Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(F)cc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5 g of 5-fluoro-2-methylaniline in 30 mL of pyridine was added 4.6 mL of acetic anhydride, and stirred at room temperature for 4 hours. After distilling off the pyridine under reduced pressure, the residue was dissolved in 250 mL of ethyl acetate, and washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine. The solution was dried over anhydrous magnesium sulfate, allowed to pass though a silica gel pad, and then the solvent was evaporated. The residue was recrystallized from ethyl acetate-diethyl ether, to afford 5.34 g of the title compound as white needle crystals. The mother liquor was further concentrated, and triturated with diethyl ether, to afford 907 mg of the title compound as purple needle crystals.
Reaction SMILES: [C:1]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.Cl>[OH:3][CH:1]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:2]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)O)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate (5.06 g) in methanol (300 cm3) was cooled with stirring at 0° C. under argon. Sodium borohydride (640 mg) was added portionwise and the resulting solution stirred at 40° C. overnight. Further sodium borohydride (500 mg) was added as TLC analysis indicated that starting material remained. After a further 3 h TLC analysis indicated that the reaction was complete. The reaction was cooled, acidified with dilute (1M) hydrochloric acid and evaporated to dryness. The residue was dissolved in ethyl acetate (250 cm3) washed with dilute aqueous acid and brine, dried over magnesium sulphate and filtered. The solvent was evaporated to leave a yellow oil which solidified on standing. After recrystallisation from methanol/diethyl ether, methyl 4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyrate was obtained as yellow needles (5.04 g, ~100%). 1H NMR (CDCl3) δ1.52 (3H, d, J=8.3 Hz, MeCHO), 2.18 (2H, m, CCH2C), 2.53 (2H, t, J=6.5 Hz, CH2CO), 3.71 (3H, s, OMe), 3.95 (3H, s, OMe), 4.13 (2H, t, J=7.3 Hz, CH2O), 5.52 (1H, q, J=8.2 Hz, CHOH), 7.29 (1H, s, aromatic) and 7.57 (1H, s, aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)=[CH:25][N:26]=2)=[O:19])=[CH:3][C:2]=1[Cl:1])(=[O:10])=[O:11]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c3)nc2)CC1

Procedure:
A solution of 2-(3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 237-1, 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (112 mg, 0.51 mmol), HATU (232 mg, 0.61 mmol) and DIEA (0.26 ml, 1.49 mmol) in DMF (2.0 ml) was stirred at room temperature overnight. The solution was subjected directly to reverse phase HPLC to give 4-(2-(5-(4-acetylpiperazin-1-yl)pyridin-2-ylamino)-2-oxoethyl)-2-chlorophenyl trifluoromethanesulfonate 237-2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[OH:34]>>[OH:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[NH:28][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@@H]1CCC[C@H]1O)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and trans-2-aminocyclopentanol hydrochloride in a manner similar to that described in Example 11.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cc(-c2ccc(C(=O)O)cc2)cnc1N
Temperature: 85.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45° C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.5 g (83% yield) of 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a very dark solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)[CH3:4].[S:26](Cl)(=[O:29])(=[O:28])[NH2:27]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:21][S:26](=[O:29])(=[O:28])[NH2:27])=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)[CH3:4]
Reactant: NS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCc1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCc1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.257 g, 6.4 mmol) was added to 6-(4-hydroxy-3,5-diisopropyl-phenyl)-hexanoic acid ethyl ester (1.46 g, 5.0 mmol) in dimethylformamide (20 mL) at 0° C. over about 3 minutes. The cooling bath was removed, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to zero degrees and sulfamoyl chloride (1.18 g, 10.3 mmol) was added over ~ 3 minutes. The reaction mixture was stirred 1.5 hours at zero degrees and was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture is diluted with diethyl ether (300 mL) and water (100 mL). The organic layer is washed with water (3×100 mL), brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The oil is chromatographed on silica gel using 4:1 hexanes/ethyl acetate as eluant. The title compound is obtained as a light yellow oil, 1.29 g. CI Mass Spectrum: [M+H+ ]+ =400.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[NH:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][C:26](=[O:36])[N:27]2[CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:23]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:22]=1>>[N:40]1[CH:39]=[CH:38][C:37]([C:23]2[N:22]=[C:21]([N:20]3[C:10]4[CH:11]=[C:12]([O:15][C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:14][C:9]=4[N:8]=[CH:1]3)[N:29]=[C:28]3[C:24]=2[NH:25][C:26](=[O:36])[N:27]3[CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:42][CH:41]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Product: O=c1[nH]c2c(-c3ccncc3)nc(-n3cnc4ccc(OC(F)(F)F)cc43)nc2n1C1CCOCC1

