Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)=O.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:21]([O:20][C:18]([C:3]1[N:4]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10]([CH:2]=1)=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1c(Br)c2cc(C(=O)O)ccc2n1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1CC(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 50.9 %

Procedure:
In 6 ml of N,N-dimethylformamide are suspended 0.30 g of 3-bromo-2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid, 0.10 g of tetrakis(triphenylphosphine)palladium(0), 0.24 ml of formic acid and 1.36 ml of triethylamine. The suspension is stirred at 80° C. for 5 hours. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to obtain 0.12 g of 2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid as a yellow solid product.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[N:4]=1.[OH-].[NH4+]>O1CCCC1.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:5]1[N:4]=[C:3]([S:2][CH3:1])[NH:7][N:6]=1
Reactant: CSc1nc(Cc2ccccc2[N+](=O)[O-])n[nH]1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Cc2ccccc2N)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2 g of 5-methylmercapto-3-(o-nitrobenzyl)-1,2,4-triazole in 45 ml of tetrahydrofuran is added 44 ml of 20% aqueous titanium trichloride dropwise at 0°. The mixture is stirred at room temperature overnight, diluted with water, cooled to 0°, basified with ammonium hydroxide and extracted three times with methylene chloride. The organic extracts are dried and evaporated and the residue is crystallized from toluene to give 3-(o-aminobenzyl)-5-methylmercapto-1,2,4-triazole, m.p. 99°-102°.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([NH:26][S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=1[CH3:38])(=[O:29])=[O:28])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14](=[O:25])[NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:12][CH:13]=1)=[O:8].[OH-].[Li+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][CH2:17][CH2:16][NH:15][C:14]([C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][CH:4]([NH:26][S:27]([C:30]2[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])(=[O:29])=[O:28])[C:3]([OH:39])=[O:2])=[O:8])=[CH:13][CH:12]=1)=[O:25]
Reactant: COC(=O)C(CNC(=O)c1ccc(C(=O)NCCNc2ccccn2)s1)NS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)c2ccc(C(=O)NCCNc3ccccn3)s2)C(=O)O)c(C)c1
Yield: 86 %

Procedure:
A mixture of 3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid methyl ester (40 mg, 0.069 mmol), lithium hydroxide (34 mg, 1.39 mmol), in acetonitrile (10 mL) was stirred for 4 hrs at room temperature. The solvent was removed and the crude reaction product was taken up in ethyl acetate (40 mL). The solution was neutralized with acetic acid (1.0 mL). Solvent was than dried over sodium sulfate and evaporated. Purification of the residue on silica gel (10% MeOH-EtOAc) gave 40 mg of pure acetic acid salt of 3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid (86%). 1HNMR (300 MHz, CD3OD) δ: 2.22 (s, 3H), 2.61 (s, 6H), 3.57 (m, 4H), 3.82 (m, 2H), 6.50(d, 1H), 6.69(m, 2H), 6.90(s, 2H), 7.42(m, 3H), 8.01 (m, 1H). Compound XXXVI: 2-Benzenesulfonylamino-3-({5-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-thiophene-2-carbonyl-amino)-propionic acid.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(C)C)(C)C.C([Li])CCC.[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH:43]=O)[CH:37]([CH3:39])[CH3:38].S(=O)(=O)(O)O>O1CCCC1.CCCCCC.O.C(OCC)(=O)C.O1CCOCC1>[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43][CH:2]=[O:3])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)COc1ccccc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)COc1ccccc1CC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In 200 ml of tetrahydrofuran are suspended 144 g of (methoxymethyl)triphenylphosphonium chloride and 43 g of diisopropylamine, to which is dropwise added 253 ml of a 1.6 mol/L solution of n-butyllithium in hexane at −50° C. over a period of one hour. The mixture thus obtained is stirred at ambient temperature for one hour. Then, a solution of 25 g of 2-isobutoxy-benzaldehyde in 100 ml of tetrahydrofuran is dropwise added to the reaction mixture obtained above at −50° C. over a period of one hour, and the mixture thus obtained is stirred at ambient temperature for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue obtained above is mixed with 260 ml of 5% aqueous solution of sulfuric acid and 100 ml of dioxane, heated under reflux for 2 hours, cooled to ambient temperature and diluted with 500 ml of water. Ethyl acetate is added to the reaction mixture and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=95:5) to obtain 17.5 g of 2-(2-isobutoxyphenyl)ethanal as a colorless oily product.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.CC1SC(C#N)=CC=1.BrN1C(=[O:24])CCC1=O.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(O)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[C:8]([C:6]1[S:7][C:3]([CH:2]=[O:24])=[CH:4][CH:5]=1)#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(CBr)s1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cc1ccc(C#N)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C=O)s1
Yield: 44.8 %

