Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C1COCC1.CCO>[NH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17]2
Reactant: CN(CCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1

Procedure:
A suspension of phenyl methyl(2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (500 mg, 1.41 mmol) and palladium on activated carbon (10%, 75 mg, 0.07 mmol) in a 1:1 mixture of THF/EtOH (20 mL) was stirred under a balloon of hydrogen for 4.5 hours. The suspension was filtered through a pad of celite. The filter pad was rinsed with 25 mL methanol and the filtrate was concentrated to give a dark viscous oil. The crude product was used without further purification (460 mg, quantitative). 1H-NMR (CDCl3) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 1H), 7.12-7.08 (m, 2H), 6.61-6.42 (m, 3H), 3.61-3.45 (m, 4H), 3.26 (t, J=6.0 Hz, 2H), 3.20 (brs, 2H), 3.13 and 3.06 (2×s, 3H), 2.70 (t, J=6.3 Hz, 2H), 1.96-1.87 (m, 2H). MS (ESI): 326.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]2([C:26](O)=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.Cl.[C:44]([O:48][NH2:49])([CH3:47])([CH3:46])[CH3:45].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:44]([O:48][NH:49][C:26]([C:13]1([N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)=[O:27])([CH3:47])([CH3:46])[CH3:45]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NOC(C)(C)C)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]- 1-[benzyl]-4-[carboxy]-piperidine (850.0 mg, 1.64 mmol) in methylene chloride (100 mL) containing N-methylmorpholine (0.6 ml, 5.48 mmol) and O-t-butylhydroxyl amine hydrochloride (620.0 mg, 4.94 mmol) is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.1 g, 5.74 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is diluted with water and extracted with methylene chloride. The combined organic extracts are dried (Na2SO4) and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to provide 4-[N-t-butyloxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>C1COCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2.45 g (61.2 mmol) of sodium hydride was introduced to 15 ml of THF and cooled to 5° C., and then 10.6 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise thereto. The resulting solution was stirred at 5° C. for 30 minutes, and then 5.0 g of 2-chloro-5-nitropyridine dissolved in 10 ml of THF was added dropwise thereto and stirred at room temperature for 3 hours. The reaction solution was allowed to stand at room temperature for 3 days, the water was added thereto, and the mixture was extracted with ethyl acetate and then washed with saturated salt water. The resultant was dried over anhydrous magnesium sulfate, and then the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane AcOEt=10:1) to obtain 8.4 g of the desired product (Yield: 92%) as yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1.CCO>C1COCC1>[OH:35][CH:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:29](=[O:33])[O:30][CH2:31][C:32]=2[C:24]=1[CH3:23])[CH2:36][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[C:3]=2[CH3:2])[O:21][CH3:22])[CH2:16][CH2:17]1
Reactant: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COC(CN1CCN(CC(O)c2ccc3c(c2C)COC3=O)CC1)c1ccc2c(c1C)COC2=O
Temperature: 120 °C

Procedure:
4-Methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride (40 mg, 0.14 mmol), 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (79 mg, 0.41 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2 mL) and THF (0.5 Ml). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 120° C. for 1 hour; LC indicated completion of the reaction. The solution was concentrated to dryness, dissolved in MeOH (3.5 Ml), filtered and was then purified by mass-directed HPLC to give 5-[2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-(methyloxy)ethyl]-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [N+:1]([C:4]([N+:21]([O-:23])=[O:22])([CH2:8][NH:9][CH2:10][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[CH2:12][CH2:13][OH:14])[CH2:5][CH2:6][OH:7])([O-:3])=[O:2].CC([CH2:27][C:28]([OH:30])=[O:29])=O>>[C:6]([O:14][CH2:13][CH2:12][C:11]([N+:15]([O-:17])=[O:16])([N+:18]([O-:20])=[O:19])[CH2:10][N:9]([N+:1]([O-:3])=[O:2])[CH2:8][C:4]([N+:21]([O-:23])=[O:22])([N+:1]([O-:3])=[O:2])[CH2:5][CH2:6][O:7][C:28](=[O:30])[CH3:27])(=[O:7])[CH3:5].[C:28]([O:30][C:13](=[O:14])[CH3:12])(=[O:29])[CH3:27]
Reactant: CC(=O)CC(=O)O
Reactant: O=[N+]([O-])C(CCO)(CNCC(CCO)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Product: CC(=O)OC(C)=O
Product: CC(=O)OCCC(CN(CC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Yield: 90 %

