Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(OC)[N:4](C)C.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1I.O.C(O)C>CN(C)C=O.C(O)(=O)C.[Fe]>[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH2:4]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(F)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
N,N-Dimethylformamide dimethylacetal (16.5 mL, 125 mmol) was added in one portion to a stirred solution of 4-fluoro-3-iodo-6-methylnitrobenzene (14.1 g, 50 mmol) in N,N-dimethylformamide (50 mL) at 130° C. under Ar. The mixture was stirred at 130° C. for 10 min then another aliquot of N,N-dimethylformamide dimethylacetal (10 mL) was added in one portion. The mixture was stirred at 130° C. for a further 10 min then another aliquot of N,-dimethylformamide (6 mL) was added in one portion. The mixture was stirred at 130° C. for 10 min then poured into water (400 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL) then dried (magnesium sulfate), filtered and concentrated in vacuo to leave a solid. The solid was dissolved in acetic acid, ethanol (1:1; 240 mL) and iron powder (33.2 g, 600 mmol) was added in one portion. The mixture was placed under an atmosphere of Ar, heated to 90° C. and stirred for 15 min (CARE: VIGOROUS REACTION—COOLING MAY BE REQUIRED). After cooling to room temperature the mixture was filtered through celite and the filtrate was concentrated in vacuo to leave a crude oil. The oil was purified by column chromatography [SiO2; dichloromethane, heptane (1:4 to 2:3)] to give the product (4.8 g, 37%, 3 steps from 2-fluoro-4-methyl-5-nitroaniline) as a green oil: NMR δH (400 MHz; CDCl3) 8.18 (1H, br. s), 7.75 (1H, d, J 5 Hz), 7.32 (1H, d, J 8.5 Hz), 7.22-7.23 (1H, m), 6.50-6.52 (1H, m); GC (25 m Quartz/Bonded Phase I; Injection Temperature 250° C.; Detector Temperature 320° C.; Temperature Ramp Rate: 100 to 320° C. at 10° C./min; Carrier Gas Helium; Flow Rate 12 mL/min) Retention Time: 8.65 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[CH3:13].B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[CH3:13][C:3]1[CH:4]=[C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1
Reactant: Cc1cc(-n2cncn2)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1cc(-n2cncn2)ccc1-c1ccc(C(=O)O)cc1
Yield: 63.9 %

Procedure:
The title compound (0.15 g) was prepared from 1-(4-bromo-3-methylphenyl)-1,2,4-triazole (D63, 0.2 g) and 4-boronobenzoic acid (0.14 g) as described in Description 15.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([C:40](O)=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:40](=[O:41])[C@H:31]([CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:25])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 0.73 g (5.26 mmol) of glycine ethyl ester hydrochloride and 0.74 mL (5.26 mmol) of triethylamine in 42 mL of chloroform were added successively, at 0° C., 2.0 g (5.26 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine and 1.09 g (5.26 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water, 3% aqueous sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate. Evaporation of the solvent afforded a residue which was triturated with ethyl acetate. Insoluble materials were removed by filtration and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isopropyl ether to give 1.15 g (48%) of the title compound as colorless crystals. The mother liquor was concentrated under reduced pressure and the residue was crystallized as before to give a second crop of crystals (0.77 g, 32.1%). Total yield 80.1%, melting point 69°-70° C. NMR and IR spectral analyses confirmed the identity of the product, which has the formula: ##STR102##
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:12]([O:11][C:9]([C:4]1[C:3]([CH2:2][N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:10])([CH3:14])[CH3:13]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)OC(=O)c1ncccc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl 3-(hydroxymethyl)pyridine-2-carboxylate (prepared in accordance with P. Ornstein et. al. J. Med. Chem. 1989, 32, 827) (200 g, 1.02 mol), methyl N-[(4-methylphenyl)sulfonyl]glycinate (249 g, 1.02 mol), and triphenylphosphine (403 g, 1.5 mol) were dissolved in dry THF (3000 mls) and cooled to zero degrees under N2. The diethylazodicarboxylate (DEAD) (267.6 g, 1.5 mol) was dissolved in dry THF (250 mls) and placed in a 500 ml addition funnel. The DEAD was added dropwise over 1 hour. The ice bath was removed and the reaction was allowed to warm slowly to RT. After 2 hours, the reaction was checked by HPLC (above conditions) and some glycinate remained. More starting reagents were added and the reaction was left to stir at RT. After 30 min, the reaction was checked again and saw a very small amount of the glycinate remaining. Concentrated reaction down to a reddish-orange oil that was carried onto the next step.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[C:9]3[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:10]=3[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[ClH:21].F[C:23]1[CH:41]=[CH:40][C:26]([CH2:27]NC2C3NC(C)=C(C)C=3C=NC=2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].C(Br)C1C=CC=CC=1>>[ClH:21].[CH2:27]([N:16]1[C:9]2[C:8]([NH:7][CH2:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][N:12]=[CH:11][C:10]=2[C:14]([CH3:18])=[C:15]1[CH3:17])[C:26]1[CH:40]=[CH:41][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1[nH]c2c(NCc3ccc(F)cc3)cncc2c1C
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Product: Cc1c(C)n(Cc2ccccc2)c2c(NCc3ccc(F)cc3)cncc12
Yield: 15.8 %

