Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzotrifluoride (1a, 1.0 g, 4.78 mmol), methyl 4-hydroxyphenylacetate (1b, 795 mg, 4.78 mmol) and potassium carbonate (661 mg, 4.78 mmol) in 10 mL of DMSO was allowed to stir at 60° C. for 24 h. Upon completion, the mixture was cooled to room temperature and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using 20% EtOAc/hexane as the eluent to give 1.31 g of [4-(2-nitro-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester. 1H NMR (CDCl3): δ 8.22 (d, J=2.00 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=8.36 Hz, 2H), 7.08 9s, 1H), 7.07 (d, J=8.48 Hz, 2H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16]#[N:17]>O1CCOCC1>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 23.6 grams of benzimidazole in 300 ml of dioxane was added 9.8 grams of a 50% dispersion of sodium hydride in mineral oil and the resulting mixture was stirred at room temperature for two hours. A solution of 20.7 grams of 4-chlorobutyronitrile in 100 ml of dioxane was added and the mixture was refluxed for 5 hours. Then, an additional 3 grams of sodium hydride suspension was added and the mixture was refluxed for 17 hours. The mixture was then filtered, concentrated, and washed with petroleum ether to remove the mineral oil. The residual brown oil was then chromatographed on silica gel packed with chloroform and eluted with chloroform and chloroform containing increasing quantities of methanol. The fractions eluted with 0.5% and 1% methanol were combined and the solvent was evaporated to leave residual crude 1H-benzimidazole-1-butanenitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Compound 5-nitrobenzo[d][1,3]dioxole (5.0 g, 30 mmol) was added in one portion to a solution of fuming HNO3 and con. HNO3 (V/V=1/1, 120 mL) at −10 to −5° C. The mixture was stirred for 3 h at this temperature and poured into ice/water, filtered to get compound 5,6-dinitrobenzo[d][1,3]dioxole (7.0 g, quantitative) as a yellow solid. The compound was used directly without purification. 1H NMR (DMSO-d6) δ 6.39 (s, 2H), 7.86 (s, 2H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 71 %

Procedure:
As described for example 342 g, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (170 mg, 71%) which was obtained as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.C1(OC2C=CC=CC=2)C=CC=CC=1.[C:36]([O:44]CC)(=O)[CH2:37][C:38]([O:40]CC)=O>>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:38]([OH:40])=[CH:37][C:36](=[O:44])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)cc(O)c2c(=O)n(C3CC3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c21
Temperature: 230 °C
Yield: 51 %

Procedure:
To 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 8 (16 g) obtained in Step 4 were added diphenyl ether (160 ml) and diethyl malonate 9 (40 ml), and the mixture was stirred under heating at 230° C. for 11 hrs while evaporating the resulting ethanol. The reaction mixture was purified by column chromatography (chloroform→chloroform:acetone=9:1) to give 3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 10 (10 g, 51%) as a brown foamy oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].Cl.[NH2:29][OH:30].CC([O-])=O.[Na+]>CO.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH:22]=[N:29][OH:30])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=NO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (1.6 g, 4.3 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (1.2 eq, 5.16 mmol, 356 mg) and a solution of NaOAc (trihydrate, 1.5 eq, 6.45 mmol, 890 mg) in water (10 ml). The resulting mixture was stirred at rt overnight might. The mixture was concentrated in vacuo and the solid residue was suspended in water (15 ml), collected, washed with water and dried to afford a white powder (1.4 g, 84%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.O[C@H]1CC(=O)C(CCC[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=O)=C1>>[O:33]1[CH2:34][CH2:28][CH2:29][CH2:30][CH:31]1[O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=C[C@H](O)CC1=O
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Product: COC(=O)CCCCCCC1=C[C@H](OC2CCCCO2)CC1=O

Procedure:
Substitution of an equivalent quantity of methyl 7-(3(R)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate for the methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate and substantial repetition of the procedure detailed above affords methyl 7-(3(R)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)heptanoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([CH3:20])[C:12]3[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([C:9]2[CH:19]=[C:18]([CH3:20])[C:12]3[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[C:21](=[O:23])[CH3:22])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: O
Product: CC(=O)N(c1cc(C)c2c(c1)oc(=O)n2C)c1cc(Cl)ncn1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
100 mg (0.300 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one were placed together with 1.00 ml (10.6 mmol) acetic anhydride in a microwave container and stirred for 20 min at 150° C. The reaction mixture was diluted with water and extracted with DCM. The organic phase was separated off, dried and evaporated down. The residue was purified by preparative HPLC. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC[O:16]CC>>[CH:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: O=C1C=CCCC1C1CCCCC1
Product: O=C1CCC[C@@H](C2CCCCC2)C1
Yield: 80 %