Procedure:
The 3,3,7,7-tetranitro-5-azanonane-1,9-diol and its 1,9-diester derivatives are secondary amines with an active N-hydrogen which can be replaced with a more energetic group. For instance, Example 5 illustrate the nitration of the diacetate to form 3,3,5,7,7-pentanitro-5-azanonane-1,9-diol-1,9-diacetate using 90% nitric acid and acetic anhydride, ##STR19## Example 6 shows the acid hydrolysis of this diacetate to form 3,3,5,7,7-pentanitro-5-azanonane-1,9-diol, ##STR20##
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3]([NH2:5])=[S:4].Br[CH2:9][C:10](=O)[C:11]([O:13]CC)=[O:12].[NH4+].[OH-].[CH3:19][CH2:20]O>>[NH:2]([C:3]1[S:4][CH:19]=[C:20]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[N:5]=1)[C:1]([NH2:7])=[NH:6]
Reactant: NC(=S)N=C(N)N
Reactant: CCO
Reactant: CCOC(=O)C(=O)CBr
Agent: [NH4+]
Agent: [OH-]
Product: N=C(N)Nc1nc(CCC(=O)O)cs1
Temperature: 10 °C

Procedure:
To 2-imino-4-thiobiuret (11.1 g, 0.094 mole) (Aldrich) in absolute EtOH (100 mL) and at reflux was added ethyl bromopyruvate (20.0 g, 0.102 mole) (Aldrich) portionwise. The solution was stirred at reflux for 2 hours. Additional ethyl bromopyruvate (2.0 g) was added and the reaction continued at reflux for 2 more hours. The reaction was cooled to 10° C. and concentrated NH4OH was added until pH=10. The resulting precipitate was filtered, washed with ether and dried to yield 2-guanidino-4-carboxyethylthiazole as a yellow solid (15.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCCl.O>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
tert-Butyl 2-[(4-nitrophenyl)amino]acetate (4.5 g) is added at a temperature in the region of 20° C. to a suspension, maintained under an argon atmosphere, of 2-[3-(3-methylphenyl)ureido]acetic acid (3.7 g) in 1,2-dichloroethane (230 cc). The reaction mixture is heated with stirring to reflux of the solvent. Sulphinyl chloride (2.12 g) is then added dropwise while refluxing is maintained. When the addition is complete, heating to reflux is continued for 10 minutes and the reaction mixture is then cooled to a temperature in the region of 10° C. and poured into a solution of sodium hydrogen carbonate (15 g) in water (300 cc). The aqueous phase is separated after settling has taken place and re-extracted with 1,2-dichloroethane (2×50 cc). The organic phases are combined, washed with water (3×20 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm) (200 g) contained in a column 3.5 cm in diameter [eluent: cyclohexane/ethyl acetate (50:50 by volume)], collecting 30-cc fractions. Fractions 16-25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(4-nitrophenyl)acetamido}acetate (2.9 g), m.p. 152° C., is obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCCCCC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 1.66 g (23.9 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 2.95 g (35.1 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (15.97 mmol) of octanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.[Mg].[CH:12](=[O:15])[CH2:13][CH3:14].O>O1CCCC1>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: ClCCCCC1C=CCC1
Reactant: CCC=O
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)CCCCC1C=CCC1
Temperature: 0 °C

Procedure:
All reactions are carried out under an inert atmosphere. 3-(4-Chlorobut-1-yl)cyclopentene {3-(4-chlorobutyl)cyclopentene} (43 g, 0.27 moles) is diluted in tetrahydrofuran (50 ml) and added dropwise to a stirred, refluxing solution of tetrahydrofuran (200 ml) containing granular magnesium (30 g, 1.25 moles). After the addition is complete and the resulting Grignard salt has formed the reaction is refluxed an additional 2 hours. The reaction vessel is then cooled in a 0° C. ice bath and propionaldehyde (15.6 g, 0.27 moles) diluted in tetrahydrofuran (20 ml) is added dropwise over a period of 30 minutes. Then water (500 ml) is added over 30 minutes and the reaction warmed to room temperature. The reaction is partitioned between ether (500 ml) and the organic phase separated. The aqueous layer is extracted with ether (2×500 ml) and the ether extracts are combined. The product is washed with brine (500 ml) and the solvent volume reduced under vacuum. The residue is dried over anhydrous magnesium sulfate and the solid filtered out. The remaining solvent is removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving the desired product as a clear, colorless oil (52 g, 0.29 moles), BP 76° C./0.25 mm.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[C:15]1([CH3:25])[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(=O)C(C)C.C(Cl)Cl>[CH:16](=[N:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14])[CH:15]([CH3:25])[CH3:20]
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(C)c1nnc(SC)n(N=CC(C)C)c1=O

Procedure:
42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one were dissolved in 60 ml of isobutyraldehyde. 0.2 g of p-toluenesulfonic acid was added, the mixture was stirred until the slightly exothermic reaction had subsided and was diluted with 200 ml of methylene chloride, and the whole was stirred with 100 ml of water, containing 0.5 g of sodium carbonate. The organic phase was separated off, washed with water and concentrated on a rotary evaporator. The residue which remained consisted of 52.0 g (97.5%) of 4-isobutylideneamino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one, melting point 16° C (from pentane); nD 20 1.5493.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 4-iodobenzoic acid (20.0 g, 80.6 mL) in CH2Cl2 (350 mL) at 0° C. was treated with oxalyl chloride (42.3 mL of a 2.0 M solution in CH2Cl2, 81.7 mmol). Dimethylformamide was added (0.5 mL) until a homogeneous solution was achieved and then the cooling bath was removed. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated to provide crude 4iodobenzoyl chloride as a waxy oil that was used without further purification.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1.[CH3:22]C1C(C2C=CC=CC=2)=NNC=1>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:20]([CH3:21])=[CH:19][N:18]([CH:2]([CH2:8][CH3:22])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:17]=1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1c[nH]nc1-c1ccccc1Br
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2Br)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(o-bromophenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained 3-(o-bromophenyl)-α-ethyl-N,N,4-trimethylpyrazole-1acetamide, b.p. 188°-190° C./0.12 mm.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[C:4]1=[O:16])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:17](=[O:25])[N:15]=3)[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CCN1CCN(c2ccnc(C#N)c2)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Yield: 52.3 %

