Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:7]=1.[OH-:29].[K+].OO.Cl>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]([NH2:16])=[O:29])[CH:7]=1
Reactant: [OH-]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C#N)c1)C(F)(F)F
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C(N)=O)c1)C(F)(F)F
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 24 mg (0.061 mmol) of 3-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzonitrile in EtOH was added 15 mg (0.23 mmol) of potassium hydroxide followed by 0.2 mL of 30% aqueous hydrogen peroxide. The mixture was stirred for 24 hours and then diluted with water, made acidic with 1 N aqueous HCl, and extracted with three 5 mL portions of EtOAc. The combined organic layers were washed with two 5 mL portions of saturated aqueous sodium bicarbonate, two 5 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude product which was purified on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with EtOAc-hexanes (1:99, then 3:97, then 6:93, then 1:9, then 2:8, then 3:7, then 4:6, then 1:1) to afford 17 mg (67%) of the title compound as a clear resin, m.p. 70° C.-75° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CNCCCc1ccccc1
Agent: Cl
Product: CN(CCCc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 1 N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) was condensed with N-methyl-3-phenylpropylamine hydrochloride (3.71 g.) and the product was purified by high pressure liquid chromatography on silica gel using hexane-ethyl acetate (3:2) as the eluant, affording 1-(tert-butyloxycarbonyl)-N-methyl-N-(3-phenylpropyl)-L-prolinamide as a syrup (2.65 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.[OH-].[Li+:20]>CO>[Li+:20].[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([C:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(/C=C/c2cccn2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1cccc1/C=C/c1ccc(C(=O)[O-])cc1
Temperature: 60 °C

Procedure:
Methyl 4-[(E)-2-(1-methyl-1H-pyrrol-2-yl)ethenyl]benzoate (40 mg, 0.166 mmol; see step (i) above) was suspended in a mixture of methanol (1 mL) and lithium hydroxide solution (16 mg of LiOH in water 2 mL). The reaction mixture was heated at 60° C. overnight with stirring. This solution was freeze-dried and the title compound used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@:8]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:27](=N)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@:8]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:18][C:13]=2[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c(N)c1
Reactant: CCCCCC(=N)OCC
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1nc2cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc2o1

Procedure:
A solution of [(R)-3-(3-Amino-4-hydroxy-phenyl)-1-hydroxymethyl-1-methyl-propyl]-carbamic acid tert-butyl ester (500 mg, 1.61 mmol) and hexanimidic acid ethyl ester hydrochloride (318 mg, 1.77 mmol) in DCM (6 ml) was stirred for 16 hours at RT. Evaporation of the solvent in vacuum was followed by silica gel chromatography (eluent: DCM/methanol 40/1). Product containing fractions were pooled and evaporated in vacuum. Crystallization from pentane provided the title compound as a colorless solid. mp: 92.7/92.6
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH:30]1([NH2:34])[CH2:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[CH:30]1([NH:34][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NC1CCC1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(NC2CCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 54 %

Procedure:
A solution of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK, 0.05 g, 0.09 mmol) and of cyclobutylamine (0.1 ml) in dimethylacetamide was heated in a microwave oven (180 deg) for 10 min before being concentrated in vacuo. The residue was dissolve in ethyl acetate, washed with water dried over sodiumsulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 5 g, Heptane/EtOAc 0-50%) to give the title compound as a white foam (24 mg, 54%). MS (m/e): 482.5 (M+H+, 100%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([N:19]([CH2:28][CH:29](OC)[O:30]C)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:18])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.FC(F)(F)C(O)=O>O1CCCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:29]([OH:30])[CH2:28][N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:17]2=[O:18])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Yield: 76 %

