Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:13]([Cl:16])(=[O:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>O1CCCC1>[ClH:16].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][S:13]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)(=[O:15])=[O:14]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dinitrobenzensulfonyl chloride (4.6 g, 17.3 mmol) in dry tetrahydrofuran (130 mL) was added oer 50 min. to a cooled, stirred solution of N,N-dimethyl ethylenediamine (4.0 mL, 34.6 mmol) in tetrahydrofuran (100 mL). After stirring at room temperature overnight, tetrahydrofuran was removed under reduced pressure and the residue flash chromatographed over silica gel. The sulfonamide (5.1 g) was eluted with 5% methanol- 95% chloroform and purified as the hydrochloride salt, mp 238°-40°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[CH:15]([S:17]([N:20]1[CH2:27][CH:26]2[CH:22]([CH2:23][NH:24][CH2:25]2)[CH2:21]1)(=[O:19])=[O:18])=[CH2:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:24]2[CH2:23][CH:22]3[CH:26]([CH2:27][N:20]([S:17]([CH:15]=[CH2:16])(=[O:18])=[O:19])[CH2:21]3)[CH2:25]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reactant: C=CS(=O)(=O)N1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CC2CN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (90 mg, 0.385 mmol) in DMF (15 mL) at room temperature, 2-(vinylsulfonyl)octahydropyrrolo[3,4-c]pyrrole (110 mg, 0.46 mmol) was added followed by HOBt (78.05 mg, 0.58 mmol), EDCI.HCl (110.7 mg, 0.46 mmol) and Et3N (116.7 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/dichloroethane) to afford the desired product (20 mg, 10% yield) as a solid. 1H NMR (400 MHz, DMSO-d6)δ: 10.17 (s, 1H), 6.91 (dd, J=10.0, 16.4 Hz, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.17-6.10 (m, 2H), 5.25 (t, J=4.0 Hz, 1H), 3.85-3.82 (m, 2H), 3.71-3.66 (m, 1H), 3.61-3.56 (m, 1H), 3.45-3.39 (m, 3H), 3.29-3.25 (m, 1H), 3.09-3.00 (m, 3H), 2.92-2.89 (m, 1H). ESI-MS m/z: 420.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(O)CCC.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44]>CO.[I-].[K+].C(OCC)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 68.9 %

Procedure:
A solution of 4.42 g (0.0164 mole) of 4-[(4-fluorophenyl)phenylmethyl]piperidine and 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 0.01 g of potassium iodide and 1-butanol was refluxed for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of oxalic acid, ethyl ether was added, and 6.39 g (68.9%) of white crystalline solid, m.p. 161°-163° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16]N1C=CN=C1.O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13](=[O:15])[CH3:16]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: Cn1ccnc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Treat a solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (30.0 g, 0.11 mol) in acetic anhydride (30 mL) with 1-methylimidazole (4.5 g, 55 mmol), stir at RT for 2 h, treat with water, stir for 5 min, and extract with EtOAc. Wash the combined organics with water, saturated. Na2CO3, then brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (EtOAc/petroleum ether) to afford the title compound (12 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=8.0 Hz, 1H), 8.02 (d, J=10.8 Hz, 1H), 4.09 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1>CN(C)C=O.ClCCl.CO>[Br:14][C:15]1[C:16]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ncc(Br)c(Oc2ccc3cccnc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial was charged with quinolin-7-ol (0.200 g, 1.378 mmol) and sodium hydride (0.066 g, 1.653 mmol) in N,N-dimethylformamide (13.78 ml) to give a brown solution. The reaction was stirred at room temperature for 30 minutes and then 5-bromo-2,4-dichloropyrimidine (0.176 mL, 1.378 mmol) was added. The mixture was stirred at room temperature overnight. Diluted with 9:1 dichloromethane/methanol; washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to afford a tan residue. (ESI(+)) m/e 337.7 (M+H)+.
Reaction SMILES: C(Cl)Cl.[OH:4][C:5]1[C:6]([CH3:19])=[C:7]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9].[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:18][S:15]([C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:19])[C:5]=1[O:4][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(O)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 0 °C
Yield: 99 %

