Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH:31][C:32](O)=[O:33])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].CCN=C=N[CH2:40][CH2:41][CH2:42][N:43](C)C.C1(N)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.[NH4+].[Cl-]>[CH:42]1([NH:43][C:32](=[O:33])[CH:31]=[CH:30][C:26]2[CH:25]=[C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:16]4[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:40][CH2:41]1
Reactant: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: NC1CC1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)NC4CC4)c3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-yl}-acrylic acid from Step 2 (1.0 eq.), EDCI (1.3 eq.), DMAP (2.0 eq.) and cyclopropylamine (10.0 eq.) in CH2Cl2 was stirred for 12 h at rt. The mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (EtOAc) afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.94 (dd, 1H), 8.46 (dd, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.76–7.50 (m, 7H), 7.48 (t, 1H), 7.39 (d, NH), 6.7 (d, 1H), 2.87 (m, 1H), 2.75 (s, 3H), 2.02 (s, 6H), 0.71 (m, 2H), 0.52 (m, 2H).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:10]=[CH:9][N:8]=1)(=O)=O.[SH:23][C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)[C:12]=1[CH3:13]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCOCCCOc1ccnc(COS(C)(=O)=O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture comprising 1.9 g of crude [4-{3-(2-methoxyethoxy)propoxy}-3-methylpyridine-2-yl]methyl methanesulfonate, 0.83 g of 2-mercapto-1H-benzimidazole and 20 ml of ethanol was stirred at a room temperature for one hour, made basic with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under a reduced pressure. The obtained residue was chromatographed over a silica gel column and eluted with ethyl acetate/n-hexane to obtain 1.5 g of an oily product.
Reaction SMILES: [CH2:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.FF.B(F)(F)F.CCOCC>C(#N)C>[CH2:9]1[CH:10]2[CH:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][CH2:7][CH2:8]1
Reactant: C1CC[C@H]2CCCC[C@@H]2C1
Agent: FB(F)F
Agent: FF
Solvent: CC#N
Solvent: CCOCC
Product: C1CCC2CCCCC2C1
Temperature: 82 °C
Yield: 50 %

Procedure:
Using a similar procedure to that described above (Method 2), trans-decalin (3.0 g, 22 mmol), elemental fluorine (44 mmol), boron trifluoride etherate (3.1 g, 22 mmol), and anhydrous acetonitrile (120 cm3) gave, after heating (82° C.) and the work-up as detailed above, a crude product mixture which was distilled to give decalin (1.5 g, 11 mmol); bp 50° C./8 mmHg. The brown solid which remained gave, after recrystallisation, N-(trans-9-decalyl)acetamide (1.0 g, 45%, 49% conv.) as a white solid; spectral and physical data as described in Example 3.
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([CH:30]=[CH2:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:32].C(N(CCOC1C=CC(CCC(O)=O)=CC=1)C)CCCCCCCCCCC>>[ClH:32].[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:30]=[CH2:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=Cc1cc(OCCN(C)CCCCCCCCCCCC)ccc1CCC(=O)OC
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)cc1
Agent: Cl
Product: C=Cc1cc(OCCN(C)CCCCCCCCCCCC)ccc1CCC(=O)O
Yield: 93 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propanoic acid, methyl ester (178 mg, 0.412 mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (175 mg, 93%) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C)C=O.O>[CH2:34]([N:36]([CH2:37][CH3:38])[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=1)=[O:9])[CH3:35]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
4-Hydroxymethylbenzoic acid (10.0 g) was dissolved in N,N-dimethylformamide (200 ml), added with 1-hydroxybenzotriazole (9.766 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl, 13.855 g) and stirred at room temperature for 1 hour. The reaction mixture was added with diethylamine (13.6 ml) and further stirred at room temperature for 1 hour. The reaction mixture was added with water (200 ml) and extracted twice with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2) to obtain 12.80 g of the title compound. Yield: 94%.
