Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.CN(C)C=O.[C:28](=[N:31]O)([NH2:30])[CH3:29]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][N:31]=[C:28]([CH3:29])[N:30]=4)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Reactant: CC(N)=NO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2cc(F)ccc2-3)n1
Reaction time: 1.5 h

Procedure:
8.60 g (28.5 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid, 30 ml of N,N-dimethylformamide and 6.16 g (38 mmol) of N,N'-carbonyldiimidazole are stirred at room temperature for 45 minutes and at 55° for 1 hour. 2.44 g (33 mmol) of acetamidoxime are subsequently added and the mixture is stirred at 75° for a further 1.5 hours. The mixture is poured into 200 ml of water, stirred for 20 minutes, suction filtered and the filter residue is dried. 8.60 g of the thus-obtained product are stirred at 115° for 2.5 hours in 50 ml of glacial acetic acid. The solution is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained (S)-7-fluoro-11,12,13,13a-tetrahydro-1-(3-methyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 248°-249°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=3)[O:36]2)[CH:32]=[CH:33][CH:34]=1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: COc1cccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1

Procedure:
2-(3-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-methoxyphenyl)chroman-4,6-diol (Example 99(b)). 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, 9.1, 2.9 Hz), 7.34 (t, 1H, J 15.7, 7.8 Hz), 7.25 (d, 1H, J 2.4 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00-7.06 (m, 3H), 6.92 (dd, 1H, J 8.8, 2.4 Hz), 6.88 (d, 1H, J 8.8 Hz), 5.64 (d, 1H, J 6.4 Hz), 5.27 (d, 1H, J 10.7 Hz), 4.95-5.00 (m, 1H), 3.79 (s, 3H), 2.30-2.35 (m, 1H), 1.92-2.01 (m, 1H).
Reaction SMILES: O.[S:2]([O-:5])([O-:4])=[O:3].[K+:6].[K+].S(S([O-])=O)([O-])(=O)=O.[K+].[K+].[C:17]([F:26])([O:21][C:22]([F:25])([F:24])[F:23])=[C:18]([F:20])[F:19]>O>[F:19][C:18]([F:20])([S:2]([O-:5])(=[O:4])=[O:3])[CH:17]([F:26])[O:21][C:22]([F:25])([F:24])[F:23].[K+:6]
Reactant: O=S([O-])[O-]
Reactant: FC(F)=C(F)OC(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)OC(F)(F)F
Temperature: -35 °C

Procedure:
A 1-gallon Hastelloy C276 reaction vessel is charged with a solution of 114 g potassium sulfite hydrate (KHSO3·H2O, 95%, Aldrich, 0.72 mol), 440 g potassium metabisulfite (K2S2O5, 99%, Mallinckrodt, 1.98 mol) and 2000 mL of deionized water. The pH of this solution is 5.8. The vessel is cooled to −35° C., evacuated to −3 psig (81 kPa), and purged with nitrogen. This evacuate/purge cycle is repeated two more times. 600 g perfluoro(methyl vinyl ether) (PMVE, 3.61 mol) is added to the vessel, which is heated to 125° C. at which time the internal pressure is 462 psig (3290 kPa). The reaction temperature is maintained at 125° C. for 6 hr. The pressure drops to 25 psig (275 kPa) at which point the vessel is vented and cooled to 25° C. Once cooled, a white crystalline precipitate of the forms, leaving clear colorless liquid above it (pH=7). 19F NMR of the white solid shows it to be the desired product in high purity (>98%). 19F NMR of the liquid shows a small but detectable amount of the hydration product of Equation (3), above.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14](Br)[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Br-].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][Zn+].C1COCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Reactant: [Zn+]Cc1ccc2ccccc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a mixture of ethyl 2-(2-acetamidopyridin-4-yl)-4-bromothiazole-5-carboxylate (190 mg, 0.510 mmol) and bis(tri-t-butylphosphine)palladium(0) (65.6 mg, 0.128 mmol) under nitrogen was added a 0.500 M solution of 2-napthylmethylzinc bromide in THF (3.60 mL, 1.80 mmol). The reaction was stirred at room temperature for 5 minutes, then at 60 degrees for 1 hour. Another portion of bis(tri-t-butylphosphine)palladium(0) (60.0 mg, 0.117 mmol) was added, followed by another portion of 0.500 M solution of 2-napthylmethylzinc bromide in THF (3.00 mL, 1.50 mmol), and the reaction was heated at 60 degrees for an additional 45 minutes. The reaction was cooled to room temperature and quenched with saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→100/0) to give 100 mg of the title compound. (40% yield). LC/MS (FA) ES+ 432.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([N:37]([CH2:42][CH3:43])[S:38](Cl)(=[O:40])=[O:39])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:38](=[O:40])(=[O:39])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21
Reactant: CCN(CC)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2(C)C
Temperature: 2.5 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (145 mg, 0.38 mmol, cf. example 67) was dissolved in dry dichloromethane (8 mL). Triethylamine (60 μL, 0.45 mmol). The solution was cooled to 0-5° C. and diethylsulfamoyl chloride (71.5 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with dichloromethane (20 mL) and washed with a 1:1 mixture of water and saturated ammonium chloride solution (20 mL). The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:ethyl acetate=180:5). Yield: 96 mg (0.19 mmol, 48.9%).
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=CC=1F)=[O:10].Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1F)c1cc(Br)ccc1OCc1ccccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.24 g, 10.16 mmol) was added to a stirred solution of (2-fluorophenyl)methyl 5-bromo-2-{[(2-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 84; 1 g, 2.03 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooled to room temperature, the solvent was removed to obtain a solid, which was dissolved in water (20 ml) and stirred in ice-water bath. 1 M HCl (aq) was added to adjust the pH to 4. The solid was filtered and dried in vacuum to yield the title compound as a white solid. 695 mg.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15]>O>[CH2:1]([N:3]([CH2:4][CH3:5])[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 25 °C
Yield: 74 %

