Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:20][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:4]3[N:3]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2](=[O:1])[N:6]([C:5]=23)[CH2:7][C:8]1=[O:14]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)N(C)C(=O)C2
Reaction time: 16 h

Procedure:
To a solution of methyl (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate (300 mg, 1.15 mmol, described in Intermediate 9) in DMF (5 mL) were added cesium carbonate (748 mg, 2.3 mmol) and iodomethane (326 mg, 2.3 mmol). After 16 h, the reaction mixture was quenched with brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=276 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C[O:10][C:11](OC)(OC)[C:12](OC)=O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.OC1C=CC=CN=1>C1(C)C=CC=CC=1>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:12]1[C:11]([N:49]1[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]1)=[O:10]
Reactant: COC(=O)C(OC)(OC)OC
Reactant: Nc1ccccc1O
Reactant: CN1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: Oc1ccccn1
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2nc3ccccc3o2)CC1
Temperature: 125 °C
Reaction time: 5 h
Yield: 47.4 %

Procedure:
A stirred solution of 2-aminophenol (300 mg, 2.75 mmol), methyl 2,2,2-trimethoxyacetate (902 mg, 5.50 mmol), and ytterbium triflate (170 mg, 0.28 mmol) in toluene (10 mL) was heated to reflux. After 5 h, the mixture was cooled, and the precipitate was collected and dried. The crude solid was suspended in toluene (5 mL), and N-methylpiperazine (1.5 mL, 13.7 mmol) was added followed by 2-hydroxypyridine (26 mg, 0.28 mmol). The mixture was heated to 125° C. in a sealed tube for 4 h. The resulting yellow solution was concentrated under reduced pressure, and the residue was purified on silica gel (12 g; 2% methanol/dichloromethane), yielding 320 mg (48%) of the title compound. MS (ESI): mass calculated for C13H15N3O2, 245.12; m/z found, 246.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.83-7.79 (m, 1H), 7.66-7.65 (m, 2H), 7.47-7.41 (m, 2H), 4.19 (t, J=5.1 Hz, 4H), 3.88 (t, J=5.1 Hz, 4H), 2.55-2.52 (m, 4H), 2.35 (s, 3H). 13C NMR (400 MHz, CDCl3): 156.1, 154.6, 149.9, 140.1, 127.1, 125.3, 121.3, 111.5, 55.3, 54.6, 46.9, 45.9, 42.8.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:4]1)#N.OO.[OH-:26].[K+].Cl.[OH2:29]>CCOC(C)=O>[CH3:12][O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:1]([OH:29])=[O:26])[CH2:4][CH:5]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:10]
Reactant: [OH-]
Reactant: COC(=O)N1CCC(C#N)CC1Cc1ccc(C(F)(F)F)cc1
Reactant: O
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)cc1
Yield: 75 %

Procedure:
Methyl 4-cyano-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.1 g, 6.44 mmol), hydrogen peroxide (5 mL, 206.78 mmol) and potassium hydroxide (3.61 g, 54.36 mmol) in water (50 mL) were heated to 80° C. overnight. 1 M HCl and EtOAc was added to the reaction mixture. The organic phase was isolated, dried with Na2SO4, filtered through Celite and the solvent was evaporated to yield 1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)-piperidine-4-carboxylic acid (1.67 g, 75%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:12]([C:11]4[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[CH:9][CH:10]=4)=[O:13])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Solvent: C1CCOC1
Product: O=C1Cc2ccc(C(=O)c3cccc(NC(=O)c4ccnn4-c4ccccc4)c3)cc2N1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A dry flask was charged with 2-Phenyl-2H-pyrazole-3-carbonyl chloride (0.164 g, 0.794 mmol) and THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 2-Phenyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.255 g, 0.600 mmol, 76%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]1[CH:11]2[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]2[CH2:9][CH2:8][NH:7]1>C(O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:7]1[CH2:8][CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[CH:11]2[CH2:6]1
Reactant: ClCC1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Solvent: CCO
Product: OC(CCl)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
0.832 g of epichlorohydrin was added to a mixture of 4.5 ml of ethanol and 1.5 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 1.56 g (yield 76%) of the title compound as a colorless foam.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3]([CH:1]=[O:2])=[N:4][NH:5]3)=[CH:10][CH:9]=2)=[O:14])=[CH:17][CH:18]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d6) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].[CH3:17][NH:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:17][NH:18][S:19]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:21])=[O:20]
Reactant: CNS(=O)(=O)Cl
Reactant: COC(=O)c1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Product: CNS(=O)(=O)Nc1ncccc1C(=O)OC
Reaction time: 15 h