Procedure:
To a solution of N-benzyl-2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methylthiazole-5-carboxamide (0.47 g, 0.96 mmol) in tetrahydrofuran (10 mL) was added water (5 mL) and trifluoroacetic acid (5 mL) at ambient temperature. The resulting reaction mixture was heated to reflux for 5 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to afford the title compound in 76% yield (0.32 g): mp 133-134° C.: 1H NMR (300 MHz, CDCl3) δ 7.35-6.97 (m, 9H), 6.10 (t, J=5.7 Hz, 1H), 5.99 (d, J=5.9 Hz, 1H), 5.03 (s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 3.60-3.54 (m, 1H), 3.27-3.23 (m, 1H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.4, 162.1, 160.8, 157.0, 153.5, 152.4, 137.9, 131.1, 129.9, 128.7, 127.8, 117.9, 115.9, 115.7, 49.3, 46.6, 44.0, 17.0; MS (ES+) m/z 441.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:15]1[CH:16]=[C:17]([CH3:22])[C:18]([CH3:21])=[CH:19][CH:20]=1.[OH-].[K+]>C1(C)C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[CH3:22][C:17]1[CH:16]=[C:15]([N:1]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: Cc1ccc(I)cc1C
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 130 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
In a 250 milliliter round-bottomed flask equipped with mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 8.46 grams (0.05 mole) of 4-aminobiphenyl, 25.53 grams (0.11 mole) of 4-iodo-ortho-xylene, 0.25 gram (0.0025 mole) of cuprous chloride, 0.45 gram (0.0025 mole) of 1,10-phenanthroline, 22.4 grams (0.4 mole) of flake potassium hydroxide and 30 milliliters of toluene solvent. The reaction was heated quickly to a reflux temperature of 130° C. and maintained at this temperature for 4 hours, after which time chromatographic analysis revealed the reaction to be complete. The reaction mixture was allowed to attain room temperature, about 25° C., and was partitioned between 200 milliliters of toluene and 150 milliliters of deionized water. The resulting organic layer was separated and water was removed by azeotropic distillation of water under a Dean-Stark trap. The product was decolorized by slurry treating the toluene solution with 36 grams of Filtrol-24™, an acid-washed clay, and 24 grams of Alcoa CG-20 alumina. After 3 hours stirring at reflux, the solution was cooled to room temperature and filtered. The product of N,N-bis(3,4-dimethylphenyl)-4-biphenylamine was recovered from the filtrate by evaporation of the solvent. Recrystallization from 40 milliliters of a one to one mixture of ethylacetate-isopropanol provided 13.2 grams (70 percent) of the above product. Chromatographic analysis by high performance liquid chromatography illustrated an excellent product purity of 99.8 percent and a melting temperature, which was determined by differential scanning calorimetry to be 113.21° C.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:23][CH:24]=1)[N:22]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-methoxy-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-methoxy-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: Br[CH2:2][C@H:3]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([NH:18][CH:19]=[O:20])[CH:5]=1.[OH:29][C@H:30]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.C(OC(C)C)(=O)C.CS(C)=O>[OH:29][C@H:30]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH2:2][C@H:3]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:6]([NH:18][CH:19]=[O:20])[CH:5]=2)=[CH:35][CH:34]=1
Reactant: NCCc1ccc(NC[C@H](O)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@H](O)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 140 °C
Yield: 100 %

Procedure:
Intermediate 4 (5.0 g, 11 mmol), intermediate 2 (3.5 g, 14 mmol), and dimethylsulfoxide (10 mL) were combined in a 100 mL round bottom flask and stirred to form a homogeneous solution. Potassium carbonate (6.0 g, 43 mmol) and sodium iodide (1.7 g, 11 mmol) were added and the reaction mixture was heated to 140° C. The reaction mixture was maintained at 140° C. for 10 min, then cooled to room temperature and diluted with water (24 mL) and isopropyl acetate (28 mL). The reaction was stirred until all solids dissolved and then transferred to a separatory funnel. The organic layer was washed with water (17 mL) followed by acetate buffer (5% v/v acetic acid, 12% w/v sodium acetate trihydrate in water, 18 ml) followed by sodium bicarbonate solution (5% w/v in water, 17 mL) followed by saturated aqueous sodium chloride (17 mL). The organic layer was dried over sodium sulfate and concentrated to afford intermediate 5 as a brown gelatinous solid (7.0 g, 11 mmol, >99%). m/z: [M+H+] calcd for C38H49N3O4Si 640.4; found 640.6.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[N:3]=1.C([OH:24])C>[OH-].[Na+]>[Cl:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:4]1[NH:3][C:2](=[O:24])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CCO
Reactant: Nc1nc(COc2cccc(Cl)c2Cl)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(COc2cccc(Cl)c2Cl)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 1.0 g (0.0031 mole) of 4-amino-2-[(2,3-dichlorophenoxy)methyl]pteridine in 35 ml of 5% aqueous sodium hydroxide. Heating time: 10 minutes under reflux. Yld: 0.5 g (50%), m.p. 219°-220.5° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](C=O)[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:31])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 4-(2-fluoro-4-formyl-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (97 mmol) in CH2Cl2 (600 ml), m-chloroperbenzoic acid (194 mmol) is added at 0° C. for 5 min and NaHCO3 (243 mmol) is added at 0° C. The mixture is stirred at 0° C. for 20 min and at room temperature for 1 h. To the mixture, m-chloroperbenzoic acid (48.5 mmol) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h, slowly quenched with saturated NaHCO3 at 0° C. and extracted with AcOEt. The combined extracts are washed with saturated NaHCO3, brine and dried over magnesium sulfate. The solvent is evaporated. To the residue, 10% KOH/EtOH is added at 0° C. and the reaction mixture is stirred at room temperature for 1 h. After the mixture is extracted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtered. The solvent is evaporated and the residue is chromatographed on silica gel using n-hexane, n-hexane:AcOEt=5:1, n-hexane:AcOEt=4:1, n-hexane AcOEt=3:1 to give the desired 4-(2-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][Mg]Cl>O1CCCC1.[Cl-].[Na+].O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])([CH3:36])[CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-{4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (210 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. was added methylmagnesium chloride in tetrahydrofuran (3 M, 0.43 ml, 1.29 mmol) dropwise. After stirring for 2 h at 0° C., the reaction mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (220 mg, 100%): LC/MS m/e calcd for C29H29FN2O3S [M+H]+ 505.63, observed 505.2.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[N:10][OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:3]3[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=3[O:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: ON=C(c1ccc(O)cc1)c1cc(O)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1ccc(-c2noc3ccc(O)cc23)cc1
Yield: 4.8 %

