Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([CH2:25][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:27]
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C(=O)OCc2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g of benzyl indole-2-carboxlate in solution in 20 ml of dimethylformamide are introduced slowly into 30 ml of a suspension of 1 g of NaOH NaH in 30 ml of dimethylformamide and 3.1 g of methyl bromoacetate are then introduced. After 12 hours at ambient temperature, with stirring, the mixture is poured into a volume of ice-water and then extracted with ethyl acetate. The dried organic phase is concentrated and the residue is recrystallised from aqueous ethanol (95%, V/V). m.p.=94° C.; yield 87%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:9])[CH2:16][CH2:15]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (8.48 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50 mL dichloromethane were cooled with an ice/ethanol bath and combined with 1.2 g (7.81 mmol) 5-chloro-2,3-dihydro-1H-indole. 7.9 mL (7.9 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 2 h with cooling and for 1 h at RT. The man 50 mL of an aqueous saturated sodium hydrogen carbonate solution were added. After 10 min stirring the organic phase was separated off and washed with water and 1 M hydrochloric acid. The organic phases was dried on magnesium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[C:9]([NH2:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19](Cl)OC(Cl)(Cl)Cl>C1COCC1.ClCCl>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][O:15][C:19](=[O:18])[NH:16][C:9]=2[CH:8]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(CCO)c(N)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2c(c1)NC(=O)OCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 3-amino-4-(2-hydroxy-ethyl)-benzoic acid tert-butyl ester (2.1 g, 8.86 mmol) in THF (150 mL) and dichloromethane (50 mL) at 0° C. was added diphosgene (0.65 mL, 5.38 mmol) all at once. The reaction turned milky and became clear after 1 minute. The reaction was warmed to room temperature and stirred for 150 minutes. The solvent evaporated to provide 6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester: MS (m/e) 264 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1>C1COCC1.C(O)C>[O:9]([CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1nc(COc2ccccc2)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of sodium hydride (55 mg, 60% dispersion in mineral oil, 1.38 mmol) in THF (1 ml) at 0° C. was added phenol (100 mg, 1.06 mmol). After stirred at 0° C. for 10 minutes, the reaction solution was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled to 0° C. again, and was added a solution of N-(4-(chloromethyl)thiazol-2-yl)acetamide in ethanol (1 ml). The reaction was stirred at room temperature overnight and then was heated at 70° C. for 5 hours. The reaction solution was concentrated and the residue was purified via preparative HPLC to afford N-(4-phenoxymethyl-thiazol-2-yl)-acetamide as a tan amorphous solid (50 mg, 20%). LC/MS m/z 249.15 (M-1)+; HPLC Rt: 2.875 min.
Reaction SMILES: [Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:22]I.N1C=CN=C1.[C:29]([O:33][C:34](=[O:46])[NH:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH2:37]O)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([O:33][C:34](=[O:46])[NH:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH2:37][I:22])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(F)cc1
Reactant: II
Agent: [Cl-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CI)c1ccc(F)cc1
Yield: 57.6 %

Procedure:
To a room temperature solution of triphenylphosphine dichloride (1.53 g (5.85 mmol) in methylene chloride was added iodine (1.481 g, 5.85 mmol). The mixture was stirred for fifteen minutes, then imidazole (663 mg, 9.74 mmol) was added. The mixture was stirred another 15 minutes, then [1-(4-fluoro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (1.0 g, 3.9 mmol) was added. The mixture was heated to reflux for two hours, then stirred at room temperature overnight. Solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (5-10% ethyl acetate/hexanes) to give 820 mg (58%) of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester, MP=138-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
5-Nitro-pyridin-2-ylamine (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting solid was triturated with chloroform, the filtrate was further purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm) 1.35 t (3H), 2.54 s (3H), 4.30 q (2H), 6.78 s (1H), 6.96-7.25 bm (6H), 8.33 dd (1H), 9.39 sd (1H)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]#[N:5].[CH3:14][NH:15][NH2:16]>C(O)C>[NH2:5][C:4]1[N:15]([CH3:14])[N:16]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:2]=[O:1]
Reactant: N#CC(=NO)C(=O)c1ccccc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c(N=O)c1N

