Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C(OCC)(=O)C>O1CCOCC1>[C:23]1([CH2:22][CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1conc1-c1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
{3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (54 mg, 0.137 mmol) was dissolved in dioxane (9 mL) and treated with conc. HCl (1.5 mL). After stirring for 12 h at rt the reaction mixture was quenched with 10 mL of satd aqueous NaHCO3. The organic layer was separated and dried over Na2SO4. Filtration followed by removal of volatiles under reduce d pressure gave crude product. 3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-ylamine (22 mg, 55%) was isolated as a white solid by column chromatography (30% ethyl acetate in hexanes). HRMS: 295.144 (M+1).
Reaction SMILES: O[C:2]1[C:3](=O)O[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1O.O[C:16]1C(=O)OC(C2C=CC(Cl)=CC=2)[C:20]=1O.OC1C(=O)OC(C(O)CO)C=1O.OC1C(=O)OC(C2C=CC(C)=CC=2CCC)C=1O.O1CC=CC1=O>>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:20]=[CH:16][CH:3]=[CH:2][CH:6]=1
Reactant: O=C1OC(c2ccc(Cl)cc2)C(O)=C1O
Reactant: O=C1OC(c2ccccc2)C(O)=C1O
Agent: CCCc1cc(C)ccc1C1OC(=O)C(O)=C1O
Agent: O=C1C=CCO1
Agent: O=C1OC(C(O)CO)C(O)=C1O
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Non-limiting examples of known compounds useful for the present invention wherein one R (R1) is H and the other (R2) is a substituted or unsubstituted phenyl group include 3,4-dihydroxy-5-phenyl-2(5H)-furanone (sometimes called 4-phenyl-2-hydroxytetronic acid); 3,4-dihydroxy-5-(4′-chlorophenyl)-2(5H)-furanone (sometimes called 4-(4′-chlorophenyl)-2-hydroxytetronic acid); 3,4-dihydroxy-5-(1′,2′-dihydroxyethyl)-2(5H)-furanone (sometimes called 4-dihydroxyethyl-2-hydroxytetronic acid); 3,4-dihydroxy-5-(4′methylpropylphenyl)-2(5H)-furanone; and 3,4-dihydroxy-5-[4-(5-methylfur)-2-yl)phenyl]-2(5H)-furanone. As mentioned above, a subgroup bearing these substituents include compounds wherein R1 is H and R2 is a phenyl bearing another phenyl, forming a biphenyl, such as 3,4-dihydroxy-5-(1,1′-biphenyl)-2(5H)-furanone (sometimes called 4-biphenyl-2-hydroxytetronic acid); 3,4-dihydroxy-5-(4″-chlorobiphenyl)-2(5H)-furanone (sometimes called 4-chloro-biphe-nyl)-2-hydroxytetronic acid); 3,4-dihydroxy-5-[(4′-nitro-1,1′-biphenyl)-4-yl]-2(5H)-furanone; 3,4-dihydroxy-5-[(4′-methyl-1,1′-biphenyl)-4-yl]-2(5H)-furanone; 3,4-dihydroxy-5-[(2′,4′-dimethyl-1,1′-biphenyl)-4-yl]-2(5H)-furanone; 3,4-dihydroxy-5-[(3′,4′-dimethyl-1,1′-biphenyl)-4-yl]-2(5H)-furanone; and 3,4-dihydroxy-5-[(4′-meth-oxy-1,1′-biphenyl)-4-yl]-2(5H)-furanone. In another subgroup of compounds, R1 is H and R2 is a phenyl substituted with a heteroaromatic (furyl or pyridyl) group such as, for example, 3,4-dihydroxy-5-[4-(5-methylfur)-2-yl)phenyl]-2(5H)-furanone; 3,4-dihydroxy-5-[4-(5-methylpyrid)-2-yl)phenyl]-2(5H)-furanone; 3,4-dihydroxy-5-[4-(3-methylpyrid)-2-yl)phenyl]-2(5H)-furanone; 3,4-dihydroxy-5-[4-(4-methylpyrid)-2-yl)phenyl]-2(5H)-furanone; 3,4-dihydroxy-5-[4-(4-methylpyrid)-3-yl)phenyl]-2(5H)-furanone; 3,4-dihydroxy-5-[4-(5-methylpyrid)-3-yl)phenyl]-2(5H)-furanone; and 3,4-dihydroxy-5-[4-(2-methylpyrid)-3-yl)phenyl]-2(5H)-furanone.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=[CH:27][CH:28]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=5:5:1) to yield the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C=O.C(Cl)(Cl)Cl.N>C(O)=O>[C:36]([C:33]1[CH:34]=[CH:35][C:29]2[O:28][C:27]([CH2:26][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C@H:10]4[CH2:11][CH2:12][N:8]([CH3:6])[CH2:9]4)=[CH:15][CH:16]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][C:30]=2[CH:32]=1)#[N:37]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C)C2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