Procedure:
4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridinecarbonitrile (0.16 g, 0.76 mmol) and methyl thiosalicylate (0.42 g, 2.5 mmol) was dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 9 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.14 g, 51%) as white crystals.
Reaction SMILES: [N+]([O-])(O)=O.[C:5]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[N+:24]([O-])=O)[NH:20][C:19](=[O:27])[CH2:18][CH2:17]2)(=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>>[N:9]1[CH:10]=[CH:11][C:6]([C:5]2[NH:13][C:14]3=[CH:15][C:16]4[CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]=4[CH:22]=[C:23]3[N:24]=2)=[CH:7][CH:8]=1
Reactant: O=C1CCc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc2N1
Solvent: O=[N+]([O-])O
Product: O=C1CCc2cc3[nH]c(-c4ccncc4)nc3cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22.7 g. (85 mmole) of the above amide were slowly introduced at 5° C. into 120 ml. 65% nitric acid. The reaction mixture was further stirred at 25° C. for 1 hour, poured on to ice and filtered off with suction. The residue was purified over silica gel (elution agent: methylene chloride/methanol saturated with ammonia; 95:5 v/v) to give 2.4 g. (10% of theory) 6-isonicotinoylamino-7-nitro-1,2,3,4-tetrahydroquinolin-2-one; m.p. 285°-288° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CO.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[C:23]1([C:2]2[N:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cn2c(Br)cccc2n1
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: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2c(-c3ccccc3)cccc2n1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a suspension of ethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 5.6 mmol), Pd(PPh3)4 (322 mg, 0.279 mmol) in a mixture of toluene (17 mL), NaHCO3 1M (6 mL) and MeOH (4 mL) was added phenylboronic acid at room temperature. The resulting reaction mixture was heated at 80° C. for 12 h, cooled, and diluted with water (50 mL). The insoluble matter was filtered off, and the phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with water and the solvent was removed under reduced pressure. The crude product was purified by chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 1.41 g of ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate (Yield: 95%) as a yellowish solid (M.P.: 123-123.8° C.)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][CH2:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C[O:17][C:18](=[O:48])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]C)=[O:45]>>[C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:48])=[O:17])([OH:46])=[O:45]
Reactant: CCCc1c(O)ccc2c1CCCC2=O
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1CCCC2=O

Procedure:
Using the procedure of example 184, 6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalen-1-one from example 9 was converted into the title compound by alkylation with 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from example 156, followed by saponification, in 68% overall yield. The diacid product was a colorless solid, mp 100°-101° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:24]([NH:26][C:27]4([C:30](O)=[O:31])[CH2:29][CH2:28]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[NH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH2:38].C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:24]([NH:26][C:27]4([C:30]([NH:38][NH:37][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:31])[CH2:28][CH2:29]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)O)CC4)ccc3C)cc12
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NNC(=O)OC(C)(C)C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a mixture of 1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylic acid (41.6 mg, 0.086 mmol), tert-butyl hydrazinecarboxylate (16.95 mg, 0.128 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (54.9 mg, 0.171 mmol) in DMF (1 mL) at r.t under N2 was added N,N-diisopropylethylamine (0.060 mL, 0.342 mmol). The mixture was stirred at r.t. for 19 hours. The mixture was added 5 ml H2O. The white precipitates were filtered, washed with 3×2 ml H2O and dried (33.1 mg), and was used without further purification. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; HPLC Rt=1.750 min.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:26]([C:28]1[C:29](=[C:36]([C:39]#[N:40])[C:37]#[N:38])[O:30][C:31]([CH3:35])([CH3:34])[C:32]=1[CH3:33])#[N:27].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:33][C:32]3[C:31]([CH3:34])([CH3:35])[O:30][C:29](=[C:36]([C:37]#[N:38])[C:39]#[N:40])[C:28]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
In an ethanol/tetrahydrofuran mixed solvent were dissolved 180 mg (0.54 mmol) of 4-[2-(4-dibutylaminophenyl)vinyl]benzaldehyde and 118 mg (0.59 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene]propanedinitrile. To this mixture, 46 mg (0.60 mmol) of ammonium acetate was added, and the mixture was stirred at room temperature. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 245 mg of a black crystal having a mp of 224-226° C. (yield: 88.4%).