Procedure:
A mixture of 2-hydroxyimino-3-oxo-3-phenylpropanenitrile (2.61 g, 15 mmol) and methylhydrazine (1.1 ml, 21 mmol) was stirred at reflux in ethanol (20 ml) for 2 hours, cooled and concentrated under reduced pressure. The residue was partitioned between ether (50 ml) and dilute hydrochloric acid (50 ml, 2N solution). The aqueous phase was separated and rendered basic by the addition of saturated aqueous potassium carbonate. The red solid which precipitated was filtered off and dried, to give the title compound, 1.40 g, (46%). m.p. 230°-231° C. (literature. m.p. 230°-231° C., Gazz. Chim. Ital., (1968), 98, 569.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([O:12][CH3:30])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: CO
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CC1C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19 Grams of 2-(4-chlorobenzoylamino)-3-(oxindol3-yl)propionic acid 1/4-hydrate prepared in Example 3 was dissolved in 30 ml of methanol, then to this solution was added dropwise 9.4 g of thionyl chloride under an ice-cooled condition, then the reaction mixture was stirred at a room temperature overnight. Methanol was removed by evaporation, the residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous sodium sulfate, then the solvent was removed by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluting agent: chloroform/methanol=40/1) to obtain 10.5 g of methyl 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionate. The chemical structure of this product was determined by means of NMR method.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.[C:20](OCC)(=[O:22])C>>[Cl:8][C:4]1[C:3]2[CH:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[O:19][C:20](=[O:22])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1C(O)Cc1ccc(F)c(F)c1
Reactant: CCOC(C)=O
Product: O=C1Nc2cccc(Cl)c2C(Cc2ccc(F)c(F)c2)O1
Yield: 64 %

Procedure:
This compound was prepared using General Method 2 (EXAMPLE 1) from (±)-1-(2-amino-6-chlorophenyl)-2-(3,4-difluorophenyl)ethanol (0.28 g, 1.1 mmol) to afford 0.21 g (64%) of (±)-5-chloro-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Cs+].I[CH:11]([CH3:13])[CH3:12]>CN(C=O)C>[CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccccc1
Reactant: CC(C)I
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Nc1ccccc1
Temperature: 30 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of aniline (0.46 mls, 5 mmol) and cesium hydroxide (0.61 mls, 15 mmol) was stirred at 25° C. for 30 mins in DMF (25 mls). 2-iodopropane (2.5 mls, 25 mmol) was added dropwise over 5 mins, the reaction was heated to 30° C. and stirred for 16 hours. The solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the intermediate 4a (55 mg, 4 mmol, 81.4% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.11-7.02 (t, J=7.9 Hz, 2H), 6.63-6.54 (t, J=7.3 Hz, 2H), 6.54-6.45 (d, J=7.8 Hz, 1H), 3.60-3.45 (hept, J=6.3 Hz, 1H), 3.41-3.25 (s, 1H), 1.14-1.06 (d, J=6.3 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH2:19][CH3:20]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cccc2c1CCC2=O

Procedure:
To a suspension of 4-hydroxy-1-indanone (1.0 g, 6.75 mmol) in acetone (30 mL) was added potassium carbonate (2.8 g, 20.24 mmol) and propyl iodide (0.72 mL, 7.42 mmol) and the reaction mixture was heated to reflux for about 7 hours. The reaction was cooled, concentrated under vacuum and partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to provide the desired product. MS (APCI): m/z 191 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CO>[Br:14][CH2:2][C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:3]
Reactant: BrBr
Reactant: CC(=O)C1=Cc2ccccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CBr)C1=Cc2ccccc2OC1
Reaction time: 2 h

Procedure:
3-Acetyl-2H-chromene (0.2 mole) is dissolved in diethyl ether (250 ml) and methanol (10 ml). The solution is cooled to 0°-5° C. Bromine (0.21 mole) is added dropwise thereto, with stirring. The resulting material is left aside 2 hours at room temperature. Anhydrous potassium carbonate (25 g) is then added and the material is evaporated to dryness. The pasty residue is placed in a flask with 600 ml hexane, and is refluxed for 1 hour. The reaction mixture is decanted hot, allowed to cool, and the organic solution is placed in the freezer. Brown-yellow crystals having a sufficient purity for the next step separate out. After two recrystallizations from hexane, a sample gives long pale yellow needles, M.p.=87° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH2:20][OH:21])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:35]1[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH2:20][OH:21])=[C:18]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2CO)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2CO)OC1(C)C
Reaction time: 1 h