Procedure:
Prepared according to the general procedure from 3-cyclohexylcyclohexen-2-one (178 mg, 1.09 mmol) in 0.2 M Et2O for 43 h at room temperature to provide the title compound as a colorless oil (157 mg, 80% yield, 90% ee) after purification by flash chromatography on silica gel (5% Et2O/pentane). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (110° C. isotherm, 1 mL/min.); (S) isomer tr=73.5 min. and (R) isomer tr=65.2 min. IR (film) 2924, 2853, 1715, 1449, 14223, 1346, 1317, 1263, 1225, 1101, 1056, 982, 892, 866 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.44-2.21 (m, 3H), 2.16-2.04 (m, 2H), 1.93-1.85 (m, 1H), 1.80-1.54 ((m, 8H), 1.47-1.33 (m, 1H), 1.32-1.11 (m, 3H), 1.08-0.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 212.9, 45.6, 44.7, 42.7, 41.6, 30.0, 29.9, 28.4, 26.6, 26.59, 25.54, 25.6; HRMS (EI+) exact mass calculated for [M]+ (C12H20O) requires m/z 180.1514, found m/z 180.1508; [α]D22+11.9° (c=1.05, CHCl3).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(O[CH:17]=[CH:18][CH:19]=[CH2:20])(=O)C.CN(C)C=O>C(O)(=O)C>[CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=COC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
15.8 parts by weight of naphthoquinone and 13.0 parts by weight of 1-acetoxybutadiene in 40 parts by volume of dimethylformamide and 10 parts by volume of acetic acid are stirred for 6 hours under nitrogen at 45° - 50° C. Air is then passed in and the batch is stirred for 2 hours at 125° C. After cooling, the anthraquinone which has precipitated is filtered off and washed with dimethylformamide. 18.0 g (90% of theory) of anthraquinone of melting point 284° C are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1noc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Temperature: 100 °C
Yield: 58 %