Procedure:
Methyl 2-amino-3-pyridine carboxylate (15.2 grams; 0.1 mole), calcium carbonate (13.0 grams; 0.1 mole) and methylsulfamoyl chloride (13.0 grams; 0.1 mole) were mixed with 200 ml of acetonitrile and the resulting reaction mixture stirred at ambient temperatures for a period of about 15 hours. Following the reaction period, the reaction mixture was filtered and the solvent removed in vacuo. The semi-solid residue thus obtained was extracted with ethanol. A white crystalline precipitate, obtained by filtering the extract solution, was recrystallized from ethanol and the desired title compound having a melting point of 133°-139° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O>[F:23][CH:19]([F:24])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC(F)F)c(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixed solution of 3-fluoro-4-hydroxybenzonitrile (3.10 g) in N,N-dimethylformamide (31 ml)/water (3.1 ml) were successively added cesium carbonate (10.3 g) and sodium chlorodifluoroacetate (7.93 g). After stirring at 110° C. for 2 hr, the reaction mixture was partitioned by adding toluene and water. The aqueous layer was extracted with toluene, and the combined organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (4.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](N)[CH2:24][NH2:25].ClC1C=CC=CC=1Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]2[NH:25][CH2:24][CH2:23][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: Cl
Product: Clc1ccc(OCC2=NCCN2)cc1
Temperature: 178 °C
Yield: 148.1 %