Reaction SMILES: N[C@@H](C(C)C)CO.[CH:8]([CH:11]1[NH:16][C:15](=[O:17])[CH:14]([CH:18]([CH3:20])[CH3:19])[NH:13][C:12]1=[O:21])([CH3:10])[CH3:9]>>[CH:8]([C@@H:11]1[NH:16][C:15](=[O:17])[C@H:14]([CH:18]([CH3:20])[CH3:19])[NH:13][C:12]1=[O:21])([CH3:10])[CH3:9]
Reactant: CC(C)C1NC(=O)C(C(C)C)NC1=O
Agent: CC(C)[C@H](N)CO
Product: CC(C)[C@@H]1NC(=O)[C@H](C(C)C)NC1=O
Yield: 78 %

Procedure:
Upon refluxing a dioxane solution containing 2 mmol of (2S,3S)-2-amino-3-methylpentan-1-ol and 0.02 mmol of catalyst 1 for 19 hrs and cooling the reaction mixture, the solid product precipitated and was filtered off and dried under vacuum to give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7c in 72% yield (Table 9, entry 2). The structure was confirmed by NMR and MS spectroscopies. Under the same conditions, cyclic peptidation of (S)-2-amino-3-methylbutan-1-ol led to 3,6-diisopropylpiperazine-2,5-dione 7d as an insoluble solid which separated from the reaction mixture and was isolated by filtration and dried under vacuum to give 78% of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7d (Table 9, entry 3). The optical rotation of the pure product (−52°) was essentially the same as reported in the literature (−) 54°. Thus, under these experimental condition, no racemization took place.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([NH2:30])[CH2:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CN1CCOCC1>O1CCOCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([NH:30][C:8](=[N:16][C:17]#[N:18])[NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: NC1(c2cccc(Cl)c2)CCC1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: N#CN=C(Nc1cccnc1)NC1(c2cccc(Cl)c2)CCC1
Reaction time: 1 h
Yield: 46 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (2.62 g, 0.0110 mol), the product from Step 4 (2.00 g, 0.0110 mol), N-methylmorpholine (3.00 ml, 0.275 mol) and 1,4-dioxane (40 ml) was refluxed, under nitrogen for 4 hours and kept ambient temperature for 1 hour. The product which had precipitated from the mixture was collected by filtration, washed with tert-butyl methyl ether and crystallized from CH3CN to give 1.65 g (46%) of the titled product, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[CH3:1][S:2][C:3]1[S:4][C:5]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[CH:6][N:7]=1
Reactant: CSc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CSc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-methylsulfanyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Cl:39])[CH:33]=1>>[Cl:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CCC4CCNCC4)c3)n2)cc1Cl

Procedure:
Intermediate 94 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure Q. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 437. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (d, 1H), 8.05 (s, 1H), 7.99 (m, 1H), 7.46 (d, 2H), 7.35 (d, 1H), 7.24 (d, 1H), 7.03 (d, 1H), 6.80 (d, 1H), 3.70 (m, 2H), 3.35 (m, 2H), 2.78 (m, 6H), 1.99 (d, 2H), 1.66 (m, 3H), 1.37 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.I.C(O)(=O)C>O>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(O)ccc1-c1cc(=O)c2ccccc2o1
Temperature: 110 °C
Yield: 48.9 %

Procedure:
To a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer was added 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (770 mg, 2.88 mmol), hydroiodic acid (10 mL) and acetic acid (4 mL). The reaction mixture was heated to 110° C. for 8 h. The reaction mixture was cooled to rt and diluted with water. The precipitate was filtered off, washed with water and dried to give the crude compound, which was purified by column chromatography using 2% MeOH in CH2Cl2, to give 2-(2-amino-4-hydroxy-phenyl)-chromen-4-one (357 mg, 49%). MS (ES) m/z: 254.05 (M+1), 149.00, 134.01, and 121.00.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][C:11]1=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-].CS[C:21]1[S:25][CH:24]=[CH:23][S+:22]=1>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12](=[C:21]2[S:25][CH:24]=[CH:23][S:22]2)[C:11]1=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CSc1scc[s+]1