Procedure:
To a solution of [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-1H-pyrazol-5-yl]methanol (40.0 mg, 0.0916 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.28 mL, 0.37 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.075 mL, 0.46 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification. MS (ES+): m/z=437.29 (100) [MH+]. HPLC: tR=1.94 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1)#[N:10].[F:19][C:20]([F:25])([F:24])[C:21](N)=[NH:22]>CO>[F:19][C:20]([F:25])([F:24])[C:21](=[N:18][NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[NH2:22]
Reactant: N=C(N)C(F)(F)F
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Triethylamine (1.54 mL, 11 mmol) and then 4-cyanophenylhydrazine hydrochloride (1.71 g, 10 mmol) were added to a solution of trifluoroacetoamidine (1.57 g, 14 mmol) in methanol (10 mL). The mixture was stirred overnight. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was isolated by filtartion, washed with diisopropyl ether-hexane, and dried in vacuo to give 2,2,2-trifluoro-N′-(4-cyanophenyl)ethanehydrazonamide (2.07 g, 90.5% yield).
Reaction SMILES: [F:1][C:2]([CH:9]=[CH:10][CH:11]([F:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][OH:8].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[F:1][C:2](=[CH:9][CH:10]=[C:11]([F:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]([OH:26])=[O:8]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCC(F)C=CC(F)=CC=CC=CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCCCCCCCCC(F)=CC=C(F)C=CC=CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of the alcohol prepared in 3P (282 mg, 0.86 mmoles) in acetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagent over 15 min. until the orange color was stable. The mixture was stirred 15 min. at 0° C. The excess of Jones reagent was reacted with isopropanol. The acetone was evaporated under reduced pressure without heating. The residue was taken up with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography on silica gel and elution with a 15:85 mixture of ethyl acetate and benzene gave pure acid (180 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(C(C)=O)cc4)CC3)nc2c1
Yield: 87 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 2.54-2.58 (m, 3H), 3.49-3.67 (m, 4H), 3.87-3.96 (m, 6H), 4.12-4.16 (m, 4H), 6.87-7.03 (m, 2H), 7.19-7.31 (m, 3H), 7.62-7.66 (m, 1H), 7.89-7.97 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12]([NH2:14])=[O:13])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:25]>[Pd].C(O)C>[ClH:25].[CH3:24][C:20]1[CH:19]=[C:18]([NH:17][C:11]2([C:12]([NH2:14])=[O:13])[CH2:15][CH2:16][NH:8][CH2:9][CH2:10]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(NC2(C(N)=O)CCNCC2)c1
Reaction time: 48 h

Procedure:
A mixture of 1-benzyl-4-(3-methylphenylamino)-isonipecotamide (0.42 g, 1.3 mmol) and 10% palladium on charcoal (0.88 g) in a mixture of ethanol (40 mL) and ethanol saturated with anhydrous hydrochloride gas (10 mL) was shaken in a Parr hydrogenator at 60 psi for 48 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated to provide the title compound.
Reaction SMILES: C(O[C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C1C=CC=CC=1)=[O:6])C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]=[C:15]([CH3:22])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])=[O:23]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NC(=O)C(=O)Nc2ccccc2O)c(C)c1
Yield: 72.5 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (5.23 g, 24.4 mmol, 1 eq) and 2-aminophenol (2.67 g, 24.4 mmol, 1.0 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (6.8 ml, 50 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (5.26 g, 17.7 mmol, 72.4% yield). 1H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H), 8.84 (s, 1H), 8.11 (s, J=7.7 Hz, 1H), 7.51 (dd, J=8.0, 1.8 Hz, 1H), 7.14 (ddd, J=1.5, 8.1, 7.2 Hz, 1H), 6.92 (m, 3H), 2.30 (s, 3H), 2.22 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.2, 157.9, 148.2, 138.2, 134.9, 129.5, 129.4, 127.7, 124.3, 122.2, 121.1, 118.9, 21.2, 18.6. Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.50; H, 5.96; N, 9.44.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4-bromo-1,8-naphthalic anhydride (10 g), aniline (3.54 g) and acetic acid (75 ml) was refluxed with stirring for 10 hrs. The reaction mixture was then cooled to room temperature, whereupon solid separated out. The solid was filtered, washed with water (50 ml) followed by acetic acid (50 ml) and dried at 100° C. for 8 hours (Yield=10.8 gm).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:24][CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][CH2:24][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 115 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
1-Cyano-4-fluoronaphthalene(1.0 g, 5.84 mmol) and ethyl nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL) and stirred at 115° C. for 20 hours. After cooling to rt ethyl acetate (50 mL) was added and the solution washed with HCl (0.4 M, 2×30 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL). The combined organic layers were washed with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried and evaporated. The crude product was purified by silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane to give the title compound (1.23 g, 68%) as a yellowish oil