Procedure:
To 100 ml methylene chloride, was dissolved methyl 3-hydroxy-4-methanesulfonyl-2-methylbenzoate in an amount of 8.8 g (0.036 mole), and the resulting solution was then added with pyridine in an amount of 8.3 g (0.11 mole), cooled at 0° C. and then added with anhydrous trifluoromethanesulfonic acid in an amount of 12.2 g (0.043 mole). After stirring the mixture for an hour at an ambient temperature, the reacted-mixture was washed with 1N-hydrochloric acid and then with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent remained in the mixture was distillated out under reduced pressure to obtain methyl 4-methanesulfonyl-2-methyl-3-(trifluoromethanesulfonyl)oxybenzoate in an amount of 13.5 g. The yield was 99%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[N:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[N:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2cnc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(Cl)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2cnc(-c3ccc(Cl)cc3)cn2)cs1
Yield: 90.9 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrazin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (10.5 g) synthesized in Example 226-1 and 4-chlorophenylboric acid (5.36 g) were dissolved in dioxane (80 mL) and aqueous sodium carbonate solution (2 mol/L, 40 mL), tetrakis(triphenylphosphine)palladium (1.32 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (10.2 g) as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH3:20])=[O:8].[K].CC(C)([O-])C.O>CN(C=O)C>[CH3:20][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=1[N:9]1[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1=[O:8])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(NC(=O)OCCCCCl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCOC2=O)c(C)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
300 mg (1.00 mmol) methyl 4-(N-[4-chlorobutoxycarbonyl]-amino)-3-methyl-benzoate are dissolved in 10 ml DMF combined with 168 mg (1.50 mmol) potassium-tert.-butoxide and stirred for 3 hours at 60° C. The reaction mixture is mixed with water and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[CH3:23].CCN(CC)CC>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:12]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:13])[CH:19]=[CH:18][C:17]=1[CH3:23]
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Reactant: Cc1ccc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(Cl)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
A solution of 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (21.1 mmol) in anhydrous dichloromethane (20 mL) was slowly added to a cooled solution (0° C.) of 6-chloro-5-methylpyridin-2-amine (21.2 mmol) in dichloromethane (50 mL) and Et3N (14.1 mL, 101 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with dichloromethane and washed with water (1×30 mL), 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield N-(6-chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (4.0 g, 63%) as a white solid. ESI-MS m/z calc. 316.1. found 317.3 (M+1)+. Retention time 1.98 minutes. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 1.72-1.69 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25](OCC)=[O:26])[C:4]1=[O:30])[CH3:2].[NH3:31]>CO>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6][CH:5]([CH2:24][C:25]([NH2:31])=[O:26])[C:4]1=[O:30])[CH3:2]
Reactant: N
Reactant: CCOC(=O)CC1N=C(c2ccccc2)c2cc(OC)c(OC)cc2N(CC)C1=O
Solvent: CO
Product: CCN1C(=O)C(CC(N)=O)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 0 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
Stir at 0° C. under an inert atmosphere for 48 hours, 70 mg (0.17 mmol) of ethyl (1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)acetate (IIbv) and 1.5 ml of methanol at 35% molar saturation with NH3. Evaporate to dryness. Purify by silica chromatography (dichloromethane 9/methanol 1). Recrystallize in ether. One obtains 12 mg of the abovenamed product as a white powder. Yield: 17%. M: 105–107° C. 1H-NMR (CDCl3, 300 MHz): d 1.10 (t, 3H, CH3), 3.02–3.09 (m, 1H —CH2), 3.22–3.29 (m, 1H —CH2), 3.75 (s, 1H, OCH3), 3.98 (s, 1H, OCH3), 4.01 (AB system, ? d=0.67, JAB=13.9, 2H, —NCH2), 4.13 (t, 1H, CH), 5.52 (s, 1H exchangeable NH2), 6.43 (s, 1H exchangeable NH2), 6.67 (s, 1H Ar), 6.85 (s, 1H Ar), 7.38–7.47 (m, 3H Ar), 7.59–7.62 (m, 2H Ar).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:24](=O)([O-])O.[K+]>CN(C)C=O>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:4]2[CH:24]=[CH:8][CH:7]=[CH:6][C:3]=2[C:2]#[N:9])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: N#Cc1cccnc1Cl
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Temperature: 90 °C

Procedure:
2-Chloro-nicotinonitrile(1.0 g, 7.215 mmol) was added to a mixture of [1,4]Diazepane-1-carboxylic acid tert-butyl ester and potassium hydogencarbonate (0.87 g, 8.66 mmol) in N,N-dimethylformamide (20 mL). The mixture was heated at 90° C. overnight. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was washed with water and brine then dried over magnesium sulfate and filtered. The solvent was removed and the residue was purified by flash column chromatography on silica using ethyl acetate/heptane (50:50) mixture as the mobile phase to give 4-(2-Cyano-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester. 1H-NMR (400 MHz, DMSO-d6) δ 1.25 (d, 27 Hz, 9H), 1.81 (m, 1H), 1.87 (m, 1H), 3.31 (m, 2H), 3.55(m,1H), 3.60 (m,1H), 3.84 (m, 2H), 3.94 (m, 2H), 6.75 (m,2H), 8.34 (m,1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH3:21])[N:23]=[CH:24]4)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Product: C[C@@H](Oc1nc(-c2ccc3c(cnn3C)c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (35 mg, 0.119 mmol) and 1-methyl-1H-indazol-5-ylboronic acid (23 mg, 0.131 mmol), (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-indazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.29 was isolated, following column chromatography.
Reaction SMILES: SCCCCCCCCC1C=C(O)C=CC=1O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Li])CCC.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=1[O:26][CH3:27]
Reactant: BrCCCCCCCCBr
Reactant: COc1ccc(OC)cc1
Agent: Oc1ccc(O)c(CCCCCCCCS)c1
Agent: [Li]CCCC
Product: COc1ccc(OC)c(CCCCCCCCBr)c1

