as a light yellow oil, a 56% yield, which crystallized upon standing. m.p. 121°-122° C.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.CI>O1CCCC1>[CH3:1][C:16]1([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: [Li]CCCC
Reactant: O=C(O)C1CCOCC1
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
Butyllithium (21.1 ml, 33.8 mmol, 1.6 M in hexanes) was added dropwise over 10 minutes to a stirred solution of diisopropylamine (4.7 ml, 33.8 mmol) in anhydrous tetrahydrofuran (40 ml) under an atmosphere of nitrogen at <10° C. Upon addition, tetrahydropyran-4-carboxylic acid (J. Am. Chem. Soc., 1993, 115, 8407) was added in anhydrous tetrahydrofuran (20 ml) under nitrogen at <5° C. The mixture was stirred at room temperature for one hour after which methyl iodide (2.4 ml, 38.4 mmol) was added dropwise at <5° C. The resultant solution was stirred at <50° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 3.5 days. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and 2N hydrochloric acid (100 ml) added. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic layers were washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and evaporated to yield the title product (1.4 g) which was used in the next step without purification. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.00 (3H, s), 1.47-1.58 (2H, m), 2.06-2.11 (2H, m), 3.49-3.60 (2H, m), 3.78-3.86 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COc2ccccc2)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.103 g, 0.24 mmol) and phenol (0.012 g, 0.26 mmol) in 1,4-dioxane (2 mL) was added sodium hydride (60% in mineral oil; 0.013 g, 0.29 mmol), and the reaction was stirred at 55° C. overnight. The mixture was quenched with H2O, and the solution was used directly in the hydrolysis step.
Reaction SMILES: CS[C:3]1[N:4]([CH2:8][C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][N:7]=1>CCO.O.[Ni]>[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][N:4]4[CH:5]=[CH:6][N:7]=[CH:3]4)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:16][CH:17]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CSc1nccn1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: c1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cn1
Yield: 35.5 %

Procedure:
To a solution of 2-(methylthio)-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole (90 mg, 0.22 mmol) in EtOH (4 ml) and water (1 ml) was added Raney Nickel (50% slurry in water) in 200 mg aliquots every 30 min. After 3 h all starting material had been consumed. The mixture was filtered through Arbocel® with EtOH (200 ml) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:10:1) to provide the title compound as a yellow oil (29 mg, 0.078 mmol, 36%). 1H NMR (400 MHz, CDCl3) δ 1.80-2.00 (m, 6H), 2.10 (m, 4H), 2.70-2.90 (m, 6H), 3.50 (t, 2H), 3.81 (m, 2H), 3.97 (s, 2H), 4.04 (t, 2H), 6.32 (s, 1H), 6.80-6.90 (m, 4H), 6.98 (d, 2H). HRMS ESI+ m/z 370.2485 [MH]+.
Reaction SMILES: C(Br)C1C=CC=CC=1.C(OC1C(O)=CC2CC[C@@H]3[C@@H](C=2C=1)CC[C@@]1(C)[C@H]3CC[C@@H]1O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:38]([O:40][C:41]1[C:42]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:43][C:44]2[CH2:45][CH2:46][C@@H:47]3[C@@H:56]([C:57]=2[CH:58]=1)[CH2:55][CH2:54][C@@:52]1([CH3:53])[C@H:48]3[CH2:49][CH2:50][C@@H:51]1[OH:59])[CH3:39]>C(O)C.ClCCl.O=[Mn]=O>[CH2:38]([O:40][C:41]1[C:42]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:43][C:44]2[CH2:45][CH2:46][C@@H:47]3[C@@H:56]([C:57]=2[CH:58]=1)[CH2:55][CH2:54][C@@:52]1([CH3:53])[C@H:48]3[CH2:49][CH2:50][C:51]1=[O:59])[CH3:39]
Reactant: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=[Mn]=O
Agent: BrCc1ccccc1
Agent: CCOc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: ClCCl
Solvent: CCO
Product: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 7 h
Yield: 8 %

Procedure:
