Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].OS(O)(=O)=O.[F:18][CH:19]([F:31])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C.FC(F)C(=O)CC(C1C=CC=CC=1)=O>C(O)(C)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][C:20]([CH:19]([F:18])[F:31])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(CC(=O)C(F)F)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccccc2)nc1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C(=O)([O-])O.[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCCN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNC(=O)c1ccccc1
Yield: 90.1 %

Procedure:
Into 300 ml of distilled water, were suspended 50 g of 3-aminopropyldimethylamine and 62 g of sodium hydrogencarbonate. To the suspension, while cooling in ice and stirring vigorously, was added dropwise 105 g (1.5 equivalents) of benzoyl chloride. After 6 hours of reaction at room temperature, the reaction mixture was acidified to pH 4 with concentrated hydrochloric acid and extracted with ethyl ether to remove the excess benzoyl chloride. The aqueous layer was adjusted to pH 12 with 5N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over sodium sulfate and stripped of the solvent by distillation under reduced pressure to give 91 g of 3-benzamidopropyldimethylamine. To this residue, was added a solution of 118 g (1 equivalent) of N-3-bromopropylphthalimide in 300 ml of tetrahydrofuran. After stirring at room temperature for 18 hours, the precipitated colorless crystals were collected by filtration, washed with tetrahydrofuran and dried to yield 188 g (90% yield) of colorless crystals of the quaternary ammonium salt. This salt was dissolved in 1,000 mg of 6N hydrochloric acid and heated at 110° C. for 8 hours to effect hydrolysis. After cooling, the precipitated phthalic and benzoic acids were removed by filtration and the filtrate was evaporated to dryness under reduced pressure to remove the excess hydrochloric acid. The residue was dissolved in distilled water and passed through a column of an ion exchange resin Dowex®-1 (Cl-type, 600 ml in volume). The effluent was evaporated to dryness under reduced pressure to yield 96 g (90% yield) of bis(3-aminopropyl)dimethylammonium trihydrochloride. This compound was too hygroscopic to determine its melting point. The PMR spectrum measured in heavy water showed the following δ values: 2.1-2.8 ppm, 4H (m), 2.4 ppm, 6H (s), 3.1-3.9 ppm, 8H (m) (wherein, the letters in parentheses indicate the signal types: m: multiplet, s: singlet). These values were in compliance with the assigned structure. The IR absorption maxima (in wave number, cm-1), as measured in KBr-tablet, were: 3425, 2975, 2625, 2000, 1600, 1480, 1470, 1350, 1320, 1300, 1230, 1200, 1160, 1140, 1060, 1040, 1000, 930, 840, and 760.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.[O:24]=[C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:28]2[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=2[NH:26]1>CO.C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:33]3[CH2:32][CH2:31][CH:30]([N:29]4[C:28]5[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=5[NH:26][C:25]4=[O:24])[CH2:35][CH2:34]3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (1-5; 0.078 g, 0.203 mmol) in MeOH (1 mL) and THF (1 mL) was added 4-(2-keto-1-benzimidazolinyl)-piperidine (0.066 g, 0.305 mmol) and DIEPA (0.131 g, 1.02 mmol). The mixture was stirred at rt overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (1-6). 1H-NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.31-7.37 (m, 4H), 7.25-7.29 (m, 4H), 7.17-7.19 (m, 2H), 7.05-7.09 (m, 3H), 4.31-4.36 (m, 1H), 3.54 (s, 2H), 2.97-2.99 (m, 2H), 2.41-2.47 (m, 2H), 2.12-2.17 (m, 2H), 1.78-1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.0.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:26]=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:2]([CH3:1])[C:29]([C:28]3[CH:33]=[CH:34][C:25]([C:21]([O:23][CH3:24])=[O:22])=[CH:26][CH:27]=3)=[N:31][N:32]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)n2C)cc1

Procedure:
A solution of N-methyl-p-carbmethoxybenzamide in chloroform was treated with phosphorus pentachloride to give E. Then E was reacted with p-carbmethoxybenzoyl hydrazine to yield dimethyl-4,4'-(4-methyl-1,2,4-triazol-3,5-diyl)dibenzoate, (F). Then III was obtained by reacting F in a similar manner as in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O.C(Cl)(Cl)Cl.Cl>O>[CH3:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:7][CH:8]=[C:9]([CH3:13])[CH:10]=1
Reactant: Cc1cnc(NCCCN)c(C)c1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cnc(NCCCNc2ncc(Cc3ccc(C)nc3)c(=O)[nH]2)c(C)c1