Procedure:
In accordance with the same procedures as in Example 2, except for using 7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine obtained by treating the compound of Example 23 with a saturated sodium bicarbonate solution and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 15.8% )
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][CH:3]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:10][P:9]([CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: BrCc1ncc(Br)s1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ncc(Br)s1)OCC
Temperature: 25 °C

Procedure:
5-Bromo-2-(bromomethyl)-1,3-thiazole (1.02 g, 3.97 mmol) and triethyl phosphite (1.389 mL, 7.94 mmol) were combined in toluene (8 mL) and stirred at reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-5% methanol in ethyl acetate) to afford diethyl[(5-bromo-1,3-thiazol-2-yl)methyl]phosphonate as a yellow oil. MS ESI calc'd. for C8H14BrNO3PS [M+H]+ 314, 316. found 314, 316. 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 4.17-4.09 (m, 4H), 3.57 (d, J=21.2 Hz, 2H), 1.32 (t, J=7.1 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(-c3nc(C(=O)O)cs3)ccc21
Reaction time: 24 h

Procedure:
To a solution of 5-(4-ethoxycarbonyl-thiazol-2-yl)-indole-1-carboxylic acid tert-butyl ester (3.34 g, 9.0 mmol) and 125 mL of THF was added 1N NaOH (aq) (30.0 mL, 30.0 mmol). The solution was stirred for 24 h then concentrated in vacuo. The crude solid was redissolved in H2O and acidified with 5% KHSO4. The solid was filtered and dried in vacuo at 60° C. to give a pinkish-white solid. MS m/z: 345 (M+1). Calc'd for C17H16N2O4S-344.39.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[C:1]([NH:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(NC(=O)c2ccccc2)nc1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
2-(N-benzoyl)amino-5-nitropyrimidine (790 mg) was added into ethanol (100 ml). 80 mg of 10% palladium on carbon was added to the solution under stirring at the room temperature. The reactant was hydrogenated and stirred for 4 hr. The solution was filtered through silica gel-sand panel funnel. The filtrate was retained and the solvent was evaporated in vacuo. The resultant substance was purified by flash chromatography with silica gel column and eluated with chloroform:methanol=95:5 to give 2-(N-benzoyl)amino-5-aminopyrimidine (200 mg).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Temperature: 65 °C
Yield: 91.5 %

