Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine) palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=CC)[OH:3].C1(OC)C(=CC=C(C=1)CC=C)[OH:15]>O>[O:15]=[CH:7][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:11][CH3:12])[CH:10]=1
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: C=CCc1ccc(O)c(OC)c1
Solvent: O
Product: COc1cc(C=O)ccc1O

Procedure:
On the basis of the substrates (a) Benzoe Siam Resin (b) isoeugenol and (c) eugenol, all dispersed in tap water as the reaction medium, the compound vanillin was produced. The substrates were taken up in flasks mounted on a shaking apparatus after which the enzyme lipoxidase (Sigma L8383) in a dose of 0.2% w/w based on the substrate was added. The temperature during the reaction was kept at 25° C. The starting mixture had a initial pH of 8. After an incubation time of 24 hours the reaction was stopped by inactivation of the enzyme (10 min. at 70° C.). The results of the experiments are shown in Table B below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13](=[O:23])[O:14][C:15]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=2[CH:17]=1>Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[C:13](=[O:23])[O:14][C:15]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=2[CH:17]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1cc2ccc(O)cc2oc1=O
Agent: Cl
Product: O=C(Nc1cc2ccc(O)cc2oc1=O)c1ccccc1Cl
Reaction time: 1 h
Yield: 54.8 %

Procedure:
2-Chlorobenzoyl chloride (23.0 mg, 0.291 mmol) was added to a mixture of 3-amino-7-hydroxy-2H-1-benzopyran-2-one (50.0 mg, 0.282 mmol), and the mixture was stirred at room temparature for 1 hour. 1N hydrochloric acid (10 ml) was added, and the mixture was stirred. The precipitated crystal was filtered and washed successively with water and diisopropyl ether to give the title compound as a light brown crystal (48.8 mg, 54.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[CH:4][CH:3]=1.C([O:17][C:18](=O)[CH2:19][S:20][CH3:21])C.C(OCl)(C)(C)C.C(N(CC)CC)C.Cl>CC#N.C1COCC1>[CH3:21][S:20][CH:19]1[C:14]2[C:2](=[CH:3][CH:4]=[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][O:9][C:8]3=[O:12])[CH:13]=2)[NH:1][C:18]1=[O:17]
Reactant: Nc1ccc(CN2CCOC2=O)cc1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(CN3CCOC3=O)cc21
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step B (0.113 mol) in a mixture of CH3CN (200 ml) and THF (200 ml) at −60° C. there is added, dropwise, ethyl(methylsulphanyl)-acetate (0.136 mol) under a nitrogen atmosphere. tBuOCl (0.136 mol) is added dropwise to the reaction mixture over 20 minutes, keeping the temperature between −60° C. and −55° C. After stirring for one hour at −50° C., triethylamine (0.152 mol) is added dropwise. The reaction mixture is brought to 0° C. and then aqueous 3M HCl solution (580 ml) is added dropwise. After stirring for 12 hours at ambient temperature, the organic phases are evaporated in vacuo and then the aqueous phase is extracted with DCM and the organic phases are combined. The organic phase obtained is washed with water and then with saturated aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The product obtained is recrystallised from a mixture of ethyl ether/ethanol. The crystals obtained are filtered off, washed with ether and dried in vacuo at 40° C. to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20]([CH3:22])=[CH2:21]>COC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][O:14][C:20]1([CH3:22])[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)OC
Reactant: O=C(N[C@H](CO)CCO)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.6 %