Procedure:
Au microelectrodes (approximately 103 μm2) or Au macroelectrodes (approximately 1 cm2) can be modified with QH2 or Fc by dipping the Au into solutions containing one or both of the thiol reagents. Preparation of 2-(8-mercapto-octyl)hydroquinone involves several steps: 1,4-dimethoxy-benzene was deprotonated with n-butyllithium and added to excess 1,8-dibromo-octane; vacuum distillation afforded 2-(8-bromo-octyl)-1,4-dimethoxybenzene; demethylation was accomplished in quantitative yield with BBr3 ; the bromide was displaced by thioacetate; and subsequent hydrolysis under acidic conditions yields the thiol which was purified by chromatography. Materials were characterized by 1H NMR spectroscopy. Anal. Calcd (Found) for C14H22O2S: C, 66.10 (66.21); H, 8.72 (8.58); S, 12.60 (12.57). The molecules self-assemble onto the Au surfaces when the Au is placed into approximately 1 mM solution of Fc or QH2 in tetrahydrofuran (THF) or ethanol:hexane, 1:1. Mixtures of Fc and QH2 self-assemble onto Au from a QH2 :Fc, 2:1 mixture in THF or in ethanol:hexane, 1:1, at a total thiol concentration of approximately 1 mM. All derivatizations were carried out under argon at 25° C. for approximately 24 hr.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][C:26]#[N:27]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[C:25](=[CH:5]/[C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([O:1][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:3]=2)/[C:26]#[N:27])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COCCOCCl
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COCCOCOc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 32.7 %

Procedure:
The hydroxyl group of 3-hydroxy-4-nitrobenzaldehyde (0.67 g) was protected by use of 2-methoxyethoxymethyl chloride (0.50 g) in accordance with (production process 1), to thereby produce an MEM form (0.97 g, yield: 95%). The resultant MEM form (944 mg) and 3,4-dimethoxybenzyl cyanide (673 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[3-(2-methoxy-ethoxymethoxy)-4-nitro-phenyl]-acrylonitrile (515 mg, yield: 34%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[3-(2-methoxy-ethoxymethoxy)-4-nitro-phenyl]-acrylonitrile (350 mg) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (267 mg, yield: 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[Na+]>CC(C)=O>[OH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])[C:3]=2[N+:19]([O-:21])=[O:20])=[CH:11][CH:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nc(C)nc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a stirred solution of 2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol (step 1, 2.0 g, 6.48 mmol) in acetone (61 ml) was added diethyl malonate (1.53 g, 9.54 mmol) at 0° C., then aqueous NaOH solution (11N, 2 ml, 22 mmol) was added dropwise over 20 min. After addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (120 ml), and the pH value was adjusted to 8.0 by addition of acetic acid. The whole was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Removal of excess diethyl malonate by azetropical distillation with toluene afforded 3.26 g (72%) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-2-nitro-phenylamine (3.04 g, 20.0 mmol) in anhydrous DMF (20 mL) at 0° C. was portionwise added 95% NaH (528 mg, 22.0 mmol) and the resulting mixture stirred for 10 min. A solution of iodomethane (1.25 mL, 20.0 mmol) in anhydrous DMF (10 mL) was then added. The ice bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water, the solid was collected by filtration, washed with H2O and hexanes to yield methyl-(5-methyl-2-nitro-phenyl)-amine MS 167 (M+1)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][NH:16][O:17][CH3:18].[CH2:19]([N:21](CC)[CH2:22]C)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]([O:17][CH3:18])[CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.0 mmol) in dimethylformamide (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (5.93 g, 60.8 mmol) and triethylamine (17.0 mL, 122 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.65 g, 60.8 mmol) and hydroxybenzotriazole (9.31 g, 60.8 mmol) were added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and partitioned between ethyl acetate (150 mL) and brine (150 mL). The organics were concentrated on rotary evaporator and the crude was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 254 (M+H)+.