Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:17][CH2:16]1
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2F)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Product: Nc1nc(N)c2c(OCC3CCC(Cc4ccccc4F)CC3)cccc2n1
Yield: 52 %

Procedure:
Cyclization of 2-fluoro-6-[4-(2-fluorobenzyl)cyclohexylmethoxy]benzonitrile (225 mg; 0.66 mmol) and guanidine carbonate (119 mg; 0.66 mmol) was carried out using Method F. Material was purified using ethyl alcohol trituration. Solids were collected by filtration. Title compound was obtained. (130 mg; 52% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.33 (t, J=8.0 Hz, 1H), 7.24 (m, 4H), 7.12 (m, 2H), 6.75 (dd, J=8.4, 0.8 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.97 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 1.83 (m, 3H), 1.69 (m, 2H), 1.51 (m, 1H), 1.06 (m, 4H). MS m/z (APCI) 381 (M+H)+.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[C:5](=[S:12])[NH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10].[OH-].[K+]>>[CH3:10][C:9]1[NH:8][C:7](=[O:11])[N:6]=[C:5]([S:12][CH3:1])[C:4]=1[Cl:3]
Reactant: CI
Reactant: Cc1[nH]c(=O)[nH]c(=S)c1Cl
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(=O)[nH]c(C)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
Methyl iodide (0.012 mol) was added to an aqueous solution prepared from 5-chloro-6-methyl-4-thiouracil (0.01 mol) and 0.725 M KOH (25 ml) and the reaction mixture was stirred at room temperature for 5 h. The solid precipitate formed was collected and was recrystallized from isopropanol; yield 65%, m.p. 268°.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].C(=O)([O-])[O-:28].[K+].[K+]>C(O)C>[C:1](/[C:3](/[C:8]([NH:7][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:9])=[C:4](/[NH:5][C:6](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)\[S:25][CH3:26])#[N:2]
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS/C(NC(=O)c1ccc(SC)cc1)=C(\C#N)C(=O)Nc1ccc(C)cc1
Temperature: 60 °C
Yield: 80.9 %

Procedure:
To a suspension of 5-Cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2.5 g, 6.59 mmol) in ethanol (30 ml) was added anhydrous potassium carbonate (1.3 g, 9.4 mmol) under continuos stirring, and at an ambient temperature. The suspension was heated slowly to 60° C. under stirring for 5 hours. Subsequently the reaction mixture was filtered, and washed with water then with ethanol and dried under vacuum to yield the title compound (2.12 g, 80.8%, m.p.: 173-175° C., purity 91.6% by HPLC). 1H-NMR (CDCl3)δ (ppm): 2.34 (s, 3H), 2.53 (s, 3H), 2.69 (s, 3H), 7.16-7.18 (d, 2H), 7.26-7.37 (m, 4H), 7.92-7.94 (d, 2H), 14.0 (s, 1H, D2O exchangeable). IR (KBr) cm−1: 3311, 2201, 1702 (—C═O). MS m/z: 398.5 (M++1).
Reaction SMILES: [CH:1]1[C:10]2[N:11]3[C:15]([C:16](=O)[C:8]4[C:9]=2[C:4]([CH:5]=[CH:6][N:7]=4)=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12]3.Cl.[NH2:19][OH:20].O>N1C=CC=CC=1>[OH:20][N:19]=[C:16]1[C:8]2[C:9]3[C:4]([CH:5]=[CH:6][N:7]=2)=[CH:3][CH:2]=[CH:1][C:10]=3[N:11]2[C:15]1=[CH:14][CH:13]=[CH:12]2
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=c1c2nccc3cccc(c32)n2cccc12
Yield: 90.9 %