Procedure:
Yellow oil. TFA salt. Synthesized from 2-(2-amino-5-(trifluoromethoxy)phenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one following the general procedure for closing the benzimidazole ring. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.30 (br s, 1H), 9.00-8.85 (br m, 1H), 8.67 (s, 1H), 8.20-8.10 (m, 2H), 7.84-7.67 (m, 1H), 7.40-7.22 (m, 2H), 4.76-4.72 (m, 1H), 4.26-4.13 (m, 2H), 3.62 (app t, 2H), 2.90-2.80 (m, 2H), 1.90 (br d, 2H); MS (EI) m/z 498.3 (MH)+.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][C:25](Cl)=[O:26]>C1COCC1>[O:26]=[C:25]1[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:23](=[O:28])[CH2:24]1
Reactant: CC(C)(C)OC(=O)CNc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 100 mL of THF at 0° C. was added dropwise over 20 min simultaneously a solution of the tert-butyl N-(2-anilinophenyl)glycinate (9.5 g, 31.8 mM) in 100 mL of THF and solution of malonyl dichloride (5.38 mL, 38.21 mM) in 100 mL of THF. The resulting solution was stirred at RT for 20 h and the solvent removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 6/14 and the combined filtrates evaporated in vacuo to give 10.2 g of product. 1H NMR (DMSO-d6) 1.40 (s, 9H), 3.19 (d, J=12 Hz, 1H), 3.69 (d, J=12 Hz, 1H), 4.55 (d, J=17 Hz, 1H), 4.71 (d, J=17 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 7.33 (m, 4H), 7.46 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:19][C:20]2[C:21](=[O:38])[N:22]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:30]([O:32]C)=O)[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:19][C:20]2[C:21](=[O:38])[N:22]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:30]([NH:42][CH:39]3[CH2:41][CH2:40]3)=[O:32])[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CCC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC2(c3ccccc3OCc3ccccc3)CCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 268d, 1.46 g) in THF (40 mL) under nitrogen was treated with cyclopropylamine (0.88 mL) followed by isopropylmagnesium chloride (3.81 mL, 2.0 M in THF) dropwise over 10 min. The reaction was stirred at room temperature for 1 h then diluted with saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (×3). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle product (1.537 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[C:10]2=[O:11])=[CH:5][CH:4]=1.[OH-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[C:12]([C:10]([OH:20])=[O:11])[C:14]3[C:19]([N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=1
Reactant: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Reactant: [OH-]
Agent: [K+]
Product: COc1ccc2nc3ccccc3c(C(=O)O)c2c1

Procedure:
The title compound can be prepared from N (4-methoxy phenyl) isatin of example 15 and 10% KOH by heating for 12 hours on a steam bath. The product is isolated as in example 25.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1

Procedure:
A suspension of trans-{4-[(naphthalene-1-sulfonylamino)methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (25 g) in chloroform (300 ml) is treated with a 4 N HCl solution in dioxane (300 ml) at 0° C. After completion, the reaction mixture is concentrated in vacuo, the residue is taken up in a 1 N sodium hydroxide solution and dichloromethane. After extraction with dichloromethane, the organics are dried over sodium sulfate and concentrated to 18.5 g of trans-naphthalene-1-sulfonic acid (4-aminomethyl-cyclohexylmethyl)-amide as a white powder melting at 157-162° C. Rf(C3) 0.36.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[C:30]([NH:31][C:32](=[S:41])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=3O)=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:24])=[N:20][CH:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:34]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=2[C:32]([NH:31][C:30]2[C:25]([C:23]([NH:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][N:20]=3)=[O:24])=[N:26][CH:27]=[CH:28][CH:29]=2)=[S:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Using a procedure analogous to Example 38-D, 1-t-butoxycarbonylpyrrolidin-3-ylmethanol (Isomer II), from the prior example, and N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoylamino]pyridine-2-carboxamide gave the title compound as a white solid (1.0 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:30]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc4ccccc34)nc2c1
Yield: 67.8 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, using methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and naphthalen-1-yl boronic acid (63 mg, 0.37 mmol, 1.10 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:20)) afforded 90 mg (69%) of methyl 3-(naphthalen-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow powder.
Reaction SMILES: O.O.[OH-].C[N+](C)(C)C.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h
Yield: 25 %