Procedure:
To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (11.17 g, 80.7 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.74 g, 32.3 mmol, Aldrich). The reaction mixture was heated at 65° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde as a yellow oil (Yield 10 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C1C[O:20][CH2:19]C1.CCCCCCC.C(C1C=CC=CC=1)C.CN(C=O)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:19]=[O:20]
Reactant: Clc1ccnc(Cl)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCc1ccccc1
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 2,4-dichloropyridine (2 g, 13.51 mmol) in tetrahydrofuran (20 mL) at −78° C., was added LDA, 2M in THF/heptane/ethylbenzene (8.11 mL, 16.22 mmol) and the solution was stirred for 30 min. DMF (10.46 mL, 135 mmol) was added and the solution was stirred for 1 h and then warmed RT. The reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 (2×10 mL), water (20 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 2,4-dichloronicotinaldehyde (2 g, 11.36 mmol, 84% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H)), 8.44 (d, J=5.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].O>ClCCl.C(O)=O>[CH:1]([NH:8][C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([OH:16])=[O:15])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[C@H](N)C(=O)O
Solvent: O=CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC=O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of acetic anhydride (18 ml) in dichloromethane (15 ml) was added drop wise to a cooled (0° C.) solution of L-tert-leucine (5 g) in formic acid (50 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. Water (25 ml) was added. The mixture was stirred for another 30 min, concentrated in vacuo and co-evaporated twice with toluene. The remaining residue was triturated with diethyl ether. The solids were collected and dried in vacuo (50° C.).
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(CC)(C)C)=O.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:18]=1N>C(#N)C>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:18]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CCC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Yield: 141 %

Procedure:
In a 50 ml three-neck flask equipped with stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetonitrile (20 ml), isopropenyl acetate (31 g, 0.31 mol) and tert-amyl nitrite (3.6 g, 0.031 mol). The resulting suspension is stirred for 15 min at ambient temperature. A solution of 2,4,6-trichloroaniline (4.0 g, 0.020 mol), dissolved in acetonitrile (20 ml) was added dropwise over a period of 25 minutes. During the exothermic addition, bubbling was observed. The mixture was stirred at 40° C. for 1 hour. The volatiles were distilled off at 55° C. and 11 mbar. The residue was taken up with dichloromethane (50 ml) and washed with water (20 ml). The aqueous phase was extracted with an additional portion of dichloromethane (30 ml). The combined organic phases were then concentrated under reduced pressure to give a crude 1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one (6.7 g, 34.8% GC; 48% yield) as a dark brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:28]([CH:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=O)[CH3:29]>ClCCCl>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:31]1[CH2:32][CH2:33][C:34](=[O:35])[C:30]=1[CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCC1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1
Solvent: ClCCCl
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1)NC1=C(CC)C(=O)CC1
Yield: 52.3 %

Procedure:
A solution of (S)-ethyl-3-[4-(3-ethyl-isoquinol-1-yl amino)phenyl]-2-aminopropionate [prepared from 1-chloro,3-ethyl-isoquinoline (from reaction of o-toluic acid with propionitrile and subsequent treatment with phosphorous oxychloride) and N-BOC-L4-aminophenylalanine ethylester] (750 mg, 2.07 mmol) and 2-ethyl-1,3-cyclopentanedione (273 mg, 2.17 mmol) in 1,2-dichloroethane (10 ml) was treated with 4 Å sieves (˜1 g) and heated at 90° for 3 days. The solution was filtered, concentrated in vacuo and the residue purified by chromatorgaphy (SiO2, 100:1 DCM/MeOH) to give the title compound as a brown solid (511 mg, 52%). δH (d6-DMSO) 9.05 (1H, s), 8.46 (1H, d, J 7.0 Hz), 7.91 (2H, d, J 8.6 Hz), 7.72 (1H, d, J 7.0 Hz), 7.64 (1H, t, J 7.0 Hz), 7.51 (1H, t, J 7.0 Hz), 7.23 (2H, d, J 8.6 Hz), 6.99 (1H, s), 4.32 (1H, m), 4.15 (2H, q, J 7.1 Hz), 3.15 (1H, dd, J 13.5, 3.5 Hz), 3.01 (1H, dd, J 13.5, 9.6 Hz), 2.69 (2H, 1, J 7.5 Hz), 2.29 (1H, m), 2.18 (1H, m), 2.06 (4H, m), 1.28 (3H, t, J 7.5 Hz), 0.91 (3H, t, J 7.4 Hz). m/z (ESI, 70V) 472 (MH+).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:26])([CH3:25])[O:11]/[C:12](=[C:14]3/[C:15](=[O:24])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)/[CH:13]=2)=[O:7])=[CH:4][N:3]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C.C(OCC)(=O)C>[F:23][C:19]1[CH:18]=[C:17]2[C:22](/[C:14](=[C:12]3/[CH:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]5)=[N:3][CH:4]=4)[C:10]([CH3:26])([CH3:25])[O:11]/3)/[C:15](=[O:24])[NH:16]2)=[CH:21][CH:20]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1NC(=O)c1ccc(F)nc1
Reactant: OCCN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1NC(=O)c1ccc(N2CCN(CCO)CC2)nc1
Temperature: 66 °C