Procedure:
8 g of 5-bromomethylthiophene-2-carbonitrile (prepared by brominating 5.7 g of 5-methylthiophene-2-carbonitrile and 8.42 g of N-bromosuccinimide in 68 ml of carbon tetrachloride under exposure to light and with the addition of 185 mg of benzoyl peroxide) is refluxed for 30 minutes in 35 ml of chloroform with 5.6 g of hexamethylenetetramine. The precipitated salt is suctioned off and refluxed in 30 ml of acetic acid and 30 ml of water for 2 hours. After extraction with ether, washing of the ether phase with water, drying, and evaporation, 2.43 g of 5-cyanothiophene-2-aldehyde is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][N:32]1[CH:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[N:33]1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cnn(C)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 1-methyl-4-tributylstannanyl-1H-pyrazole (0.105 mL, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-100% EtOAc/hexanes+1% AcOH) to give 52 mg of the title compound. MS: (+) m/z 467.37 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: BrCc1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccc2)c1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then benzyl bromide (228 μl). The mixture was stirred at room temperature for 40 minutes. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p 75-76° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccc(Cl)cc2)nc1C
Yield: 61.7 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g) synthesized in Example 1(3), 4-chlorophenylboronic acid (13.9 g), copper acetate (16.3 g) and pyridine (14.4 mL), and in the same manner as in Example 17(1), the title object compound (6.9 g, 62%) was obtained as a white solid.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[Cl:9][C:10]([Cl:15])([Cl:14])[C:11](Cl)=[O:12].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:8][C:5]1[S:6][CH:7]=[C:3]([NH:2][C:11](=[O:12])[C:10]([Cl:15])([Cl:14])[Cl:9])[N:4]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1csc(Br)n1)C(Cl)(Cl)Cl
Yield: 53.9 %

Procedure:
4-Amino-2-bromo-thiazole hydrobromide (15.6 g) and trichloroacetyl chloride (14.3 g) were suspended in methylene chloride (100 ml) with stirring and treated dropwise with pyridine (16 ml) over 15 minutes maintaining reaction temperature at 0° C. with an ice bath. After completing the addition, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (250 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue treated with charcoal in hexane and recrystallised from hexane to give the title compound (10.5 g) m.p. 77°-80° C. (Found: C, 19.0; H, 0.7; N, 8.5. C5H2Cl3BrN2OS requires C, 18.5; H, 0.6; N, 8.6%)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12
Product: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12

Procedure:
256 g of 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are refluxed in 1 liter of phosphorus oxychloride for 24 hours. The excess phosphorus oxychloride is decomposed by pouring the solution on ice and the crystallized 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4', 3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester is filtered off, yield 245 g (91%); m.p. 170°-172° (butyl alcohol).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:9]=1.C(O)C.O.Cl>O1CCOCC1.C(Cl)Cl>[NH:30]1[CH2:31][CH2:32][CH:27]([C:10]2[CH:9]=[C:8]([NH2:7])[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[C:12]3[N:11]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1cc(C2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 60 °C
Yield: 73.8 %

Procedure:
To a 20 mL scintillation vial was charged tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)-amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (80 μmol, 56 mg) followed by ethanol (2 mL) and H2O (500 μL). To this solution was added 2 mL of 4N HCl in 1,4-dioxane. This solution was heated to 60° C. for 2 hours. Upon completion, the reaction mixture was diluted with DCM (10 mL) and washed with NaHCO3(aq) and extracted with DCM twice more. The combined organics were then dried over Na2SO4 and the solvent was removed in vacuo to yield 5-(piperidin-4-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (20.3 mg, 59 umol) as cream-colored solid
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([F:15])=[CH:8][C:7]=1[Cl:16])(=[O:4])=[O:3].Cl.[OH-].[Na+]>O.[Fe]>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([F:15])=[CH:8][C:7]=1[Cl:16])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Oc1cc(N)c(F)cc1Cl
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A suspension of 2-chloro-4-fluoro-5-nitrophenyl methanesulfonate (27.0 g) and iron (33.5 g) in water (140 ml) was heated for reduction of the nitro group into amino group. When the temperature of the reaction mixture reached 80° C., 35% hydrochloric acid (3.2 g) was added thereto. Upon cooling to room temperature, the pH of the reaction mixture was adjusted to 9.0 with the addition of an aqueous sodium hydroxide solution. The reaction mixture was then extracted with toluene and tetrahydrofuran. The organic layer so separated was washed with water, dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent, affording the titled compound (22.3 g) as a pale yellow oil which was then purified by silica gel chromatography to give colorless crystals with melting point 79°-80° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)(O)[O-].[Na+].COCCOCCOC.[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42](O)[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42]([SH:2])[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Oc1ncnc2[nH]c(-c3ccccc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reaction time: 1 h
Yield: 94.8 %