Procedure:
A mixture of (2,5-dihydroxyphenyl)(4-hydroxyphenyl)methanone (1.0 g, 4.3 mmol), hydroxylamine hydrochloride (2.0 g, 29 mmol), pyridine (5 mL) and EtOH (30 mL) was heated to reflux. After stirring for 4 h, the reaction was cooled, poured into 2N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated to give a yellow foam (0.92 g, 87% yield). The product, (2,5-dihydroxyphenyl)(4-hydroxyphenyl)methanone oxime (0.9 g, 3.7 mmol) was taken in THF (25 mL) and triphenylphosphine (1.5 g, 5.6 mmol) first was added, followed by the dropwise addition of diethylazodicarboxylate (0.9 mL, 5.6 mmol). After 30 min the reaction was filtered, concentrated and the resulting oil was purified by column chromatography (eluent 30% EtOAc/hexanes) to give a solid. The solid was triturated with CH2Cl2, and filtered to give a solid (0.04 g, m.p. 266-268° C.); 1H NMR (DMSO-d6) 10.32 (s, 1H), 10.30 (s, 1H), 8.00 (d, 2H, J=8.7 Hz), 7.50 (d, 1H, J=8.7 Hz), 7.02 (d, 1H, J=2.3 Hz), 6.95 (d, 2H, J=8.7 Hz), 6.93 (dd, 1H, J=8.7 Hz, 2.4 Hz); MS m/e 228 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][CH:10](OCC)[O:11][CH2:12][CH3:13])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:7]([O:9][CH:10]([O:11][CH2:12][CH3:13])[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:8]
Reactant: CCOC(OCC)OCC
Reactant: Cc1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)n1cnc(C)c1

Procedure:
4-Methylimidazole (16.4 g), triethylorthoformate (118.4 g), and p-toluene sulphonic acid (1 g) were mixed and heated at 130° until evolution of ethanol ceased (approximately 2 hours). Volatile material was removed in vacuo and the residue was distilled under vacuum from anhydrous sodium carbonate (1 g) to afford the title compound, b.p. 126°-130°/5 mm (22.06 g). The product was characterised spectroscopically and used without further purification (Preparation 26).
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:16]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:17]([C:21]([N:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])=[O:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Val-Pro-OBzl was prepared by dissolving H-Pro-OBzl (20 g, 83 mmol) in 50 mL of chloroform and adding Boc-Val-OH (18.0 g, 83 mmol), HOBt (23.0g, 165 mmol), NMM ( 9.0 mL, 83 mmol) and DCC (17.0 g, 83 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was filtered and solvent was evaporated. Ethyl acetate was added and insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl, 5% NaHCO3, and saturated aqueous NaCl. It was dried over Na2SO4, filtered and evaporate to give a white solid (30 g, 75 mmol, 90%). ESI/MS calculated for C22H32N2O5 +H: 405.2. Found 405.6.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].NC1C=CC(C)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:11][C:10]1[C:9](=[N:8][NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])[C:12]([NH2:13])=[N:30][N:29]=1
Reactant: NN
Reactant: Cc1ccccc1NN=C(C#N)C#N
Solvent: N#CCC#N
Solvent: Cc1ccc(N)cc1
Solvent: O
Product: Cc1ccccc1NN=C1C(N)=NN=C1N
Temperature: 25 °C
Yield: 40 %

Procedure:
This compound was prepared using 92 mg (0.5 mmol) of 2-(o-tolylhydrazono)-malononitrile, which was derived from 4-toluidine (107 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 43 mg (40%) of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18]2[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]1([C:18]2[N:19]([C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1c[nH]c(C2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])c(C2CCCCC2)n1

Procedure:
15.9 g (0.1 mol) 2,4-Difluoro-nitrobenzene, 16.5 g 2-Cyclohexyl-4-methylimidazole, 30 g potassium carbonate, and 150 ml acetonitrile were heated 24 hours at 60° C. After cooling the product was filtered off, washed with 100 ml acetonitrile, evaporated to dryness and chromatographed on silica gel with 5% MeOH/CH2Cl2.