Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:19]=3)[CH:12]=[CH:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[C:30]([N:35]=[C:36]=[S:37])(=[O:34])[O:31][CH2:32][CH3:33].O>CS(C)=O>[C:27]([C:24]([C:20]1[CH:19]=[C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([CH:10]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[S:37])=[N:7][CH:6]=2)=[O:29])[CH:23]=[CH:22][CH:21]=1)([CH3:26])[CH3:25])#[N:28]
Reactant: CCOC(=O)N=C=S
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)nc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (4.71 g, 12.2 mmol) in dimethyl sulfoxide (100 mL) was added ethyl isothiocyanatocarbonate (1.73 mL, 14.6 mmol), and the mixture was stirred at room temperature for 6 hr. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({5-[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenoxy]pyridin-2-yl}carbamothioyl)carbamate as a yellow amorphous solid. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][O:8][C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:4].S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cn1c(-c2ccccc2)cc2onc(-c3ccccc3)c2c1=O

Procedure:
A mixture of 26.1 g (0.0815 mole) of N-methyl-5-phenacyl-3-phenyl-4-isoxazole carboxamide and 261 ml. of 2 M sulfuric acid is refluxed for 24 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and then recrystallized from ethanol to give 5-methyl-3,6-diphenylisoxazolo[4,5-c]pyridin-4(5H)-one, m.p. 149°-151.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br.ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([F:8])=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[CH:7]=1
Reactant: Oc1cc(F)ccc1Cl
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1cc(F)c(Br)cc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-fluorophenol (24.1 g, 165 mmol) was dissolved in anhydrous chloroform (200 mL), heated to 75° C. and treated with a solution of bromine (8.5 mL, 165 mmol) in anhydrous chloroform (40 mL) added dropwise over 5 minutes. After 3 hours the reaction was treated with additional bromine (1.7 mL, 33 mmol) in anhydrous chloroform (15 mL) and stirred at 75° C. After 2 hours, the reaction was cooled to room temperature and treated with dichloromethane (300 mL) and Na2S2O3 (100 mL, saturated aqueous solution). After mixing vigorously, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting yellow liquid was purified by vacuum distillation. Compound C.1 (22.3 g, 60%) was obtained as a colorless liquid. LC-MS ESI (neg.) m/e: 224.9 (M−H). 1H NMR (400 MHz) (CDCl3) □ 7.51 (d, J=6.9 Hz, 1H); 6.85 (d, J=9.2 Hz, 1H); 5.69 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[C:9]1([CH:4]([CH2:3][CH2:2][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1cn[nH]c1
Reactant: COC(=O)C(CCCl)c1ccccc1
Product: COC(=O)C(CCn1cccn1)c1ccccc1
Yield: 32.2 %

Procedure:
Methyl (RS)-4-chloro-2-phenylbutanoate (prepared as described in J. Amer. Chem. Soc., 443, 73, 1951) (1 g) and pyrazole (1 g) were heated together at 120° C. for 5 hour, cooled and the residue partitioned between ether and water. The organic layer was washed with water and extracted with 2M hydrochloric acid. The acid extracts were basified with sodium carbonate and extracted with ether. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (0.37 g, 33%) as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.C(OCC)C>[Si:17]([O:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCCO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.8 %

Procedure:
To a solution of 4-hydroxy-1-phenyl-butan-1-one (3.29 g, 20 mmol) in DMF (20 mL) was added tert-butylchlorodimethyl-silane (4.5 g, 30 mmol) and imidazole (4.1 g, 60 mmol). After stirring at room temperature for 14 hours, the reaction mixture was diluted with diethyl ether (150 mL) and washed with 1M HCl (2×70 mL), water (2×70 mL) and brine (100 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (6% ethyl acetate in hexanes) to provide the product (5 g, 90%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19](C=O)C.CN>O>[N+:15]([C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:19][CH3:18])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a mixture of 2-chloro-1,3-dinitro-5-trifluoromethyl-benzene (20 g) and DMF (30 mL), 40% of aqueous methylamine solution (15 ml) was added drop-wise under ice-cooling. The mixture was stirred for 6 hours under ice-cooling, and then the reaction mixture was added to iced water. The precipitated powder was collected by filtration, and washed with water to give 20 g of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7](C(O)=O)[C:8](=[O:15])[NH:9]2.Cl>N1C=CC=CC=1>[Br:1][C:7]1[C:8](=[O:15])[NH:9][C:10]2[C:5]([CH:6]=1)=[C:4]([Cl:3])[CH:13]=[C:12]([Cl:14])[CH:11]=2
Reactant: BrBr
Reactant: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50.8 mmol of bromine are added dropwise to a suspension containing 25.4 mmol of 5,7-dichloro-2(1H)-quinolone-3-carboxylic acid in 65 ml of pyridine at 0 C. After stirring for 10 minutes at room temperature, the whole mixture is brought to 90 C. for one hour. After cooling, 300 ml of 1N hydrochloric acid are added. The expected product is obtained by filtering the precipitate, then washing the latter with 1N hydrochloric acid and with water and drying.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)=O)=[CH:9][CH:8]=2)[N:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)=[S:28])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(C(=S)NC3CC3)cc2)cs1
Temperature: 70 °C