Procedure:
After adding 6.19 g of phosphorus pentasulfide, 6.24 g of sodium bicarbonate and 25 ml of diglyme to 2.45 g of the 6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 1 hour, an additional 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate were added and the mixture was stirred for 1 hour. There were further added another 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate, and the mixture was stirred for 1 hour. It was then returned to room temperature, water was added, the mixture was stirred for 10 minutes, and the precipitated crystals were filtered out, washed with water and dried to obtain 2.5 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8](=[O:9])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=C(Nc1ccccc1)c1ccc[nH]c1=O
Product: Cc1nc(-n2cccc(C(=O)Nc3ccccc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-oxo-N-phenyl-1,2-dihydropyridine-3-carboxamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 15% yield: mp 225-227° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.64-8.55 (m, 2H), 8.18 (dd, J=6.6, 2.1 Hz, 1H), 7.58-7.47 (m, 5H), 7.32-7.26 (m, 4H), 7.24-7.17 (m, 1H), 6.75-6.70 (m, 1H), 4.37 (d, J=5.9 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.8, 156.0, 151.4, 146.0, 145.7, 140.2, 140.0, 129.7, 129.5, 128.7, 127.6, 127.2, 127.2, 120.1, 118.4, 107.8, 43.1, 17.4; (ES+) m/z 445.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: Cc1cccc(C)c1B(O)O
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2,6-dimethyl-phenylboronic acid (25 mg, 0.17 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.20 (d, 1H), 8.14 (m, 3H), 8.02, (d, 2H), 7.87 (d, 1H), 7.37 (dd, 1H), 7.34 (d, 2H), 7.21 (t, 1H), 7.14 (d, 2H), 2.05 (s, 6H).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.[O:13]1CCCC1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CCOCC.O>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:13])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC1OC1C2
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2
Reaction time: 4 h

Procedure:
A solution of 8.0 g. (0.048 mole) of 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in 100 ml. of tetrahydrofuran is cooled to 0° and 20 ml. of water and 0.5 ml. of 70% perchloric acid are added. After 4 hr., a further 1.5 ml. of acid is added and the solution stirred for 16 hr. at ambient temperature and diluted with 100 ml. each of ether, 10% sodium bicarbonate and saturated salt solution. The aqueous layer is separated and washed with 150 ml. of 1:1 ether-tetrahydrofuran. The organic phase is washed with saturated salt solution, dried and evaporated to give an oil which solidifies on trituration with chloroform. Recrystallization gives in two crops, 4.85 g. of solid which is recrystallized from ethyl acetate to give 3.84 g. m.p. 179.5°-181.5°. Two further recrystallizations of a small sample give the analytical specimen, m.p. 183°-184°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[CH:26]=[C:25]([CH3:27])[N:24]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:23]=3)[O:19][N:18]=2)=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>CN(C=O)C.C(#N)C.O>[CH3:27][C:25]1[N:24]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:23]=[C:22]([C:20]2[O:19][N:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:15]=3)[N:21]=2)[CH:26]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CBr)cc4)no3)cc2C)cc1
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN5CCCCC5)cc4)no3)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a mechanically stirred solution of piperidine (24 mg, 0.28 mmol) in DMF (1.5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 11.3 mg, 0.28 mmol), and the mixture was stirred at 0° C. for 30 min. 3-[4-(Bromomethyl)phenyl]-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Intermediate LL, 100 mg, 0.24 mmol) was added, and the mixture was stirred at rt over night whereupon it was directly subjected to preparative HPLC (RP-18 column; acetonitrile/water gradient containing 0.1% trifluoroacetic acid). The product-containing fractions were combined and the solvent was partly removed. A neutral pH was established by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (20 mL each). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (62 mg, 61%): 1H-NMR (400 MHz, DMSO-d6) δ 8.01 (d, 2H), 7.50 (d, 2H), 7.17 (d, 2H), 7.12 (d, 2H), 6.90 (s, 1H), 5.42 (s, 2H), 3.50 (s, 2H), 2.42-2.30 (m, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 1.55-1.47 (m, 4H), 1.44-1.35 (m, 2H); ES-MS m/z 428 (MH)+; HPLC RT (Method K) 1.10 min.