Procedure:
A mixture of 25.1 g of 4-chlorophenoxyacetonitrile, 35.0 g of ethylenediamine p-toluenesulfonate and 112.5 ml of 1,2-dichlorobenzene was heated with stirring in a 500 ml round-bottomed three-necked flask at reflux (178° C.) for 1.0 hour. The reaction mixture was cooled, then diluted with methylene chloride and filtered. The crystals that were obtained were dried in a vacuum oven. The dried crystals were slurried in water, the resulting slurry basified and then extracted with methylene chloride. The methylene chloride extract was treated with diatomaceous earth and activated charcoal and then filtered. The methylene chloride was evaporated and 27.4 g of the free imidazoline obtained, m.p. 116°-118° C. The free imidazoline was then put in solution in isopropyl alcohol and acidified with HCl in isopropyl alcohol. The mixture was then cooled and filtered which gave 27.4 g of 2-((4-chlorophenoxy)methyl)-2-imidazoline hydrochloride, m.p. 185°-186° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9][CH2:10][C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=2)=[N:5][C:4]2[CH2:18][CH2:19][O:20][CH2:21][C:3]1=2.[F:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CC#N.O>C(O)=O>[C:16]([C:14]1[S:15][C:11]([CH2:10][N:9]([CH2:8][C:6]2[NH:7][C:2](=[O:1])[C:3]3[CH2:21][O:20][CH2:19][CH2:18][C:4]=3[N:5]=2)[C:36](=[O:37])[CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:40][CH:39]=3)[CH2:30][CH2:31]2)=[CH:12][CH:13]=1)#[N:17]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(CNCc2nc3c(c(=O)[nH]2)COCC3)s1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: N#Cc1ccc(CN(Cc2nc3c(c(=O)[nH]2)COCC3)C(=O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)s1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.01 g) from 5-(((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)methyl)thiophene-2-carbonitrile and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.03-8.18 (m, 2H), 7.50-7.79 (m, 1H), 7.21-7.34 (m, 2H), 7.01-7.14 (m, 1H), 4.81-4.89 (m, 2H), 4.51-4.62 (m, 2H), 4.33-4.49 (m, 4H), 3.85-4.04 (m, 2H), 3.67-3.82 (m, 2H), 3.38-3.65 (m, 1H), 3.08-3.28 (m, 2H), 2.46-2.68 (m, 2H), 1.98-2.27 (m, 4H). HRMS calculated for C28H23F1N3O4S1 550.1924. found (ESI, [M+H]+) 550.1933. MS (ESI) m/z 550.6 (M+H)+. Retention time: 3.3 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O.[CH2:26]([NH2:28])[CH3:27].[OH-].[Na+]>O>[CH2:26]([NH:28][S:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:5])=[O:3])[CH3:27]
Reactant: CCN
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCc1ccccc1S(=O)(=O)NCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A 1 liter flask equipped as in Example 5 was charged with 1.72 moles (200.4 gms) of chlorosulfonic acid, and 0.49 moles (100 gms) of 1-phenylnonane was added to the vigorously stirred chlorosulfonic acid under N2 in 2 hours at 20° C. to 25° C. with cold water bath cooling. The mixture was stirred at 25° C. for 1/2 hour, then left to stand at room temperature under N2 overnight. The resulting crude sulfonyl chloride mixture was then added to a solution of 0.98 mole of ethylamine and 3.22 mole of NaOH in 275 ml of water in 0.5 hours at 55° C.±2° . The temperature was maintained at 55-°60° for 0.5 hour more with the pH above 10. Working up of the reaction mixture as in Example 5 gave 74.8 gms (49% yield) of amber liquid having a proton NMR spectra in CDCl3 consistent with the desired structure. The acidity of the product was 1.68 meq. per 100 gms. GC analysis showed that it was 98.8 percent sulfonamide (27.1 percent ortho, 5.7 percent meta and 67.2 percent para isomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.CC([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[CH:21]=1)=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O>>[CH2:1]([O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)/C=C(/C)c1cccc(OC)c1
Reactant: COc1cccc(C(C)=O)c1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C(/C)c1cccc(OCc2ccccc2)c1

Procedure:
In like manner, ethyl 3-(3-methoxyphenyl)crotonate is prepared from 3-methoxyacetophenone (43.1 g.) and carbethoxymethylene triphenylphosphorane (200 g.).
Reaction SMILES: [C:1]1([C:7](C)(O)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].ON1C2C=CC=CC=2N=N1.CN1CC[O:32][CH2:31]C1.C(N=C=NCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:14][N:15]([O:16][CH3:17])[C:31](=[O:32])[CH:8]([OH:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNOC
Reactant: CN1CCOCC1
Reactant: CC(O)(C(=O)O)c1ccccc1
Agent: CCN=C=NCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of 2.0 g (12 mmol) of phenyllactic acid, 1.17 g (12 mmol) of N,O-dimethylhydroxylamine hydrochloride, and 1.78 g (13 mmol) of 1-hydroxybenzotriazole in 20 ml of dimethylformamide was treated sequentially with 2.77 ml (25 mmol) of 4-methylmorpholine and 2.53 g (13 mmol) of N-ethyl-N'-(dimethylaminoethyl)carbodiimide. After being stirred at ambient temperature overnight, the solution was diluted with ethyl acetate; washed sequentially with water, 10% citric acid, aqueous NaHCO3, and saturated brine; dried over MgSO4; and concentrated in vacuo to give 2.5 g (100%) of the crude desired compound. 1H NMR (CDCl3) δ 2.85 (dd, J=14, 7 Hz, 1H), 3.08 (dd, J=14, 4 Hz, 1H), 3.23 (s, 3H), 3.72 (s, 3H), 4.62 (m, 1H), 7.2-7.3 (m, 5H). Mass spectrum (M+H)+ =210.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccccc1
Product: N#Cc1cc(N)ccc1Oc1ccccc1
Yield: 26.1 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 2 using 2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g), the title compound (3 g) was obtained. melting point: 89° C.
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:14](N)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>CO>[CH2:14]([NH:1][C:2]([C:4]([NH:6][CH2:12][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:8])=[S:5])=[S:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN
Reactant: Nc1ccccc1
Reactant: NC(=S)C(N)=S
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCNC(=S)C(=S)NCCCCCCCCCCCC
Temperature: 35 °C
Yield: 32.8 %