1.8 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate was dissolved in 28 ml of formic acid, and the solution was stirred at 70° C. for 1 hour. The resulting reaction solution was concentrated to dryness, and the residue thus obtained was dissolved in 8 ml of formic acid. 0.29 ml of 37% formaldehyde was added thereto, and then refluxed under heating for 4 hours. After cooling, the reaction solution was mixed with chloroform, and then adjusted to pH 10-11 with aqueous ammonia, and the resulting organic layer was collected and dried. Thereafter, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography using a chloroform/methanol mixture as an eluant. In this way, 1.07 g of the title compound was obtained in an oily form.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].[Br:20][C:21]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3([CH2:34][CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:32][CH2:33][C:22]=1[C:23]=23>CN(C=O)C>[Br:20][C:21]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3([CH2:34][CH2:35][CH2:36][CH2:37][N:2]4[CH2:3][CH2:4][C:5]5[C:13]6[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=6)[NH:7][C:6]=5[CH2:1]4)[CH2:31][CH2:32][CH2:33][C:22]=1[C:23]=23
Reactant: O=C1Nc2ccc(Br)c3c2C1(CCCCBr)CCC3
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Br)c3c2C1(CCCCN1CCc2c([nH]c4ccccc24)C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A 31 mg (0.18 mmol) portion of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 62 mg (0.54 mmol) of potassium carbonate were added to 1 ml of DMF solution containing 58 mg (0.15 mmol) of 6-bromo-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from acetone-diisopropyl ether to obtain 50 mg of the title compound (70% in yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([O-:33])=[O:32].[K+].O>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([N+:31]([O-:33])=[O:32])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)cc(Br)c1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n1-c1cc(Cl)cc(Br)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of 1,3-dihydro-1-(5-chloro-3-bromo-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (1 g, 2.5 mmol) in glacial acetic acid (5 ml) was under stirring on an ice bath added acetic anhydride (2.5 ml) and two drops of concentrated sulfuric acid. When the starting material had gone into solution, an ice cold solution of potassium nitrate (0.3 g, 3 mmol) in concentrated sulfuric acid (1 ml) was added, and the mixture was stirred for 15 minutes. The reaction mixture was poured into water, the crystalline product was collected by filtration and the acetate was hydrolysed by reflux in ethanol (50 ml) and 4M sodium hydroxide (5 ml) for one hour. The reaction mixture was acidified by addition of 4M hydrochloric acid and water was added until starting precipitation. The mixture was cooled and the crystals were collected by filtration yielding the title compound as slightly yellow crystals, M.p. 262°-264° C.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[O:6]1[CH2:9][CH:8](N)[CH2:7]1>O>[S:1]([NH:5][CH:8]1[CH2:9][O:6][CH2:7]1)(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: NC1COC1
Solvent: O
Product: NS(=O)(=O)NC1COC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Sulfamide (15.6 mmol) was dissolved in H2O (8 mL), added oxetan-3-amine (6.85 mmol) and stirred at 70° C. for 16 h and then at 100° C. for another 16 h. The obtained reaction mixture was cooled to rt and freezedried affording the title compound as white solid. Used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[N:14]3[CH2:15][CH2:16][N:17]([C:19]([C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[O:20])[CH2:18][C@@H:13]3[CH2:12][CH2:11][CH2:10]2)=[C:5]([CH3:31])[C:4]=1[CH3:32].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[N:14]3[CH2:15][CH2:16][N:17]([C:19]([C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[O:20])[CH2:18][C@@H:13]3[CH2:12][CH2:11][CH2:10]2)=[C:5]([CH3:31])[C:4]=1[CH3:32]
Reactant: COc1ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c(C)c1C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(O)ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c1C