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)C(=O)C1=C1SC=CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Sodium hydride (60% dispersion in oil) (80 mg) is suspended in tetrahydrofuran (10 ml), and thereto are added 1-benzyl-2,4-dioxopiperidine (200 mg) and 2-methylthio-1,3-dithiolium iodide (273 mg). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured onto water and extracted with chloroform. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1) and recrystallized from isopropyl alcohol to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (262 mg, 87.8%) as pale yellow needles, m.p. 122°-124° C.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH:10]([O:35][CH2:36][CH3:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:14]([CH3:34])[CH:13]=1)C1C=CC=CC=1.CO>CCOC(C)=O>[CH2:36]([O:35][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:14]([CH3:34])[CH:13]=1)[C:9]([OH:38])=[O:8])[CH3:37]
Reactant: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from 2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid benzyl ester (0.63 g, 1.22 mmol) in the same manner as described for example 1 with the difference that MeOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/iPrOH (95:5) as the eluent and the title compound was obtained as a solid (0.303 g, 58.3%). 1H NMR (500 MHz, CDCl3): δ 7.99-8.02 (m, 2H), 7.43-7.46 (m, 3H), 7.08-7.11 (m, 2H), 6.96-6.97 (d, 1H), 4.01-4.03 (m, 1H), 3.85 (s, 2H), 3.61 (m, 1H), 3.37 (m, 1H), 3.04-3.07 (dd, 1H), 2.95-2.97 (dd, 1H), 2.43 (s, 3H), 2.13 (s, 3H), 1.12-1.14 (t, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)#[CH:18]>>[CH3:16][N:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([C:5]1[N:6]=[N:7][C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=3)=[CH:3][CH:4]=1)[CH2:14]2
Reactant: C#Cc1ccc(NC(C)=O)cc1
Reactant: CN1C2CCC1CN(c1ccc(Br)nn1)C2
Product: CC(=O)Nc1ccc(C#Cc2ccc(N3CC4CCC(C3)N4C)nn2)cc1

Procedure:
Was prepared according to Method B from 3-(6-bromo-pyridazin-3-yl)-8-methyl-3,8-diaza-bicyclo[3.2.1]octane and N-(4-ethynyl-phenyl)-acetamide. Mp 292° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:7]1)=O.Cl>[OH-].[Na+]>[OH:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:7]1
Reactant: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCOC=O)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCO)c2n1

Procedure:
1,4-Dihydro-1(2-formyloxyethyl)-7-methyl-4-oxo-N(1H-tetrazol-5-yl)-1,8-naphthyridine-3-carboxamide (Example 4(1)) (0.5 g) in aqueous sodium hydroxide (3.5 ml), 2N) was heated on a steam bath for 10 minutes. The solution was acidified to pH 1 with a dilute hydrochloric acid and the solid was collected and dried, m.p. 315°-316° (d), (32 %).
Reaction SMILES: [CH2:1]([C@@H:7]1[C:10](=[O:11])[O:9][C@H:8]1[CH2:12][CH:13]([O:18][C:19](=[O:28])[C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:21][CH:22]=[O:23])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C1COCC1.[Pd]>[CH2:1]([C@@H:7]1[C:10](=[O:11])[O:9][C@H:8]1[CH2:12][CH:13]([O:18][C:19](=[O:28])[C@H:20]([CH2:24][CH:25]([CH3:26])[CH3:27])[NH:21][CH:22]=[O:23])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCC(C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H]1C(=O)O[C@H]1CC(CCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
A solution of 10 mg of N-formyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester in 0.5 ml of THF was treated with 2.5 mg of 5% Pd/C and hydrogenated. After the hydrogen uptake was finished the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed over silica gel with toluene/ethyl acetate (8:2) and there was obtained amorphous N-formyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl]-methyl]pentyl ester as a mixture of 2 diastereomers.