Procedure:
A solution of 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (265 mg, 1 mmol), in THF (5 mL), was treated with Lawesson's reagent (0.75 eq) and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 275.4 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])=O.[NH3:26]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:26]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: N
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2F)c1C
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3F)nc2c1C
Yield: 28 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-(o-fluorobenzoylamino)benzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from ethanol/water to give 2-(o-fluorophenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 98° to 100° C. in a yield of 28%.
Reaction SMILES: [NH3:1].[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1OCC)[CH2:10][CH:11]=[CH2:12])([CH3:5])[CH3:4]>>[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:1])[CH2:10][CH:11]=[CH2:12])([CH3:5])[CH3:4]
Reactant: N
Reactant: C=CCN(CC(=O)OC(C)(C)C)c1c(OCC)c(=O)c1=O
Product: C=CCN(CC(=O)OC(C)(C)C)c1c(N)c(=O)c1=O
Yield: 71 %

Procedure:
Ethanolic ammonia (25 mL) was added to a flask containing N-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester (2.5 g, 8.5 mmol) at room temperature. After 5 hours the reaction mixture was concentrated and purified by flash chromatography (5 cm diameter, elution with 5% methanol in dichloromethane) to yield N-(2-amino-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester as a white solid (1.6 g, 71%, mp 175°-176° C.); IR (KBr, cm-1): 3300, 3140, 1810, 1740, 1670, 1650; MS (EI): 266 (M+, 34), 210 (24), 165 (100), 109 (54), 95 (89), 68 (68); 1H NMR (DMSO, 400 MHz): δ 7.70 (br s, NH2), 5.84-5.77 (m, 1H), 5.26 (d, J=17 Hz, 1H), 5.19 (d, J=10 Hz, 1H), 4.3-4.0 (br m, 4H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C@@:5]1(O)[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1Cl)(=[O:3])[CH3:2].[CH3:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]2[C:35]([CH3:41])=[CH:36][C:37]([CH3:40])([CH3:39])[NH:38][C:32]2=[CH:31][CH:30]=1>CC(C)=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:38]1[C:32]2[C:33](=[CH:34][C:29]([O:28][CH2:27][CH3:26])=[CH:30][CH:31]=2)[C:35]([CH3:41])=[CH:36][C:37]1([CH3:39])[CH3:40])(=[O:3])[CH3:2]
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: CC(=O)N[C@]1(O)C(Cl)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
2-Acetamido-3,4,6-tri-O-acetyl-D-glucopyranosyl chloride (18.3 g) and ethoxyquin (22.1 g) were vigourously stirred together at 80° for 3 hours. Acetone (50 ml) was added to the hot reaction mixture and stirring was continued for 0.5 hours. After cooling, the solid ethoxyquin-hydrochloride was filtered, washed with acetone and the combined filtrates were evaporated under reduced pressure. The crude product was purified by column chromatography on silica (ethylacetate-benzene 1:4). 16.5 g of 1-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranosyl)-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline were obtained. Analytical grade sample was obtained by recrystallisation from ether or isopropanol. m.p. 186°-187°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:26])[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:17]1([NH:26][C:14]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=2)=[O:15])[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=[CH:18]1
Reactant: Nn1ccc2cccnc21
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2cccnc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1.13 mmol) in EtOAc (20 mL) is added to a stirred solution of pyrrolo[2,3-b]pyridin-1-ylamine (1.13 mmol) and K2CO3 (1.13 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridin-1-ylamide (305 mg, 81%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.57 (d, H) 7.13-7.55 (m, 4H), 7.99 (m, H), 8.10-8.40 (m, 3H), 9.27 (s, 2H), 12.57 (br, N—H).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=1[N+:21]([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:16]1[CH:17]=[CH:18][C:13]([CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:14]([N+:21]([O-:23])=[O:22])[C:15]1=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccn(C)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (2.5 g, 19 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% w/w, 0.96 g, 23.9 mmol) in batches at 0° C. The mixture was stirred at room temperature for 30 minutes. Then the solution of 4-chloro-1-methyl-3-nitropyridin-2(1H)-one (3.0 g, 16 mmol) in tetrahydrofuran (50 mL) was added in one portion. The resultant solution was stirred and heated to 50° C. for 12 hours. Once the starting material had been consumed, the reaction solution was quenched with water (100 mL) at 0° C., and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give ethyl 2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxobutanoate (2.5 g, 56%) as a yellow solid. LRMS (M+H+) m/z: calcd 282.09. found 282.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]([C:8]([O:10]CC)=[O:9])=[CH:6][N:7]=1.[OH-].[Li+]>O1CCOCC1>[CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cnc(N(C)CCc2ccccc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CCc1ccccc1)c1ncc(C(=O)O)s1
Temperature: 75 °C