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A CH2Cl2 solution of [(6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-methanone obtained in step 5 (2.30 g, 5.14 mmoles) is treated with 15.4 mL of HCl (1 M in Et2O) and allowed to stand for 10 min. This solution is concentrated in vacuo and then dissolved in 70 mL anhydrous CH2Cl2. This solution is cooled to −70° C. (dry ice/isopropanol bath) under nitrogen and treated with BBr3 (1 M in DCM, 20.6 mL) dropwise via syringe over 20 mins. The mixture is stirred for 18 h while warming to ambient temperature. After this time, the mixture is cooled to 0° C., treated with 150 mL saturated NaHCO3 and stirred vigorously for 30 min. The phases are separated and the aqueous phase is extracted three times with CH2Cl2. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to afford [(6R,9aS)-6-(4-hydroxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-methanon as a light brown solid which is used without additional purification. LC/MS: 434 (M+1). 1H NMR (mixture of rotamers, 400 MHz, CDCl3): 8.74 (1H, d), 7.94 (1H, dd), 7.88 (1H, dd), 7.22 (1H, dd), 6.64 (1H, dd), 4.92 (1H, bs), 4.50 (1H, dd), 3.41-3.30 (2H, bm), 3.21 (1H, m), 3.03 (1H, m), 2.91-2.53 (3H, bm), 2.25-2.14 (6H, m), 1.92-1.58 (5H, bm), 1.20-1.32 (3H, bm).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1O>>[CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14][C:29]2[CH:28]=[CH:27][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:10]1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1ccc2ccccc2c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc3ccccc3c2)C1
Yield: 40 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 2-naphthol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous yellow solid (yield 40%). MS (m/e): 454.5 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13][CH2:14][C:15]([O:17]C)=[O:16])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13][CH2:14][C:15]([OH:17])=[O:16])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)CSCc1ccc(OC)c([N+](=O)[O-])n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(CSCC(=O)O)nc1[N+](=O)[O-]
Yield: 97 %

Procedure:
To 150 mL of sodium carbonate 1N solution, methyl 2-((5-methoxy-6-nitropyridin-2-yl)methylthio)acetate (10 mmol, 2.72 g) was added and the mixture was reacted at 50° C. for 16 hrs. The mixture was evaporated in vacuo to give 2-((5-methoxy-6-nitropyridin-2-yl)methylthio)acetic acid. Yield 97%; m.p. 239-230° C. (dec); 1H-NMR (D2O) δ: 3.04 (s, 2H, CH2), 3.65 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 7.54 (d, 1H, J=8.4 Hz, Py-H), 8.429 (d, 1H, J=8.4 Hz, Py-H); 13C-NMR (O2O) δ: 35.79, 36.48, 56.96, 125.75, 130.76, 145.07, 147.96, 148.14, 177.11; DEPT-135 (D2O) δ: 35.79 (CH2), 36.48 (CH2), 56.96 (CH3), 125.75 (CH), 130.76 (CH); HR-MS (ESI+) m/z 257.0101 [M−H]−, C9H10N2O5S requires 258.0310.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=O)[C:26]=12)=[O:29])(=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:31](=[O:30])[C:26]3[C:27](=[CH:33][CH:34]=[CH:35][C:25]=3[NH:24][C:21](=[O:23])[CH3:22])[C:28]2=[O:29])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 402.8 %

Procedure:
N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of example 4 from 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.6 g, 0.2 mmol), 3-acetamido-phthalic anhydride (0.4 g, 0.2 mmol) and sodium acetate (0.16 g, 0.2 mmol) in acetic acid (15 ml) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as white solid (0.4 g, 40%): mp 118-120° C.; 1H NMR (CDCl3) δ1.45 (t, J=7.0 Hz, 3H, CH3), 2.27 (s, 3H, CH3CO), 2.92 (s, 3H, SO2CH3), 3.66 (dd, J=3.8, 14 Hz, 1H, CH2), 4.11 (q, J=6.8 Hz, 2H, OCH2), 5.88-5.94 (m, 1H, NCH), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.12-7.16 (m, 3H, Ar), 7.49 (d, J=7.5 Hz, 1H, Ar), 7.66 (t, J=7.5 Hz, 1H, Ar), 8.77 (d, J=8.5 Hz, 1H, Ar), 9.44 (s, 1H, NH); 13C NMR (CDCl3) δ 14.5, 24.9, 41.7, 48.3, 54.1, 64.9, 11.5, 113.6, 115.0, 115.8, 118.3, 120.0, 120.2, 123.1, 125.1, 130.9, 135.4, 136.2, 137.7, 140.4, 150.9, 167.4, 169.1, 169.4; Anal Calcd for C22H22F2N2O7S: C, 53.22; H, 4.47; N, 5.64. Found: C, 53.18; H, 4.20; N, 5.64.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3]C(C)(C)C)=O.[CH2:20]([NH:27][CH2:28]C(OCC)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:20]([N:27]1[CH2:28][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C1CN(Cc2ccccc2)C(=O)[C@H](Cc2ccccc2)N1