Procedure:
A solution of (S)—N-(benzyloxycarbonyl)-2-aminobutane-1,4-diol (8.00 g, 33.4 mmol) and toluene-4-sulfonic acid monohydrate (318 mg, 1.67 mmol) in 2,2-dimethoxypropane (320 mL) was stirred at room temperature, then after 2 h 2-methoxypropene (7.71 g, 107 mmol) was added, then after 72 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was taken up in dichloromethane (200 mL), then after addition of SiO2 (80 g) and water (4.8 mL) the slurry was stirred for 64 h at room temperature. After dilution with dichloromethane and addition of anhydrous magnesium sulfate, insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and chromatographed (SiO2; heptane/ethyl acetate 1:1) to afford the title compound (8.92 g, 96%). Light yellow oil, MS (ISP)=280.1 (M+H)+.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH2:3][CH2:4][C:5](=[O:12])[O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9]>C(O)C.[Pd]>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][C:5](=[O:12])[O:6][CH2:7][C:8]([Cl:10])([Cl:11])[Cl:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCC(Cl)(Cl)Cl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCC(Cl)(Cl)Cl)C(=O)O
Yield: 74.3 %

Procedure:
Boc-Glu(OTce)-OBzl (0.50 g) was hydrogenated in ethanol (25 ml) with 10% palladium on carbon (0.10 g). The catalyst was filtered off and the filtrate was evaporated. The residue was extracted with ethyl acetate. The organic layer was washed successively with 2% hydrochloric acid, water and saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was pulverized with petroleum ether, filtered and dried to give Boc-Glu(OTce)-OH (0.30 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([CH:25]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])(O)=O.N1CCCCC1.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)[C:7](/[CH:10]=[C:25](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)s1
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OCC)n1Cc1ccc(C(=O)OC)s1
Yield: 60.4 %

Procedure:
A mixture of 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)methyl]imidazol-5-carboxaldehyde (0.5 g, 1.66 mmol), ethyl 2-carboxy-3-(2-thienyl)propionate (1.14 g, 4.99 mmol), piperidine (0.155 g, 1.83 mmol), 0.5 ml of pyridine in 50 ml of benzene were refluxed for 18 hours under argon in the presence of a Dean-Stark trap. The crude product was flash chromatographed over silica gel eluting with ethyl acetate/hexane (1:1) to give 0.474 g (49%) of ethyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2propenoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33]CC4C=CC=CC=4)[C@@H:21]([O:22]CC4C=CC=CC=4)[C@@H:12]3[O:13]CC3C=CC=CC=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([NH2:41])[N:3]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[C@@H:11]1([N:8]2[C:7]3[C:2]([NH2:1])=[N:3][C:4]([NH2:41])=[CH:5][C:6]=3[N:10]=[CH:9]2)[O:31][C@H:30]([CH2:32][OH:33])[C@@H:21]([OH:22])[C@@H:12]1[OH:13]
Reactant: [H][H]
Reactant: Nc1cc2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2c(N)n1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1cc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2c(N)n1
Yield: 78.4 %

Procedure:
A mixture of 5.0 g of 4,6-diamino-3-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-3H-imidazo[4,5-c]pyridine, 1.5 g of 20% palladium on carbon, 1.6 ml of acetic acid and 150 ml of methoxyethanol is hydrogenated at 50° C. and ca. 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 50 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness and recrystallized from ethanol-water to provide 2.0 g of 3-β-D-arabinofuranosyl-4,6-diamino-3H-imidazo-[4,5-c]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]2)=[O:16])=[C:4]([F:33])[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:44]=[C:45]=[O:46])=[O:43])=[CH:37][CH:36]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:45]([NH:44][C:42](=[O:43])[CH2:41][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[O:46])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]([N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:21][CH2:22]1)=[O:16]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc(N)cc2F)CC1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)CC1