Procedure:
3-Methyl-benzo[d]isoxazol-6-ol (1v) (reference for synthesis, see Indian J. Chem. Sect.B; 19:571-575 (1980)) (1.58 g, 10.6 mmol) and 2,5-difluoro-benzonitrile (2v) (1.47 g, 10.6 mmol) were combined with potassium carbonate (1.46 g. 10.6 mmol) in 15 mL of dry DMA. The reaction was heated in a 100° C. bath for 6 hours. The reaction was cooled and diluted with EtOAc (200 mL) and washed three times with water, NH4Cl, NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude residue was purified by column chromatography (silica, 70-80% CH2Cl2/hexane) to provide compound (3v) (1.65 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27](Cl)(=[O:29])[CH3:28].CCN(CC)CC>C(Cl)Cl>[C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26])(=[O:29])[CH3:28]
Reactant: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a mixture of 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (140 mg, 1.0 eq) in DCM (8 mL) was added acetyl chloride (1.5 eq) and Et3N (2.0 eq), the mixture was stirred at room temperature overnight. At the end of reaction, the mixture was concentrated and water was added then extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated until the aim product precipitated, filtrated and washed with some DCM to afford 1-(4-acetamido-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (90 mg, 59%). MS (ESI) 389.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.56 (s, 1H), 8.77 (d, J=3.9 Hz, 2H), 8.51 (d, J=4.2 Hz, 1H), 8.27 (d, J=3.9 Hz, 2H), 7.72 (m, 2H), 7.23 (t, J=4.5 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.55 (t, J=4.2 Hz, 1H), 6.57 (t, J=4.2 Hz, 1H), 3.05-3.15 (m, 1H), 2.90-3.05 (m, 1H), 2.60-2.75 (m, 1H), 2.05-2.15 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH:9]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]3[C:39](=[O:40])[CH2:38][O:37][C:36]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:35]3)=[CH:29][CH:28]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16]([CH3:26])([C:22]([O:24]C)=[O:23])[CH2:17]3)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([CH:9]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][N:34]3[C:39](=[O:40])[CH2:38][O:37][C:36]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[N:35]3)=[CH:31][CH:32]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16]([CH3:26])([C:22]([OH:24])=[O:23])[CH2:17]3)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11 mg (0.26 mmol) of lithium hydroxide monohydrate were added to a solution of 74 mg (0.13 mmol) of methyl 4-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (Example 131A) in 2 ml of THF and 1 ml of water, and the mixture was stirred at room temperature for 12 h. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. This gave 64 mg (0.11 mmol, 88% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].Cl.[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][N:54]1[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH2:16][N:4]([C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[F:1])[CH:18]=1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCCN2)cc1OC
Reactant: O=C(O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCCN2C(=O)c2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)c2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)C=C.[CH2:16]1[C:25]2C(=CC=CC=2)CC[CH2:17]1>>[CH2:25]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:15])[NH:11]2)[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc2[nH]c(=O)ccc2c1
Reactant: c1ccc2c(c1)CCCC2
Product: C=CCc1c(O)ccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
10 Grams of 6-allyloxy-2(1H)-quinolinone was suspended in 50 ml of tetralin, and this suspension was stirred at 200° to 230° C. for 4 hours in nitrogen gas atmosphere. After the reaction, the reaction mixture was cooled to room temperature. The crystals thus precipitated were collected by filtration, washed with n-hexane and a small amount of diethyl ether in this order and dried. There was obtained 10 g (100%) of 5-allyl-6-hydroxy-2(1H)-quinolinone as crystalline powder. Melting point: Decomposed from 290° C.
Reaction SMILES: OO.[C:3]1([CH:9]2[O:11][C:10]2([C:17]#[N:18])[C:12]([O:14][CH2:15]C)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.[O-:21]P([O-])([O-])=O.[Na+].[Na+].[Na+]>CCOCC>[NH2:18][C:17]([C:10]1([C:12]([O:14][CH3:15])=[O:13])[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:11]1)=[O:21]
Reactant: CCOC(=O)C1(C#N)OC1c1ccccc1
Reactant: O=P([O-])([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(C(N)=O)OC1c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
100 ml of 30% hydrogen peroxide was added over a 20-minute period to a stirred mixture of 67 g of 1-phenyl-2-cyano-2-(ethoxycarbonyl)-1,2-epoxyethane (Reference II), 400 ml of methanol, 20 g of tribasic sodium phosphate (hydrate) and 8 g of 18 crown 6 ether at 25° C. The temperature was allowed to rise to 50° C. during the addition. The mixture then was cooled to 45° C. and 150 ml of the hydrogen peroxide solution was added over a 10-minute period. The temperature rose to 48° C. It was held there for one hour, then was raised to 60° C. and held there for 2 hours. The volatile materials were evaporated under reduced pressure. The residue was recrystallized from chloroform to give 8, mp: 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](=O)[C:16](O)=[O:17]>>[OH:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:16](=[O:17])[C:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[N:1]2
Reactant: Nc1ccc(O)cc1N
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc(O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-diaminophenol (which is prepared by treating 3,4-dinitrophenol with H2NNH2.H2O, Pd/C refluxed in MeOH), and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-hydroxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2oncc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2oncc2CCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of diethyl malonate (11.0 g) in tetrahydrofuran (60 ml) was gradually added sodium hydride (60%, oil, 2.50 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.48 g) in tetrahydrofuran (80 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (80 ml) and acetic acid (120 ml). The mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate-hexane to give a colorless prism (5.03 g, yield 70%) of 3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid. melting point: 121–122° C.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:16][C:17]#[C:18][CH3:19]>C(O)(C)C>[Na+:1].[CH2:16]([O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=1)[C:17]#[C:18][CH3:19]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: CC#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC#CCOc1ccc(S(=O)(=O)[O-])cc1
Yield: 81 %

Procedure:
To a solution of 4-hydroxybenzenesulfonate sodium salt (52.35 g, 0.225) in 1L of isopropanol and 225 mL of a 1.0N solution of sodium hydroxide was added 59.96 g (0.45 mol) of 1 bromo-2-butyne. The resulting mixture was heated to 70° for 15 h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtrtation, washed with isopropanol and ether and dried in vacuo to give 45.08 g (81%) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCNC(=O)C1
Reactant: Nc1ccc(F)cc1
Product: O=C1C=C(Nc2ccc(F)cc2)CCN1
Yield: 94.2 %

Procedure:
A mixture of 4-fluoroaniline (978 mg) and 2,4-dioxopiperidine (1.0 g) was heated at 120° for 1 h, and then cooled. The solid was triturated with ether (30 ml) and the solvent was decanted to leave the title compound (1.71 g), m.p. 195°-198°.