Benzyl bromide (4.5 g, 38 mmol) was added under argon atmosphere at 0° C. to a suspension of 2-ethoxy-β-estradiol (2) (4.5 g, 13 mmol) and potassium carbonate (8.6 g, 62 mmol) in anhydrous ethanol (100 mL). The resulting mixture was stirred at reflux for 7.5 h. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic extract was washed with water (100 mL), sodium bicarbonate (120 mL), brine (100 mL) and dried over sodium sulfate. Evaporation of the ethyl acetate under reduced pressure gave a viscous oil containing (17), which was used without further purification. Activated MnO2 (3 g) was added under an arcon atmosphere to a solution of crude alcohol (17) (1.6 g, 3.9 mmol) in anhydrous dichloromethane (50 mL). After 7 h, an additional amount of MnO2 (5 g) was added and the reaction mixture was left over night at room temperature. MnO2 (4 g) was added again and stirring was continued for 7 h. The mixture was filtered through a celite pad and the filtrate was evaporated under reduced pressure to give crude product, which was purified by column chromatography on silica gel using hexane, followed by hexane-CH2C2 (2:8) to afford pure ketone (18) (0.42 g, 8%): IR (neat) 3065, 2929, 2869, 2825, 1727, 1607, 1504, 1450 cm-1 ; 1H NMR (CDCl3) δ 0.92 (s, 3 H), 1.30-2.60 (m, 16 H), 2.83 (m, 2 H), 4.07 (q, J=8.5 Hz, 2 H), 5.10 (s, 2 H), 6.68 (s, 1 H), 6.88 (s, 1 H), 7.20-7.60 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3ccccc3)cc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of methyl 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoate (1.5 g, 3.41 mmol) dissolved in ethanol (85 ml) and ethyleneglycol dimethyl ether (3.41 ml), 10% NaOH (34.1 ml, aqueous solution) was added dropwise. The resulting mixture was stirred under reflux and the progress of the reaction was monitored by TLC. Upon completion of the reaction, ethanol was removed under reduced pressure and the resulting aqueous solution was cooled to 0° C., neutralized with HCl 6N and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure, to obtain 1.26 g of 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid: Yield 88%; m.p. 260° C. (dec); IR 3408, 3268, 1684, 1525, 1496, 1264 cm−1; 1H-NMR (300 MHz, δ ppm, DMSO-d6) 11.57 (s, 1H), 8.00 (t, J=5.9 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.80 (d, J=7.3 Hz, 2H), 7.46-7.35 (m, 7H), 7.27 (d, J=7.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.67 (d, J=2.2 Hz, 1H), 4.47 (d, J=5.5 Hz, 2H), 3.76 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 167.1, 160.9, 157.9, 144.8, 133.0, 131.5, 130.1, 129.2, 128.8, 128.5, 128.0, 127.3, 126.7, 124.6, 122.3, 113.1, 108.5, 55.0, 42.0.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)OCC.[C:34](O)(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:37]>C(Cl)Cl>[CH2:9]([C:8]1[O:27][C:34](=[O:42])[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Triethylamine (0.46 ml) was added to a suspension of stearic acid (853 mg) in methylene chloride (8.5 ml). Then, ethyl chlorocarbonate (0.32 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1 hour at 0° C., the mixture, with a mixed solution of anthranilic acid (411 mg) and triethylamine (0.42 ml) in methylene chloride (2 ml) dropwise added thereto, was stirred for 16 hours at 45C and cooled with ice. The reaction mixture, with triethylamine (0.46 ml) and ethyl chlorocarbonate (0.32 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and for 1.5 hours at room temperature successively, and then concentrated. The residue, with ethyl acetate added thereto, was washed with water, neutralized with diluted hydrochloric acid, and washed with saturated brine. The organic layer was dried over magnesium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 35 g, chloroform-methanol), thereby yielding 966 mg of the aimed compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[C:6]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:7]=[CH:2][C:3]=1[CH3:19])=[O:17]
Reactant: C#CC(O)(CCC)CCC
Reactant: Cc1c(Br)cccc1C(O)CCNC(=O)C(F)(F)F
Product: CCCC(O)(C#Cc1ccc(C)c(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(3-bromo-2-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 to give 2,2,2-trifluoro-N-(3-hydroxy-3-(5-(3-hydroxy-3-propylhex-1-ynyl)-2-methylphenyl)propyl)acetamide as a yellow oil. Yield (1.11 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 9.38 (t, J=5.2 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.0, 1.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.26 (d, J=4.4 Hz, 1H), 5.08 (s, 1H), 4.74-4.70 (m, 1H), 3.35-3.25 (m, 2H), 2.21 (s, 3H), 1.78-1.70 (m, 2H), 1.68-1.40 (m, 8H), 0.89 (t, J=7.2 Hz, 6H)