Procedure:
A solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (28 g.) and hydroxylamine hydrochloride (28 g.) in pyridine (560 cc.) is maintained at the boiling point, with stirring. The brown solution thus obtained is poured into water (3.92 liters). After stirring for 3 hours, the mustard yellow crystals obtained are filtered off and then washed copiously with water. After drying, 7-hydroxyimino-7H-indolizino[5,6,7-ij]isoquinoline (27.2 g.), melting at 254° C. with decomposition, is obtained. After recrystallisation from a mixture of water and pyridine (6- 5 by volume), the pure product melts at 258° C. with decomposition.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>CC(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[C:10]([S:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[CH:11]=[CH:12][CH:13]=2)[CH2:18]1
Reactant: O=S(=O)(c1cccc2c1CNCC2)N1CCOCC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cccc(S(=O)(=O)N5CCOCC5)c4C3)c2cc1OC
Yield: 84.9 %

Procedure:
8-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (15.7 g, 55.6 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (12.5 g, 55.6 mmol) were refluxed overnight in 2-propanol (400 mL). The solvent was removed under vacuum and the resultant solid was partitioned between aqueous ammonia and CH2Cl2. The mixture was extracted three times with CH2Cl2 and the combined extracts were dried and concentrated. Flash chromatography (0.1:3:97 NH4OH/MeOH/CH2Cl2) followed by recrystallization of the product fractions from EtOH provided, in two crops, 22.2 g (85%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>O1CCOCC1.ClCCl>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:16][N:15]=1
Reactant: NN
Reactant: O=C(c1nccs1)c1cccnc1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cnc2[nH]nc(-c3nccs3)c2c1
Temperature: 150 °C

Procedure:
To a suspension of 2-chloro-3-[(2-thiazolyl)carbonyl]pyridine (257.5 Mg, 1.2 Mmol, 1 equiv) in dioxane (3 mL) in a sealed tube was added hydrazine (2 mL). The mixture was heated at 150° C. overnight, cooled to room temperature and concentrated in vacuo to provide a crude residue. The resultant residue was diluted with dichloromethane (300 mL), washed with water (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide 3-thiazol-2-yl-1H-pyrazolo[3,4-b]pyridine (212.3 Mg) as a yellow powder which used without further purification: LCMS (ES) M+H 203.5, Rf 2.68 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Br:13][C:14]1[CH:15]=[C:16]([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[C:36]#[N:37])=[N:22]S(C(C)(C)C)=O)[CH:17]=[CH:18][C:19]=1[F:20].Cl>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:21]2([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:29]3[C:30](=[C:31]([F:35])[CH:32]=[CH:33][CH:34]=3)[C:36]([NH2:37])=[N:22]2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Reactant: Ic1ccncc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
A solution of 4-iodopyridine (0.530 g, 2.59 mmol) in THF (5 mL) was added dropwise to a is mixture of tert-butyllithium (1.6 M in pentane, 2.94 mL, 4.70 mmol) in THF (20.00 mL) at −100° C. under an argon atmosphere. N-((3-Bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 2.35 mmol) in THF (7.50 mL) was added and the resulting reaction mixture was stirred at −100° C. for 30 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was dissolved in MeOH (15.00 mL), and then hydrogen chloride (2 M in diethyl ether, 2.351 mL, 4.70 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The solvents were removed in vacuo, and the residue was partitioned between aqueous sodium bicarbonate (saturated) and chloroform. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane afforded 0.088 g (9% yield) of the title compound. MS (ES+) m/z 400 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCNCc1cnccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrazinylmethyl-amino)ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2-(2-pyrazinyl-methylamino)ethyl]guanidine.
Reaction SMILES: Br[CH:2](Br)[C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:37][CH2:2][C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1
Reactant: CCCc1nc(C(Br)Br)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCc1nc(CF)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
A mixture of 4′-{[2-(dibromomethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), tetrabutylammonium fluoride (1.0 M, 3.3 mL) and tetrahydrofuran (10 mL) were stirred at 80° C. for 12 hr. The solvent was evaporated from the reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 27%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[NH3:15]>CO>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH2:15])=[O:6]
Reactant: N
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Solvent: CO
Product: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Methyl 3-methyl-2-nitrobenzoate (10.02 g, 51.3 mmol) was added to a 7N solution of ammonia in methanol (50 mL) and the mixture was heated at 100° C. in a Fisher-Porter tube for 3 hours. The solution was then cooled, concentrated and triturated with dichloromethane to give the title compound of Step A as a white solid (1.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]([NH2:22])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]#[N:22])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1CC(N)=O
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine-3-acetamide (3 g) in dioxane was cooled to 5°-10° C. To the suspension there was added over a period of 5 minutes a solution of trifluoroacetic anhydride (6 g) in dioxane. The mixture was maintained cool and stirred for 30 minutes. Thereafter the mixture was allowed to warm to room temperature and was stirred for a further four hours. The mixture was thendiluted with ice water and the precipitate was filtered. After recrystallization from ethylacetate the desired compound was obtained (m.p. 163°-166° C.).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.20 min, MH 459. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.31,(1H, t), 9.17,(1H, d), 8.39,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.83,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.29-7.25,(2H, m), 6.94,(2H, m), 6.84,(1H, d), 4.52,(2H, d), 3.75,(3H, s), 2.45,(3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C([O-])(=O)C.[Na+].[N+:20](CC)([O-])=O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:20])[CH3:2]
Reactant: CCOc1ccc(C=O)c(OCC)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccc(C#N)c(OCC)c1
Yield: 37.8 %