Procedure:
Into a 100 ml round-bottomed flask, equipped with a magnetic stirrer and heating bath, were placed 2.4 g (0.02 mol) of dithiooxamide, 1.8 g (0.02 mol) of aniline, and 40 ml of methanol. The solution was stirred and heated at 35° C. for 30 minutes. The reactive amine, dodecylamine (3.7 g, 0.02 mol), was then added, and the solution was stirred for an additional 3 hours at 35° C. The crude reaction mixture was cooled to 25° C., and the acidity was adjusted to a pH of about 2 by the addition of 37% aqueous HCl. The mixture was filtered, washed with a small amount of methanol, and dried to afford 1.5 g of N,N'-didodecyldithiooxamide. Water (40 ml) was added to the filtrate with stirring, which was continued for 10 minutes. The precipitate was collected by filtration and washed with a minimum amount of a 50:50 mixture of water and methanol. The product was dried to afford 3.2 g (55%) of N-dodecyldithiooxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:68]=[CH:67][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:64]([NH2:66])=[O:65])=[N:52][N:53]([C:55]4[CH:63]=[CH:62][C:58]5[O:59][CH2:60][O:61][C:57]=5[CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1>CN(C=O)C>[O:59]1[C:58]2[CH:62]=[CH:63][C:55]([N:53]3[C:54]4[C:46]5[CH:45]=[C:44]([NH:43][C:5](=[O:7])[C:4]6[C:8]([Cl:11])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=6)[CH:68]=[CH:67][C:47]=5[CH2:48][CH2:49][C:50]=4[C:51]([C:64]([NH2:66])=[O:65])=[N:52]3)=[CH:56][C:57]=2[O:61][CH2:60]1
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of step 4 of Example 161 (2 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of step 4 of Example 161 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was triturated in warm CH3CN (80° C.) to give 2.2 g of the title compound (yield 73%). Mp: 292–293° C. 1H NMR (300 MHz, d6-DMSO): δ 2.90–2.92 (m, 4H), 6.09 (s, 2H), 6.94–7.04 (m, 2H), 7.12 (d, 1H, J=2 Hz), 7.26–7.38 (m, 4H), 7.51 (s, 1H), 7.81 (s, 1H), 8.61 (s, 1H), 10.54 (s, 1H). M+1=523.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]=[CH:4][CH3:5].[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].[C:19]1([C:25]2[NH:34][C:28]3=[N:29][CH:30]=[C:31]([NH2:33])[CH:32]=[C:27]3[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>ClCCl.CN1CCCC1=O>[CH3:1][CH:2]([O:6][C:7](=[O:8])[NH:33][C:31]1[CH:32]=[C:27]2[N:26]=[C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:34][C:28]2=[N:29][CH:30]=1)/[CH:3]=[CH:4]/[CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Reactant: CC=CC(C)O
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C/C=C/C(C)OC(=O)Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
32 mg 3-penten-2-ol (0.38 mmol,) in 1 ml dry dichloromethane were treated at 0° C. with 62 mg 1,1′-carbonyl-diimidazole. The mixture was stirred at 0° C. for 2 hrs. 80 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine (0.38 mmol,) in 0.5 ml N-methylpyrrolidone (NMP) were added and the mixture stirred over night at room temperature. 1 ml water was added, the precipitate filtered, and the filter residue washed thoroughly with water and ether and further purified by chromatography.