Procedure:
200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer and then 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 20°-30° C. The mixture was agitated at ambient temperature and then 500 ml of water were added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 149° C.; yield: 74%).
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=CCC.C(OC)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CN(C=O)C>[CH:16]1[CH:15]=[N:14][CH:13]=[C:12]([C:6]2[CH2:7][CH2:8][CH2:9][N:5]=2)[CH:17]=1
Reactant: CCC=CN1CCCC1=O
Reactant: COC(=O)c1cccnc1
Solvent: CN(C)C=O
Product: c1cncc(C2=NCCC2)c1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
Sodium hydride (17.26 g, 072 mol of 60% dispersion in a mineral oil) was washed with toluene (25 ml×2) to remove mineral oil and added to 25 ml of DMF. To this a solution containing 1-(but-1-enyl)-pyrrolidin-2-one (I, 50 g, 0.3597 mol) and methyl nicotinate (41.8 g, 0.3057 mol) in 50 ml of DMF was added. The reaction mixture was heated to 90° C. for 2 hrs. DMF was partially removed under reduced pressure and 100 ml water and HCl (165 ml) were added. The reaction mixture was heated to 110° C. for 12 hr, cooled and washed with ethyl acetate (50 ml×2). The aqueous layer was cooled to 0° C., pH adjusted to about 14 using NaOH, extracted with dichloromethane (100 ml×4), the extract dried over Na2SO4, the solvent removed completely and the crude solid was purified by high vacuum distillation to get myosmine (34.38 g, 77.2% yield, 98.5% purity by GC).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(C)=[O:22]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]([OH:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCN=C1C(c1ccccc1)c1ccccn1
Reactant: CS(C)=O
Product: CN1CCN=C1C(O)(c1ccccc1)c1ccccn1