Procedure:
The title compound was prepared from (E)-tert-butyl 1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate (42 mg, 0.092 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to that of Step D of Example 33. The crude product was adsorbed onto silica gel and purified by flash chromatography eluting with 0-5% MeOH/EtOAc to give the product (20 mg, 33%) as a white solid. 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.59 (s, 1H), 9.03 (s, 1H), 8.37 (d, 1H, J=5.6 Hz), 7.82-7.74 (m, 2H), 7.47 (d, 1H, J=15.8 Hz), 7.42-7.33 (m, 4H), 7.20-7.13 (m, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.63 (d, 1H, J=5.6 Hz), 4.31 (d, 1H, J=13.7 Hz), 4.19 (d, 1H, J=12.7 Hz), 3.74 (s, 2H), 3.56-3.47 (m, 1H), 3.22-3.13 (m, 1H), 2.84-2.76 (m, 1H), 1.76 (s, 2H), 1.37 (s, 9H), 1.32-1.20 (m, 2H); MS(ESI+): m/z 636.23 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[NH2:21][C:22]1[CH:23]=[C:24]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 26A) (2.13 g, 6.0 mmol), 3-aminothiophenol (0.75 g, 6.0 mmol) and cesium carbonate (4.0 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was heated to 95° C. for 3 hours. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution adjusted to pH 6 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (2.87 g, 99%).
Reaction SMILES: C([O:4][C:5]([C:7]1([C:46]([O:48]C(C)C)=[O:47])[CH2:45][C:9]2([CH:12]=[C:11]([C:13]3[C:14]([CH3:44])([CH3:43])[C@H:15]4[C@:28]([CH3:31])([CH2:29][CH:30]=3)[C@@H:27]3[C@:18]([CH3:42])([C@@:19]5([CH3:41])[C@H:24]([CH2:25][CH2:26]3)[C@H:23]3[C@H:32]([C:35]([CH3:37])=[CH2:36])[CH2:33][CH2:34][C@:22]3([C:38]([OH:40])=[O:39])[CH2:21][CH2:20]5)[CH2:17][CH2:16]4)[CH2:10]2)[CH2:8]1)=[O:6])(C)C.[OH-].[Na+].Cl>O1CCOCC1>[C:38]([C@:22]12[CH2:34][CH2:33][C@@H:32]([C:35]([CH3:37])=[CH2:36])[C@@H:23]1[C@@H:24]1[C@@:19]([CH3:41])([CH2:20][CH2:21]2)[C@@:18]2([CH3:42])[C@@H:27]([C@:28]3([CH3:31])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:44])([CH3:43])[C:13]([C:11]2[CH2:12][C:9]4([CH2:8][C:7]([C:5]([OH:6])=[O:4])([C:46]([OH:48])=[O:47])[CH2:45]4)[CH:10]=2)=[CH:30][CH2:29]3)[CH2:26][CH2:25]1)([OH:40])=[O:39]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 100 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(6,6-bis(isopropoxycarbonyl)spiro[3.3]hept-1-en-2-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.025 g, 0.021 mmol (based on 60% purity)) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.25 ml, 0.250 mmol). The mixture was heated to 75° C. for 66 h, then was cooled to rt. LC/MS was inconclusive. To the mixture was added 5 mL of 1N HCl, then the mixture was extracted with dichloromethane (3×15 mL) and dried with sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was again dissolved in 1,4 dioxane (3 mL) and 0.1 mL of 10N NaOH was added. The mixture was heated to 75° C. for 16.5 h, then was cooled to rt. To the mixture was added 10 mL of 1N HCl then the mixture was further diluted with 10 mL of water and it was extracted with dichloromethane (3×20 mL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO and was purified by prep HPLC (method 12, retention time: 10.2 minutes). The fractions containing the expected product were combined and concentrated under reduced pressure to give 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-carboxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid (0.015 g, 0.021 mmol (based on 86% purity), 99% yield) as a white solid. LCMS: m/e 617.4 (M−H)−, 2.42 min (method 3). 1H NMR (500 MHz, acetic acid-d4) δ=5.93 (s, 1H), 5.58 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.62 (br. s., 1H), 3.08-2.99 (m, 1H), 2.81 (s, 4H), 2.69-2.59 (m, 2H), 1.71 (s, 3H), 2.40-0.80 (m, 37H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 99.7 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonyl-1-propenyl) indol-1-ylmethyl]-3-methoxybenzoate (3.3 g) in methanol (30 ml) was treated with 10% (w/w) palladium on carbon (0.8 g) and shaken under 3.45 bars of hydrogen for 18 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonylpropyl)indol-1-ylmethyl]-3-methoxybenzoate (3.3 g, 100%) as a colorless oil: partial NMR (80 MHz, CDCl3) 3.40(t, 2H, NHCH2), 3.94(s, 3H, OCH3), 4.10(q, 2H, OCH2), 5.33(s, 2H, NCH2), 6.14(br t, 1H, NH), 6.63(d, 1H, Ar), 7.04(s, 1H, H2 -indole), 7.85(br s, 1H, H7 indole).