Procedure:
To a stirred solution of 6-fluoro-N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]nicotinamide (75 mg, 0.20 mmol) in DMF (3 mL) was added 1-(2-hydroxyethyl)piperazine (70 mg, 0.54 mmol). The reaction mixture was heated in 66° C. bath for 30 minutes, cooled to room temperature, and diluted with ethyl acetate (80 mL). The ethyl acetate solution was washed with brine (4×20 mL), dried over Na2SO4, and concentrated to give the crude product. Purification of the crude product by silica gel chromatography with a gradient of methanol in chloroform (5-20%) gave N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-6-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinamide as a yellow solid. Yield: 42 mg, 43%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 94 %

Procedure:
4-Benzyloxyphenyl 2-chloro-4-trifluoromethylphenyl ether (25 g., 0.066 mole), purified by recrystallization from methanol, ethyl acetate (200 ml.) and 10% palladium on charcoal (1.0 g.) are charged to a 2-liter Paar hydrogenation bottle and shaken in a hydrogen atmosphere (40-45 psi) until hydrogen uptake ceases. The catalyst is then removed by filtration and the solvent and toluene are removed in vacuo to give 17.9 g. (94% yield) of 4-(2-chloro-4-trifluoromethylphenoxy)phenol, mp 55°-6° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nccs2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(O)cc1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (2.1 g) obtained in Example 47 was dissolved in dichloromethane (210 ml) and boron tribromide (3 ml) was added. The mixture was stirred for one day. The reaction mixture was poured into cold water and the precipitated crystals were collected by filtration to give 5-(4-hydroxyphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.7 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[NH2:32][NH2:33]>C(O)C.O>[CH2:25]([C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]2[C:11]([C:12]=1[CH2:27][C:28]([NH2:30])=[O:29])=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[CH:17][CH:16]=2)[CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)NN)ccc2n1Cc1ccccc1
Yield: 37 %

Procedure:
A mixture of 211 mg (0.05 mmol) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of hydrazine in 5 mL of ethanol was heated to maintain reflux for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with MeOH and the insoluble material filtered to give 177 mg (37% yield) of 2-ethyl-5-(4-hydrazino-4-oxobutoxy)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 176-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O>C(Cl)Cl>[Cl:12][CH:13]([C:17]1[O:11][N:10]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:14]
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(Cl)c1nc(-c2cccc(Cl)c2)no1
Temperature: 120 °C
Yield: 67 %

Procedure:
1.80 g 3-chloro-N′-hydroxybenzenecarboximidamide and 3.7 mL DEA were dissolved under Ar in DCM (100 mL) and cooled on an ice/water bath, followed by addition of 2-chloropropanoyl chloride. After 1 h at r.t. the mixture was concentrated and the crude taken up in DMF (120 mL), followed by heating for at 120° C. for 2 h. The mixture was concentrated onto celite and purified via column chromatography (hep 100% to hep/EA=7/3) yielding the title compound (1.72 g, 67%). 1H NMR: 8.09 (t, 1 H), 7.93-8.02 (m, 1 H), 7.38-7.54 (m, 2 H), 5.22 (q, 1 H), 2.02 (d, 3 H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
24.2 g (0.2 mol) of 3-hydroxybenzaldehyde and 25.32 g (0.2 mol) of benzyl chloride were placed in 500 ml of acetone and 21.2 g (0.2 mol) of sodium carbonate was added thereto. The resulting solution was stirred for 12 to 24 hours with heating, cooled to room temperature. The solvent was removed under a reduced pressure and the residue thus obtained was washed with water and the extracted with ethyl acetate twice. The organic layer was dried and the solvent was removed under a reduced pressure to obtain a residue. The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9:1) as an eluent to obtain 35.6 g (yield 84%) of the title compound as a colorless liquid.