Procedure:
2-(3-Aminopropylamino)-3,5-dimethylpyridine (0.81 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) were fused together on an oil bath at 140° C. for 6 hr. On cooling the resulting mixture was equilibrated between chloroform and water (pH adjusted to 5.5 with dil. hydrochloric acid). The pH of the aqueous solution was raised to 6.5 and the product extracted out with chloroform. After drying (MgSO4) and stripping, recrystallisation from ethyl acetate and finally twice from ethanol/water gave 2-[3-(3,5-dimethylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 2.4H2O, (0.83 g; 49%) m.p. 104°-5° C. (softens ca 90° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[CH:4]=[CH:5][N:6]=1
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCC1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of 2-methylimidazole (2 g, 0.025 M) and sodium hydride (1.2 g, 50% in mineral oil, 0.025 M) in dimethylformamide (20 ml) was stirred at room temperature for 1/2 hr. The reaction mixture was then heated at 50° C. and the solution of 4(3-bromopropyl)piperidine carboxaldehyde (4.6 g, 0.02 M) in dimethylformamide (20 ml) was added slowly. After completing the addition, the reaction was heated at 50° C. for 4 hrs and then solvent was removed in vacuo. Water (80 ml) was added to the residue and the mixture was extracted with methylene chloride. The combined extracts, dried over sodium sulfate, were stripped to dryness to yield an oil. The oil was purified on silica gel column, eluted with methanol chloroform (1:9 v/v) to give 4-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-1-piperidinecarboxaldehyde (3.86 g, 88% yield).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.[B:33](OCC)([O:37]CC)[O:34]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:12]2[C:11]3[C:6]([C:5]([C:4]4[CH:13]=[CH:14][CH:15]=[CH:2][CH:3]=4)=[C:22]4[C:23]=2[CH:24]=[C:25]([B:33]([OH:37])[OH:34])[CH:26]=[CH:27]4)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -80 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
An amount of 4.68 g (11.4 mmol) of 2-bromo-9,10-diphenylanthracene was dissolved in dehydrated THF and cooled to −80° C. An amount of 7.9 ml (12 mmol) of a solution of n butyllithium in n hexane was added dropwise and, 40 minutes later, 3.33 g (22.8 mmol) of triethyl borate was further added. After two-hour reaction, a dilute hydrochloric acid solution was added and the mixture was allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 3.07 g (8.2 mmol) of 9,10-diphenylanthracene-2-boronic acid. The yield was 72%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:23]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:10]=1.Cl.CO>CCOC(C)=O>[NH2:23][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:10]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Yield: 53 %

Procedure:
A mixture of N-(3-fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamide (32 mg, 0.09 mmol), 6 M HCl (0.2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The mixture was cooled, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using 30-40% EtOAc in hexanes containing 1% Et3N gave the title compound (15 mg, 46%) as a white solid. 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.25 (d, 1H, J=5.5 Hz), 7.43 (br s, 2H), 6.92-6.85 (m, 3H), 6.45 (dd, 1H, J=13.5, 2.1 Hz), 6.38-6.35 (m, 2H), 5.35 (br s, 2H). MS (ESI+) m/z 315.17 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32](O)=[O:33])[S:26]1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=4)=[O:23])=[CH:12][N:13]=3)[CH2:22][CH2:21]2)=[O:33])[S:26]1
Reactant: O=C(O)CC1SC(=O)NC1=O
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC4SC(=O)NC4=O)CC3)nc2)cc1I

Procedure:
6-{4-[2-(2,4-Dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the ECDI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and 2-(2,4-dioxo-thiazolidin-5-yl)-acetic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C22H22IN5O4S (m/e) 579, obsd 580 (M+H).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1>>[C:1]1([CH:7]([CH3:11])[C:8]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]4[C:32]5[C:37]([CH:38]=[CH:39][C:24]3=4)=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:19][CH:18]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)c1ccccc1
Yield: 22.2 %

Procedure:
2-Phenylpropionic acid (30 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (10 mg, yield 22%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][NH2:18])[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][NH:18][C:29](=[O:30])[O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2CC(CN)O3)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccc3c2CC(CNC(=O)OCc2ccccc2)O3)cc1
Yield: 89.9 %

Procedure:
Treatment of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.94 g, 7.03 mmol) with diisopropylethylamine (1.36 g, 10.55 mmol) followed by benzyl chloroformate (1.32 g, 7.74 mmol) generally according to the procedure described for Intermediate 12 provided 2.36 g (90%) of (±)-benzyl {[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 134-136° C.; Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 77.08; H, 6.3; N, 3.69.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)C>[CH3:24][C:22]1[CH2:21][C:20](=[O:25])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Yield: 42.8 %