Reaction SMILES: S(=O)(=O)(O)O.O[C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[C@H:14]([CH3:26])[CH2:13][C:12]1=[CH:11][C:10](=[O:27])[CH2:9][CH2:8]2.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH3:26][C@@H:14]1[CH2:13][C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:27])[CH:11]=2)=[C:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1CC2=CC(=O)CCC2=C2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
To 15 ml of concentrated sulfuric acid (98%) cooled to ˜5° C. was added dropwise ˜20 Mm of a mixture containing 10-hydroxy-7α-methyl-estra-4-ene-3,17-dione (III) and 5,10-dihydroxy-7α-methyl-estra-3,17-dione (IV) from example 2 dissolved in 15 ml of methylene chloride. About 20 minutes after the addition was complete, TLC ({fraction (1/1)} ethyl acetate/hexane, Rf 0.4) showed that the reaction was complete. The deep red reaction mixture was poured over ice, washed in with methylene chloride, partially neutralized with potassium carbonate, and the phases separated. The organic phase was washed with dilute aqueous potassium carbonate, brine, and dried over sodium sulfate, and concentrated under vacuum to a solid product. This material was column chromatographed on 150 g of silica gel with gradient elution from ⅓ to {fraction (1/1)} ethyl acetate/hexane. Fractions 6-9 were combined to give a solid which was recrystallized from ethyl acetate to provide the title product. Mp 208-209° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:46]([CH3:48])[CH3:47])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][C:33]=3[O:41][C:42]([F:45])([F:44])[F:43])=[CH:28][CH:27]=2)[N:25]=1)=[O:15])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH2:92])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:75])[CH3:74].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH:92][C:38]([C:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:24]5[N:25]=[C:21]([C@@H:17]6[CH2:18][CH2:19][CH2:20][N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[CH:46]([CH3:48])[CH3:47])[NH:22][CH:23]=5)=[CH:31][CH:30]=4)=[C:33]([O:41][C:42]([F:44])([F:45])[F:43])[CH:34]=3)=[O:40])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:74])[CH3:75]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)O)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid TFA (600 mg, 0.9 mmol) and HATU (364 mg, 0.96 mmol) in DMA (8 mL) was stirred at RT for 15 min and then 0.5 M (R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester in DMA (1.7 mL) was added followed by N,N-diisopropylethylamine (0.76 mL, 4.36 mmol). The resulting mixture was heated at 55° C. overnight, washed with EtOAc (100 mL) and water (25 mL). The organic layer was washed again with water and then with brine, dried over sodium sulfate, filtered, and concentrated to yield a dark reddish oil which was purified by silica gel chromatography (40 g silica column, 0-80% hexane:EtOAc) to provide (R)-4-{5-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-pyridin-2-yl}-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (646 mg) as a light brownish solid.
Reaction SMILES: O1C([O:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(OCc1ccccc1)c1c(CCCOC2=CCCCO2)ccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)c1c(CCCO)ccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A solution of Example 10D (2.0 g, 4.95 mmol) in methanol was treated with para-toluenesulfonic acid hydrate (84 mg, 0.44 mmol), stirred at room temperature for 2 hours, partitioned between ethyl acetate and water, dried (Na2SO4), filtered, concentrated and purified on silica gel with 30% ethyl acetate/hexanes to provide 1.5 g (95%) of the desired compound as an yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cccs1
Product: c1csc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 2-thiophenylboronic acid (118 g, 0.92 mmol) and 1a (110 mg, 0.46 mmol) according to Method C. Yellow solid. Yield: 101 mg, 0.42 mmol, 91%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.13 (s, 2H), 6.90 (s, 1H), 7.11 (t, J=4.4 Hz, 2H), 7.41-7.43 (m, 2H), 7.57-7.59 (m, 2H), 7.63 (d, J=8.2 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 118.9, 119.0, 125.1, 128.13, 128.14, 129.8, 130.3, 135.7, 137.3, 144.0, 148.4, 152.9; MS (ESI): m/z=242.10 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH:12]1(O)[CH2:16][CH2:15][CH:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH:15]1([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1C=CCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (1.57 g), 2-cyclopentenol (1.00 g) and triphenylphosphine (3.15 g) in methylene chloride (30.0 ml) was added at 0° C. diethylazodicarboxylate (1.89 ml). After stirring at room temperature overnight the reaction mixture was concentrated in vacuo. The residue was purified by chromatography to give the desired product.