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][C:15]=3[CH:14]=2)=[C:7]([Br:21])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)phenyl]acetate (730 mg, 1.3 mmol), phenylacetylen (210 mg, 2.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (82 mg, 0.12 mmol), copper (I) iodide (32 mg, 0.17 mmol) and triethylamine (11 mL) was stirred at reflux. After 2 hours, dichloromethane (2 mL) was added to the reaction mixture, followed by further heating for 16 hours. The reaction mixture was allowed to cool down to room temperature, dissolved in dichloromethane and washed once with a saturated solution of aqueous ammonium chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was purified on column (silica gel, gradient elution from chloroform/heptane 1:2, to chloroform/methanol 5:1), to give 600 mg (86%) of methyl[3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)phenyl]acetate as a pale yellow solid mass. 1H-NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=7.4 Hz, 2H), 7.76 (s, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.53 (t, 3H), 7.42 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 3.82 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[CH3:13][CH2:14][CH2:15]CCC>CS(C)=O>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])[CH:14]=[CH2:13]
Reactant: CCCCCC
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Solvent: CS(C)=O
Product: C=CCOc1cc(Cl)c(C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 37.5 g of 4B in 200 ml of dimethyl sulfoxide (DMSO) was added drop-by-drop over 30 minutes to a stirred solution of 4.8 g of freshly hexane-washed sodium hydride in 200 ml of DMSO, the temperature being held at 30° C. Then 26.6 3-bromopropene was added drop-by-drop over 10 minutes, and the mixture was stirred at 70° C. for 5 hours. The mixture was mixed with 1 liter of cold water and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and the solvent was evaporated, to give 1-(2-propenyloxy)-5-chloro-4-methyl-2-nitrobenzene (7A), as brown solid, m.p.: not determined.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[OH:25])(O)[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(O)(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[OH:25])[C:9]2=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)ccc1O
Agent: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1C(c2cc(F)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 3B, and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one was obtained (78%): 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.39-7.26 (m, 9H), 7.22-7.16 (m, 2H), 7.15-7.05 (m, 2H), 7.05-6.97 (m, 1H), 6.96-6.85 (m, 2H), 6.68-6.61 (m, 1H), 6.58-6.50 (m, 1H), 5.16 (s, 1H); MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:15][OH:16])[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].C(N(CC)CC)C.[P:25](Cl)(Cl)([Cl:27])=[O:26].O>ClCCl>[Cl:27][P:25]1(=[O:26])[O:4][CH:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:15][O:16]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(CO)C(O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COP(=O)(Cl)OC1c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 82.1 %

Procedure:
2,2-Dimethyl-1-(2-naphthyl)-1,3-propanediol (34.86 g, (0.151 mol) and triethylamine (42.9 g, 0.424 mol) were dissolved in dichloromethane (200 ml). Phosphorus oxychloride (24.3 g, 0.158 mol) dissolved in dichloromethane (50 ml) was added dropwise to the above solution under cooling to 1 to 4° C. with stirring for 1 hr 40 min. The solution was stirred at the same temperature for 1 hr, and water (60 ml) was added thereto to partition the solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained dark brown oil was added ether (50 ml) and the mixture was stirred thoroughly and left at room temperature overnight. The solidified reaction product was pulverized, filtered, washed with ether and dried to give the title compound (38.62 g, yield 82.1%).