Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C[O:13][C:14](=[O:18])[CH2:15][CH2:16]Br.O>CS(C)=O>[N:3]1([CH2:16][CH2:15][C:14]([OH:18])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCn1ccc2ccccc21
Reaction time: 24 h

Procedure:
KOH (11.5 g, 0.2 mol.) was added to a solution of indole (5.0 g, 40.0 mmol.) and 3-bromopropionic acid methyl ester (4.37 ml, 40 mmol.) in DMSO (35 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, washing was carried out with ether (5×20 ml), and the aqueous phase was adjusted to pH 4 with 1M HCl and extracted with ether (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with methanol yielded 3-indol-1-ylpropionic acid in a yield of 3.8 g (white solid, m.p. 54–56° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1nccn1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Temperature: 0 °C
Yield: 22 %

Procedure:
Ethyl 1-methylimidazole-2-carboxylate was carefully dissolved in 1000 mL of concentrated sulfuric acid cooled to 0° C. 90% nitric -acid (1 L) was slowly added maintaining a temperature of 0° C. The reaction was then refluxed with an efficient condenser (−20° C.) in a well ventilated hood for 50 min. The reaction was cooled with an ice bath, and quenched by pouring onto 10 L ice. The resulting blue solution was then extracted with 20 L DCM, the combined extracts dried (sodium sulfate) and concentrated in vacuo to yield a tan solid which was recrystallized from 22 L of 21:1 carbon tetrachloride/ethanol. The resulting white crystals are collected by vacuum filtration to provide pure Ethyl 1-methyl-4-nitroimidazole-2-carboxylate. (103 g, 22% yield). TLC (7:2 benzene/ethyl acetate v/v) Rf 0.5, 1H NMR (DMSO-d6) δ8.61 (s, 1H), 4.33 (q, 2H, J=6.4 Hz), 3.97 (s, 3H), 1.29 (t, 3H, J=6.0 Hz), 13C NMR (DMSO-d6) δ158.2, 145.4, 135.3, 127.4, 62.2, 37.3, 14.5; IR(KBr) 3139, 1719, 1541, 1498, 1381, 1310, 1260, 1122, 995, 860, 656.; FABMS m/e 200.066 (M+H200.067 calc. for C7H10N3O4).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:21]
Reactant: COC(=O)c1cccnc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1CCl

Procedure:
Methyl 2-(chloromethyl)pyridine-3-carboxylate (4.45 g, 23.98 mmol) was taken up in DCM (50 mL) and mCPBA (5.91 g, 26.4 mmol) was added. The resulting solution was allowed to react at room temperature overnight and then purified directly by silica gel chromatography (0-20% MeOH-EtOAc) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]>CCOCC>[NH2:14][C:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C=C(N)c1ccc(C(F)(F)F)cc1
Yield: 87.4 %

Procedure:
To the Grignard reagent prepared from 98 g (0.436 mol) of p-bromobenzotrifluoride and 10.59 g (0.436 mol) of magnesium in ether was added 24.65 g (0.218 mol) of ethyl cyanoacetate dropwise with stirring and cooling in an ice bath. The resultant mixture was stirred at reflux for 24 hours. The usual workup gave 49.4 g of dark red-brown residue; distillation of this material gave 16.73 g (30%) of product, boiling point 120°-123° (0.15 torr).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=4[Cl:33])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.272 g of 2,4-dichlorobenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 3 hours. Work-up gives a solid which is crystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 199°-201° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]([N:21]1[C@H:23]([CH3:24])[C@@H:22]1[C:25]([O:27][CH3:28])=[O:26])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C@@H:22]([C@H:23]([CH3:24])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[NH:21][C:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: Cn1ccc2ccccc21
Reactant: COC(=O)[C@H]1[C@@H](C)N1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.3 %

Procedure:
To a mixture of 1-methylindole (4.26 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate (2.70 g) in dry methylene chloride (50 ml) was added boron trifluoride etherate (1.33 ml) under ice-bath cooling. The mixture was stirred for five minutes at ambient temperature and the solvent was evaporated off. The residue was chromatographed on silica gel (chloroform and a 1:1 mixture of hexane and ether as eluent) to give (αR,βR)-N-benzyloxycarbonyl-1,β-dimethyltryptophane methyl ester (1.62 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:32]([F:35])([F:33])[F:34])[CH:24]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1cccc(CSc2ccc(Cl)cc2N)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 65.3 %