Procedure:
Add 5 g. of 1-methyl-2-(2-pyridylbenzyl)imidazoline and 25 ml. of dimethyl sulfoxide to a solution of potassium t-butylate (prepared from 1.4 g. of potassium and 200 ml. of t-butanol) and stir the resulting solution in a stream of dry air for 30 hrs. Add 2.1 ml. of acetic acid to the resulting mixture and remove the alcohol in vacuo. Shake the residue with 200 ml. of benzene and 50 ml. of cooled 5% sodium carbonate. Separate the benzene phase, water-wash, dry, filter and evaporate in vacuo. Recrystallize the residue from isopropanol acetate to yield 1-methyl-2[α(-2-pyridyl)hydroxybenzyl] imidazoline, m.p. 105°-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=1
Reactant: C1COCCN1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.05 g), HOBt (361 mg) and WSC.HCl (549 mg) were dissolved in DMF (50 ml), morpholine (332 μl) and diisopropylethylamine (780 μl) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=C([F:54])C=1)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[C:22]([F:54])[CH:23]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(CO)c(F)c1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 15b from 193 mg (0.93 mmol) 4-benzyloxy-1H-pyridin-2-one and 230 mg (0.93 mmol) 2-bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone (preparation 16f).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O.O>[N:1]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-n1cnc2ccccc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Benzimidazole (2.00 grams, 16.9 mmol) was dissolved in 30 mL of anhydrous dimethylformamide. To this was added sodium hydride (0.68 grams 60%, 16.9 mmol). This was stirred at ambient temperature for 30 min. before addition of 1.80 mL (16.9 mmol) of 2-fluorobenzonitrile. The reaction was stirred at 50° C. for 18 hours after which time the mixture was cooled in an ice-water bath and diluted with 100 mL of water. The product was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo giving the title compound. Mass spectral and NMR data agree with the structure. Also synthesized analogously was the 5,6-dimethyl benzimidazole analog.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:37])[NH:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To the suspension of 4-phenyl-1H-indole (1.1 g, 5.7 mmol) in 2-methyl-2-propanol (33 mL), ethanol (22 mL) and acetic acid (11 mL) was added pyridinium tribromide (90% purity from Aldrich, 6.1 g, 17.1 mmol) portionwise over 10 minutes. The mixture was stirred at room temperature for 2 hours, and then to the mixture was added acetic acid (50 mL). After stirring at room temperature for one hour, water (0.5 mL) and zinc (3.7 g, 57 mmol) were added to the reaction mixture and stirring was continued for another hour. The unreacted zinc dust was filtered off and washed with methanol. The filtrate was concentrated and the syrupy residue was suspended in water (100 mL) for overnight. The solid product was filtered, washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, 800 mg (67%) of 4-phenyl-1,3-dihydro-indol-2-one as a light yellow solid was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:8]([C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
To a toluene solution (10 ml) of 1-bromo-3-nitro-benzene (303 mg), palladium acetate (9.0 mg), BINAP (37 mg) and cesium carbonate (978 mg), morpholine (209 μl) was added, degassed under ultrasonic irradiation. This was stirred at 100° C. for 6 hours, followed by addition of water (20 ml), which was extracted with ethyl acetate (20 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1), to obtain the desired compound (236.7 mg, 57%).
Reaction SMILES: Br[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:10]([NH:12][C:13](=[O:15])[O-:14])[CH3:11].[OH:16][C:17]1[C:18]([Cl:30])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>CC#N.O.C(Cl)Cl>[CH2:10]([NH:12][C:13](=[O:14])[O-:15])[CH3:11].[CH2:2]([O:16][C:17]1[C:18]([Cl:30])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1)[CH3:3]
Reactant: CCBr
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1cc2c(cc1Cl)C(C)C1CNCC21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Bromoethane (17 mL, 0.23 mmol) and K2CO3 (105 mg, 0.75 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (44 mg, 0.15 mmol) in CH3CN (1.5 mL). The reaction was stirred overnight at 70° C., diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C17H22ClNO3+H: 324, observed: 324.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:18][CH:19]1[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a stirred solution of oxalyl chloride (0.83 g) in dry dichloromethane (15 mL) at -60° C. was added dimethylsulfoxide (1.0 mL) in dichloromethane (3 mL) dropwise. The reaction mixture was stirred at -60° C. for 10 min, then N-tert-butyloxycarbonyl-trans-4-aminocyclohexanol (1.28 g) in dichloromethane (70 mL) was added over 15 min. The resulting mixture was stirred at -60° C. for a further 15 min, then triethylamine (4.2 mL) was added and the solution was allowed to warm to room temperature. The mixture was washed with water (20 mL) and this aqueous layer was extracted once with dichloromethane (20 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum gave N-tert-butyloxycarbonyl-4-aminocyclohexanone (1.25 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc2cn[nH]c2c1
Yield: 73.3 %

Procedure:
To the solution of 2,6-dichloro-3-nitropyridine (4 g) and 6-aminoindazole (2.8 g) in acetonitrile (50 ml) was added triethylamine (3.2 ml), and then the solution was reacted at 35-40° C. for 12 hr. The reaction mixture was cooled at room temperature with slowly adding H2O (20 ml), and then reacted at 20-25° C. for 1 hr. The reaction mixture was filtered, washed with acetonitrile (6 ml) and H2O (15 ml), and then dried at 50° C. in vacuo to obtain the desired compound (4.4 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].NC1C(C)=C(C=CC=1C)C(O)=O>[Pd].CO>[NH2:11][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[C:8]([CH3:14])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C(=O)O)c(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cc1ccc(C(=O)O)c(C)c1N
Solvent: CO
Product: Cc1cc(N)c(C)c(C(=O)O)c1

Procedure:
2,5-Dimethyl-3-nitrobenzoic acid (10.0 g.) was hydrogenated in 200 ml. of methanol in the presence of 0.5 g. of 5% palladium on carbon. The catalyst was removed on a filter and the filtrate was concentrated to dryness to give 8.3 g. of 3-amino-2,4-dimethylbenzoic acid, m.p. 145.5°-146.5° C.