Yield: 88.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-phenylalanine (12.8 g, 48.2 mmol), ethyl N-benzylglycinate (9.32 g, 48.2 mmol) and dicyclohexylcarbodiimide (96.5 mL 0.5M in dichloromethane, 48.2 mmol). The crude diketopiperazine was triturated with hexane to give the title compound as a white powder (12.5 g). NMR (300 MHz, CD3OD) δ 7.0-7.4 (10H, m), 4.61 (1H, d, J=16 Hz), 4.37 (1H, t, J=5 Hz), 4.24 (1H, d, J=16 Hz), 3.42 (1H, d, J=18 Hz), 3.28 (1H, dd, J=4, 16 Hz), 2.96 (1H, dd, J=6, 16 Hz), 2.55 (1H, d, J=18 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C:8](=[O:40])[C@@H:9]([NH:22]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2.N1CCCCC1>>[NH2:22][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[C:8]([N:7]([CH2:6][C:4]1[C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]=2[S:1][CH:5]=1)[C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])=[O:40]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 97.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-1-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-6) 500 mg (0.68 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 339 mg (98%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[CH:18]=[O:19].[H-].[Na+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:17]([CH:18]=[O:19])[CH:20]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
3-Hydroxyphenylacetic acid (1.34 g, 8.8 mmol) and 5-bromo-2-fluorobenzaldehyde (1.78 g, 8.8 mmol) were combined in DMF (30 mL) at room temperature. Sodium hydride (60% in mineral oil; 0.72 g, 18.0 mmol) was added, and the reaction was stirred at 70° C. for 2 hours. Aqueous work-up yielded the title compound.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C[S-].[Na+]>CN(C)C=O>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC(c3ccc(O)cc3)=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]1CC13OCCOC12OCCO3

Procedure:
17,17-bis-(ethylenedioxy)11-(4-methoxyphenyl)-5,9(11)-estradiene is dissolved in 100 ml of absolute dimethylformamide, mixed with 5.6 g of sodium methanethiolate and the reaction mixture is refluxed for 3 hours. After cooling it is poured on water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed several times with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane and 8.67 g of 3,3;17,17-bis-(ethylenedioxy)-11-(4-hydroxyphenyl)-5,9(11)-estradiene is obtained as white foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH-].[Na+]>C(#N)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)CCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCOC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester (300 mg, 0.89 mmol) and acetonitrile (5 mL) were added 2-dimethylaminoethanol (89 μL, 0.89 mmol) and benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (390 mg, 0.89 mmol) at 0° C., which was stirred overnight at room temperature. A 1N sodium hydroxide aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed first with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, so s to obtain the titled compound (380 mg, purity of 77%).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27]CO)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:6]([O:13][C:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][CH2:1][Cl:5])=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12)OCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc([N+](=O)[O-])c(CCCl)c2ccccc12)OCc1ccccc1
Reaction time: 3 h
Yield: 96.2 %

Procedure:
CCl4 (0.2 mL, 2.18 mmol) was added to a solution of 2-[4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]ethanol (0.1 g, 0.27 mmol) and Ph3P (0.29 g, 1.09 mmol) in CH2Cl2 (5 mL) under N2 atmosphere and stirred for 3 h. Flash chromatography (10% AcOEt-Petroleum ether) afforded of 2-[4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]ethyl chloride (0.1 g, 96%) as an orange solid. M.p. 122-124° C.; 1H NMR (CDCl3, 500 MHz) δ 8.18 (d, 8.5, 1H), 7.89 (d, 8.5, 1H), 7.70 (t, 7.0, 1H), 7.62 (t, 7.0, 1H), 7.45 (d, 7.0, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 6.95 (s, 1H), 4.93 (brs, 1H), 4.51 (d, 5.0, 2H), 3.86 (t, 8.0, 2H), 3.56 (t, 8.5, 2H); IR (neat) 3087, 3033, 2927, 2856, 1594, 1519, 1439, 1342, 1124, 752, 699 cm−1. FABMS (NBA) m/z 340 (M−CO2+), ESMS m/z 341 (M−CO2+H+).