Procedure:
Following General Procedure B, the title compound (1.65 g, 65%) was prepared from methyl 3-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.59 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.28 g, 4.59 mmol) in pyridine (10 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)(=[O:18])=[O:19])=[CH:13][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1ccccc1-n1ccnc1
Temperature: 150 °C
Yield: 77 %

Procedure:
2,4-Difluoro-1-(2-{4-[(2-fluorophenyl)sulfonyl]phenyl}ethyl)benzene (Example 124, 100 mg, 0.26 mmol), potassium carbonate (126 mg, 0.39 mmol) and imidazole (26 mg, 0.39 mmol) were combined in dimethylsulfoxide (1.3 mL) and heated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% ethanol/ethyl acetate to yield the title compound as a white solid (85 mg, 77%). δH (400 MHz, d6 DMSO): 8.31-8.29 (1H, m), 7.87-7.79 (2H, m), 7.41-7.39 (2H, m), 7.31-7.23 (5H, m), 7.16-7.12 (1H, m), 6.99-6.95 (1H, m), 6.88 (1H, t, J=1.1 Hz), 6.85 (1H, t, J=1.3 Hz), 2.92-2.84 (4H, m). m/z (ES+) 425 [MH+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH2:14]([O:16][C:17](=[O:25])[C:18](=[CH:21]OCC)[C:19]#[N:20])[CH3:15]>C(O)(=O)C.O>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[C:2]([F:1])([F:12])[F:13])[N:11]=[CH:21][C:18]=1[C:17]([O:16][CH2:14][CH3:15])=[O:25]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1N
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 31.58 g of 2-(trifluoromethyl)-4-chlorophenylhydrazine and 27.92 g of ethyl(ethoxymethylene)cyanoacetate dissolved in 225 of acetic acid and 75 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The precipitated solid was collected by filtration and combined with the solids isolated from the filtrate to provide 43 g of 5-amino-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. MP=114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](OCC)=[O:14]>C(Cl)(=O)C>[CH3:11][C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:13](=[O:14])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CC(=O)Cl
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Yield: 80 %

Procedure:
15.1 g (100 mmol) of 2-amino-5-methyl-benzoic acid was refluxed with 60 mL of ethyl chloroformate for 6 h, and then was refluxed for another 3 h after addition of 60 mL of acetyl chloride. The solid was collected, washed with hexane to give 14.2 g (80%) of the 5-methylisatoic anhydride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:27])[OH:25])=[C:3]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
1-bromo-4-chloro-2-[(phenylmethyl)oxy]benzene (2.976 g, 10 mmol) in dry tetrahydrofuran (40 ml) was cooled to −100° C. n-Butyl lithium, 1.6M solution in hexanes (6.9 ml, 11 mmol) was added dropwise over 10 min under nitrogen. The reaction mixture was then allowed to warm to −70° C. for 1 h. Triisopropylborate (5.514, 30 mmol) was added dropwise under nitrogen. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature before being quenched with 2N hydrochloric acid (30 mL) and stirred vigorously at room temperature for 1 h. The product was then extracted with ether, dried over magnesium sulphate and evaporated down to an oil which was dissolved in iso-hexane and the solid which separated out was filtered off and dried. Yield 1.89 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].O>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@H:8]2[CH2:7][CH2:5][NH:6][C:15]2=[O:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.07 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 5 ml of dimethylsulfoxide, and one g of potassium carbonate and 1.53 g of (R)-3-(p-tosyloxy)-2-pyrrolidone are added thereto. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and then concentrated under reduced pressure to dryness. The residue is crystallized with isopropyl ether, and the crystals are recrystallized from aqueous methanol. 0.86 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetate is obtained. The physico-chemical properties of this product are identical with those of the product obtained in Example 1-(2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1OCc1cccc(F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3cccc(F)c3)n2)c1