Procedure:
4-Methoxy-phenylhydrazine hydrochloride (5.6 g, 32 mmol; product of Aldrich Chem. Co.), sodium acetate trihydrate (5.45 g, 40 mmol; product of Kishida Chemicals) and ethyl acetoacetate (4.16 g, 32 mmol; product of Kishida Chemicals) were dissolved in 40 ml ethanol, and the solution was heated under reflux for two hours to complete the reaction. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure, 40 ml ethanol was added to the residue, and the insoluble matters were removed by filtration. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in a small volume of a solvent mixture of benzene and ethyl acetate (4:1), and the solution was subjected to silica gel chromatography (150 g of Silica Gel 60; product of Merck) Elution was performed by using a solvent mixture of benzene and ethyl acetate (4:1), the eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized with methanol, giving 2.80 g (yield: 42.9%) of PMPMP. Its structure was confirmed by 1H NMR and 13C NMR. The spectra thus obtained are shown in Table 1 below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:26]=1[N:40]1[CH2:45][CH2:44][C:43]2[C:46]3[CH2:52][CH2:51][CH2:50][CH2:49][C:47]=3[S:48][C:42]=2[C:41]1=[O:53])(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[C:41](=[O:53])[C:42]3[S:48][C:47]4[CH2:49][CH2:50][CH2:51][CH2:52][C:46]=4[C:43]=3[CH2:44][CH2:45]2)=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Product: COCc1cc(Nc2cc(-c3cccc(N4CCc5c(sc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Yield: 69.9 %

Procedure:
Following Example 176d, 327 mg of 5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 176b and 481 mg of 111a were reacted to give 177a as a yellow solid (420 mg, 70%). LCMS: [M+H]+ 602
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].OO.[OH:28]S(O)(=O)=O>C(Cl)CCl.O>[CH:11]1[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]([Cl:18])=[C:7]([N:6]2[N:5]=[C:4]([C:19]#[N:20])[C:3]([S+:21]([O-:28])[C:22]([F:25])([F:24])[F:23])=[C:2]2[NH2:1])[C:12]=1[Cl:13]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: ClCCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 13.5 °C
Yield: 74.4 %

Procedure:
1.5 liter of ethylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was then cooled to 12-15° C. and 68.0 gms of H2O2 (50.0% w/w) & 500.0 gms of H2SO4 (90.0% w/w) were simultaneously added over a period of 3.0 to 4.0 hours. The reaction temperature was then raised to 28-30° C. & maintained for about 2.0 hours. The reaction mass obtained thereafter was slowly added into 1700 ml of chilled water at 10-20° C. over a period of 2.0 hours. To this mass, 1500 ml of ethylene dichloride was added and the mixture was heated to 60° C. in order to separate the aqueous and organic layers. The obtained organic phase was washed with water & then with 5% NaHCO3 solution followed by water wash, till a neutral pH was obtained. The crude yield of fipronil after removal of solvent was 425.0 gms. The crude fipronil was crystallized from same solvent after partial evaporation to yield 325 gms of crystalline fipronil with 94.0% purity.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30](=[O:39])[C:29]2=[O:40].[CH3:41][O:42][C:43]1[N:48]=[C:47]([C:49](=[O:51])[CH3:50])[CH:46]=[CH:45][CH:44]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:30](=[O:39])[C:29]2([OH:40])[CH2:50][C:49]([C:47]1[CH:46]=[CH:45][CH:44]=[C:43]([O:42][CH3:41])[N:48]=1)=[O:51]
Reactant: COc1cccc(C(C)=O)n1
Reactant: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: COc1cccc(C(=O)CC2(O)C(=O)N(CC(C)C)c3ccc(Cl)cc32)n1

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one from 5-chloro-1-isobutylindoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 7.75 (m, 1H), 7.67 (d, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 7.00 (dd, 1H), 6.79 (d, 1H) 5.40 (bs, OH), 4.00 (m, 4H), 3.57-3.43 (m, 3H), 2.14 (m, 1H), 0.97 (dd, 6H). calculated mass for C20H21N2O4, 388.12, observed, 389.1 (M+1).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH:7]=[C:6]2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].CCO.O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH:7]=[C:6]2[C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(C3CCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc2cc(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 1-cyclobutyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole (0.83 g, 2.60 mmol), iron powder (0.84 mg, 15.0 mmol), ammonium chloride (0.96 g, 18.0 mmol), and EtOH/water (25 mL/8 mL) was stirred at 80° C. for 1 h and concentrated. The residue was suspended in DMF (20 mL) and MeOH/CH2Cl2 (1:1, 20 mL). The mixture was passed through a Celite pad, washed with MeOH/CH2Cl2 (1:1), concentrated and water was added to afford a precipitate which was collected by filtration and washed with water. The solid was dissolved in CH2Cl2, dried over MgSO4, concentrated and purified on silica gel (EtOAc/hexane 20%) to provide 4-(1-cyclobutyl-6-methoxy-1H-indole-2-yl)-phenylamine (0.57 mg, 75%) as a white solid.