Procedure:
A solution of tetramethylammonium hydroxide dihydrate (TMA(H)·2H2O) (1.8 g, 14.0 mmole), benzamide (1.2 g., 9.9 mmole) and 10 ml of xylene was stirred under nitrogen at 70° C. The water and xylene was removed by vacuum distillation at 740 mmHg/70° C. Nitrobenzene (1.2 g., 9.7 mmole) was added dropwise and the solution was stirred for 4 hours under nitrogen after which time an aliquot was removed for HPLC analysis. 4'-Nitrobenzanilide was produced in 25% yield based on benzamide. Azoxybenzene was generated in 8% yield in this reaction.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24])([O-:14])=[O:13].N1C=CC=CC=1>CC(C)=O>[C:1]([O:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
66.64 g (0.4 mole) of cinnamoyl chloride and 300 g of methyl ketone (hereinafter referred to as MEK) were placed in a reaction vessel to be stirred by heating at 60° C. under a nitrogen current. 73.64 g (0.4 mole) of 2,4-dinitrophenol, 50 g of pyridine, and 500 g of MEK were added dropwise to the above reaction vessel using a dropping funnel. After that, reflux stirring was conducted for approximately 20 hours under a nitrogen current. After the completion of the reaction, the precipitate was separated by filtration. The filtrate was concentrated until crystals separated out and poured into methanol. 90 g of light yellow colored needle-like crystals (2,4-dinitrophenyl cinnamate) were yielded.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([C:4]([Br:42])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: CCCCC(=O)C(c1ccccc1)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC(=O)C(Br)(c1ccccc1)C(C)C

Procedure:
To a magnetically stirred solution of 2-methyl-3-phenyloctan-4-one (Intermediate IIa-1) (4.31 gram, 0.02 mol) in CCl4 (40 ml) was added a catalytic amount of dibenzoyl peroxide and NBS (6.56 gram). The resulting mixture was heated for 6 hours at reflux temperature. The obtained mixture was allowed to attain room temperature. The formed precipitate was removed by filtration. The filtrate was concentrated to give crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate IIb-1)—contaminated with some starting material—as a dark-colored oil (6.77 gram). 1H-NMR (400 MHz, CDCl3) Characteristic signals: δ 0.68 (d, J=6, 3H), 0.78 (t, J=7, 3H), 1.08 (d, J=6, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:11]=1[O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC2CCCC2)c(OC2CCCC2)c1
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(OC2CCCC2)c(OC2CCCC2)c1
Yield: 99.1 %

Procedure:
3-Chloro-4,5-bis(cyclopentyloxy)benzoic acid (5) (380 mg, 99%) was prepared from methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (400 mg, 1.18 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (10 mL) was used instead of THF: m/z 323 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.07 (1H, br s), 7.52 (1H, d), 7.45 (1H, d), 4.97-4.91 (2H, m), 1.99-1.90 (2H, m), 1.70-1.57 (14H, m).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[NH:15][C:14](=[S:16])[NH:13][C:9]3=[N:10][C:11]=2[CH:12]=1.[OH-].[Na+].[CH3:21]I>CO>[CH3:21][S:16][C:14]1[NH:15][C:8]2[C:9]([N:13]=1)=[N:10][C:11]1[CH:12]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=[CH:5][C:6]=1[CH:7]=2
Reactant: FC(F)(F)c1ccc2cc3[nH]c(=S)[nH]c3nc2c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2nc3cc(C(F)(F)F)ccc3cc2[nH]1
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A suspension of 1,3-dihydro-6-(trifluoromethyl)-2H-imdazo[4,5-b]quinolin-2-thione (0.53 g, 2 mmol) in methanol (5 mL) was treated with 50% aqueous sodium hydroxide (0.18 g) to afford a solution which was cooled in an ice bath. Methyl iodide (0.3 g, 0.13 mL, 2.1 mmol) was added and the mixture stirred for 90 minutes before being filtered. The solid was washed with methanol and dried in air to give 2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (0.34 g, 61%), m.p. >270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[CH2:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])=[C:4]([Cl:24])[CH:3]=1.[C:25]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([CH3:51])[C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=O)[CH2:36][CH2:35]1>>[C:25]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:52])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][N:42]([C:43](=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:19])[CH3:20])[CH3:21])=[C:4]([Cl:24])[CH:3]=2)[CH3:51])[CH2:36][CH2:35]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: CN(CCCN(C)C(=O)c1ccc(N)cc1Cl)C(=O)OC(C)(C)C
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)c(Cl)c1
Yield: 58.7 %

Procedure:
The compound (149 mg, 0.420 mmol) obtained in Example 85a and the compound (163 mg, 0.351 mmol) obtained in Example 4g were used to give the title compound (166 mg; yield, 59%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10]Br>>[Br:10][C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: Nc1ccc(F)cc1F
Reactant: BrBr
Product: Nc1c(F)cc(F)cc1Br

Procedure:
reacting 2,4-difluoroaniline with Br2 so as to form 2-bromo-4,6-difluoroaniline.HBr;