Procedure:
A mixture of 2,4-diethoxybenzaldehyde (5.0 g, 25.7 mmol), sodium acetate (4.23 g, 51.6 mmol), nitroethane (3.86 g, 51.4 mmol) in acetic acid (7 mL) was heated at reflux for 6 h. The mixture was then cooled and poured onto ice-water. The solids were filtered off, washed with water and dried. Chromatography of the residue over silica gel using 2-5% ethyl acetate in hexanes followed recrystallization in ethyl acetate gave 2,4-diethoxybenzonitrile (1.86 g, 38%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:29]=[O:30])C.[OH-].[Na+]>C(OCC)C>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]=2[CH:29]=[O:30])[CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN1CCN(Cc2ccc(-c3ccccc3)cc2C=O)CC1
Yield: 28 %

Procedure:
A solution of 1-biphenyl-4-ylmethyl-4-methyl-piperazine (26 mmol) in diethyl ether (50 mL) was added n-BuLi (38 mmol) and DMF (15 mL) and was refluxed for 6 h. The reaction was cooled and added 2 N NaOH (50 mL) and extracted with diethyl ether. Evaporation in vacuo gave a black oil that was purified by flash chromatography. Yield: 28% as black oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[O:5])[NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1nccs1)c1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccccc1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
2-hydroxy-N-1,3-thiazol-2-ylbenzamide (502, 267.1 mg, 1.21 mmol) was placed into a 10 mL round bottom flask equipped with a stirbar and a septum with a dry nitrogen inlet. Dichloromethane (5.0 mL) and triethylamine (500 μL, 3.59 mmol) were added to form a light pink solution. Methanesulfonyl chloride (100 μL, 1.3 mmol) in dichloromethane (ca. 1.0 mL) was added dropwise to the stirring solution over ca. 30 seconds, and the reaction was stirred at room temperature for ca. 20 minutes before being quenched into saturated NaHCO3, and extracted with dichloromethane. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was recrystallized from hexanes/ethyl acetate to yield (284 mg, 78%) of 11 as a colorless crystalline solid. Example 11 (2-thiazol-2-ylcarbamoyl)phenyl methanesulfonate) has the empirical formula C11H10N2O4S and a molecular weight of 298.34.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cn1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC)cn1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(5-methoxypyridin-2-yl)indole-3-carboxylic acid ethyl ester (139 mg, 0.35 mmol, see step (b) Example 13) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 110 mg (58%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=Cc2cccc(Cl)c2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Temperature: 1 °C