Procedure:
Example 26 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(3-fluorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.CC([O-])=O.[Na+].Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1.CC(O)=O>O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCC(NC(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide, 0.05 mol of anhydrous NaOAc, 0.05 mol of 4-methoxyphenylhydrazine hydrochloride, and 155 ml of glacial HOAc was stirred for 1 hr at room temperature and then refluxed for 1 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 191°-193°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:22][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 1) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as off-white amorphous solid. MS: 431.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[NH:5][N:4]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:5]2[C:6]([C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=3)=[CH:7][C:3]([C:2]([F:1])([F:15])[F:16])=[N:4]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2cc(C(F)(F)F)n[nH]2)cc1
Reactant: Ic1ccccc1
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2)cc1

Procedure:
This compound was isolated by silica gel chromatography following arylation of 3-trifluoromethyl-5-(p-tolyl)-1H pyrazole using iodobenzene as described in Example 1.1.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:26])[CH3:25])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 56.5 g (0.25 mol) of purified anthralin in 1750 cm3 of anhydrous toluene being stirred at room temperature, 27.3 cm3 (0.34 mol) of anhydrous pyridine was added first and then 21.4 cm3 (0.3 mol) of acetyl chloride was added dropwise by means of a dropping funnel. Slight heating occurred during addition then, after the end of addition, the mixture was heated to a temperature of around 90° C. for 1 hour. The mixture was cooled and 27.3 cm3 of pyridine and then, dropwise, 21.4 cm3 of acetyl chloride were again added at 30°-35° C. The mixture was then stirred for 1 hour at 85°-90° C. After a check to insure that the anthralin had been transformed to the 10-acetyl derivative, the reaction mixture was cooled to room temperature then washed 3 times with water (250 cm3). The toluene phase was decanted, dried over sodium sulfate and then concentrated to around 300 cm3. The solution was then deposited on a column of silica gel and eluted with toluene and a 1:1 mixture of toluene and methylene chloride. The first fractions were combined and then concentrated under vacuum. The solid obtained was then recrystallized from toluene to yield 21 g of bright-yellow crystals of 1,8-dihydroxy-10-acetylanthrone having a melting point of 146° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[CH:66][CH:65]=1>>[CH2:74]([O:73][C:71](=[O:72])[CH2:70][C:67]1[CH:66]=[CH:65][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:69][CH:68]=1)[CH3:75]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 35.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (120 mg, 0.257 mmol), was reacted with diisopropylethylamine (207 mg, 1.60 mmol), diphenylphosphinic chloride (146 mg, 0.618 mmol), then reacted with ethyl 2-(4-aminophenyl)acetate (56 mg, 0.315 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (57 mg, 47%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([NH2:12])[N:3]=1.[OH-].[K+].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([C:27]([F:30])([F:29])[F:28])[C:19]=1Cl)([O-:17])=[O:16].Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([NH:12][C:19]2[C:20]([C:27]([F:29])([F:30])[F:28])=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[N:3]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1nc(Cl)ccc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2nc(Cl)ccc2C(F)(F)F)c(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
In 20 ml. of dimethylformamide, 1.8 g. of 2-chloro-6-amino-5-trifluoromethylpyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 2.7 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.9 g. of the object compound having the melting point of 129° to 131° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].Cl>CC(O)(C)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:18])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of benzo[d][1,3]dioxole-5-carbaldehyde (254a, 2 g, 13.3 mmol), Na2H2PO4 (6.38 g, 53.2 mmol), and 2-methyl-2-butene (9.85 mL, 93.1 mmol) in t-BuOH (41 mL) and water (17 mL) was added sodium chlorite (7.19 g, 79.9 mmol). The resulting reaction mixture was stirred for 2 hours at room temperature. Water (100 mL) and 1M HCl (25 mL) were added and the mixture was extracted with EtOAc (2×50 mL). The organic phase was separated, dried with sodium sulfate and evaporated under reduced pressure. The resulting solid was triturated with EtOAc (20 mL) to yield the title compound 255a as a white solid (1.9 g, 86% yield). 1H NMR: (DMSO) δ 12.72 (br s, 1H), 7.53-7.50 (m, 1H), 7.34-7.32 (m, 1H), 6.99-6.95 (m, 1H), 6.10 (s, 2H).