Procedure:
To a solution of ethyl 2-[methyl(2-phenylethyl)amino]-1,3-thiazole-5-carboxylate (0.56 g, 1.93 mmol) in dioxane (10 mL) was added lithium hydroxide (5.8 mmol, 1.9 mL of a 3.0M solution) and the reaction was warmed to 75° C. for 2.5 hours. The reaction was partitioned between 1M HCl and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give the title compound. 1H NMR (600 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.22 (m, 5H), 3.68 (t, J=7.33 Hz, 2H), 3.31 (bs, 1H), 2.99 (s, 3H), 2.87 (t, J=7.63 Hz, 2H); ESIMS calcd 263.1 (M++H), found 263.0 (M++H).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([O:31]CC)=[O:30])=[C:27]([C:34]([OH:37])([CH3:36])[CH3:35])[N:26]=[C:25]2[CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([OH:31])=[O:30])=[C:27]([C:34]([OH:37])([CH3:36])[CH3:35])[N:26]=[C:25]2[CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of 4.8 g of lithium hydroxide monohydrate in 100 ml of water was added to a solution of 11.6 g of ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] in 60 ml of dioxane, and the resulting mixture was stirred at room temperature for 16 hours. The dioxane was removed by distillation under reduced pressure, and then the concentrate was mixed with ice-water and with ethyl acetate, after which 114 ml of 1N aqueous hydrochloric acid were added. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The crystalline residue was triturated in diisopropyl ether and collected by filtration to give 9.09 g of the title compound, melting at 155°-157° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH:23]1([NH:26][C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:33]([C:32]4[CH:31]=[CH:30][C:29]([C:27]([NH:26][CH:23]5[CH2:25][CH2:24]5)=[O:28])=[CH:36][CH:35]=4)[NH:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Product: N#Cc1ccc(COc2ccc3nc(-c4ccc(C(=O)NC5CC5)cc4)[nH]c3c2)cc1

Procedure:
Compound 669 was prepared according to the procedure similar to that described in Scheme III from 1-(4-cyanobenzyl)oxy-3,4-dinitrobenzene and 4-(cyclopropylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H20N4O2: 409.16; found: 409.04.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.I[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C1COCC1>[C:2]1([CH2:1][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: Cc1nccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCc2nccc3ccccc23)CC1
Temperature: -78 °C
Reaction time: 1.75 h
Yield: 66 %

Procedure:
The procedure described in Example 7a was followed using 1-methyl isoquinoline (0.50 g, 3.49 mmol), 1M LDA (4.2 mL, 4.2 mmol), and 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (1.2 g, 3.84 mmol) in dry THF (45 mL) except that after addition of the reagents, the mixture was stirred at −78° C. for 1.75 hours. Purification by chromatography (30% EtOAc/toluene) gave the title compound (0.784 g, 66%) as a yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9](Cl)[CH:10]=[C:11]([Cl:13])[N:12]=2)=[CH:5][CH:6]=1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(O)CCC>[Cl:13][C:11]1[N:12]=[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:8]=[C:9]([NH:15][C:16]2[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:10]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3)n2)[nH]n1
Temperature: 117 °C
Yield: 29.4 %

Procedure:
A suspension of Fenclorim (4,6-dichloro-2-phenylpyrimidine)(0.1 g, 0.44 mmol), 3-amino-5-methylpyrazole (0.045 g, 0.47 mmol), N,N-diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were heated at 117° C. for 18 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 3:2 Petrol:EtOAc) to afford 0.037 g (29% yield) of (6-Chloro-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as a off-white solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 85° C. under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The concentrate was dissolved in EtOAc, and washed with NaHCO3 (sat, aq.). The organic layer is concentrated in vacuo, and the crude product by preparative HPLC. The residual disulfide that still remained in the mixture after HPLC may be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7 mg, 13% yield) as an off-white solid: mp 235-236° C.; 1H NMR (DMSO) δ 2.10 (3H, s), 2.21 (3H, s), 6.33 (1H, br s), 7.50 (3H, m), 7.7-7.59 (2H, m), 7.76-7.78 (2H, m), 8.25 (2H, m), 9.72, 10.26 and 11.93 (3H, 3×br s); IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Fc1cc(I)ccn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(I)ccn1
Yield: 95.4 %

Procedure:
500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91%) of crude 4-iodo-2-methoxypyridine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1.[CH3:29][CH2:30]O>[Pd]>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH:14]=[C:9]([OH:8])[CH:10]=1)[CH3:30]
Reactant: CCO
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Product: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 5 h

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (2.5 g, 5.5 mmol) in EtOH (50 mL) was added 10% Pd/C (5% wt) and the resultant black suspension stirred under an atmosphere of H2 for 5 hours. The resultant mixture was filtered through celite and evaporated to dryness. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester as a white solid, yield 2.3 g (93%).