Procedure:
A 5 L round bottom flask was equipped with mechanical stirring, a reflux condenser and ice bath. 488.2 g distilled 7-chloro-2-methylindene (2.97 mol) was added, dissolved in 2 L ether and 32.2 g Ni(dpp) (0.059 mol, 2 mol%) slurried in the solution, and stirred to cool to 0-2° C. 1.05 L of 3.1M phenylmagnesium bromide in ether (3.25 mol, 10% excess) was added slowly from an addition funnel so that the temperature remained below 5° C. Once complete, the ice bath was removed, and the reaction stirred up to room temperature. The reaction was refluxed for 8 hours, and checked for completion by GC. The reaction flask was cooled with an ice bath, and 250 mL water added, then 1 L 10% HCl. The aqueous and organic layers are separated, and the organic layer dried over anhydrous Na2SO4. Ether was distilled, and the residual oil placed on a column of 100 g silica gel. Elution with hexane was performed, the hexane distilled under reduced pressure to a temperature of 90° C. 2-methyl-7-phenylindene (Spaleck compound 13a) was obtained by distillation at <1 mm Hg with a 36 cm Vigreux column at 125° C. A fore-cut containing biphenyl was obtained at 70-90° C. and discarded. Yield was 507.8 g (2.47 mol) equal to 80%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](I)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C[Sn](C)(C)[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: C[Sn](C)(C)c1ccco1
Reactant: Cc1ccc(-n2c(N)nc3ccccc32)cc1I
Product: Cc1ccc(-n2c(N)nc3ccccc32)cc1-c1ccco1

Procedure:
2-Amino-1-[3-(2-furyl)-4-methylphenyl]benzimidazole was prepared from 4-(2-amino-1-benzimidazolyl)-2-iodotoluene and 2-trimethylstannylfuran according to method C. mp 155°-157° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Compound 454 (1.67 g, 6.00 mmol) and DMAP (36.7 mg, 0.300 mmol) were suspended in pyridine (24 mL), and cyclopropanecarbonyl chloride (1.09 mL, 12.0 mmol) was added thereto, followed by stirring at 60° C. for 90 minutes. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=99:1), followed by recrystallizing from ethanol to afford the entitled Compound 456 (1.35 g, 65%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1>CC#N>[CH3:12][C:13]1[N:14]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=2)[CH:15]=[CH:16][N:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: Cc1ncc[nH]1
Solvent: CC#N
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(O)c1
Yield: 78 %

Procedure:
A solution of 5-fluoro-2-nitrophenol (2.03 g) and 2-methylimidazole (2.14 g) in CH3CN (50 mL) was stirred at reflux under N2 for 16 h. The solvent was removed and the residue was purified by chromatography on silica gel with 0-10% MeOH in CH2Cl2 to give 2.21 g of 5-(2′-methylimdazol-1-yl)-2-nitrophenol. ESI mass spectrum z (rel. intensity) 220.1 (M+H, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:13]2[C:12]([CH3:15])([CH3:14])[O:11][C:10]([CH3:17])([CH3:16])[C:9]=2[S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:7]2[S:8][C:9]3[C:10]([CH3:17])([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[C:13]=3[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:25])=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Product: CCOC(=O)c1c(NC(=O)c2ccc(F)cc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 18A and commercially available 4-fluoro-2-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 1.49 (s, 6H), 1.54 (s, 6H), 4.30 (q, J=7.1 Hz, 2H), 7.76 (ddd, J=9.1, 8.6, 2.4 Hz, 1H), 7.88 (dd, J=9.3, 2.5 Hz, 1H), 7.96 (dd, J=8.6, 5.3 Hz, 1H), 11.48 (br s, 1H). MS (ESI+) m/z 460 (M+H)+. Anal. calcd. for C21H21F4NO4S: C, 54.90; H, 4.61; N, 3.05. Found: C, 54.84; H, 4.60; N, 3.02.