Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26](OCC)=[O:27])=[N:22][CH:23]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33].[OH-].[K+]>C(O)C.O>[CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[N:22][C:21]([CH2:24][CH2:25][C:26]([NH:32][OH:33])=[O:27])=[CH:20][CH:19]=2)[C:8]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: CCOC(=O)CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CCc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cn1)NO
Reaction time: 0.33 h
Yield: 16.9 %

Procedure:
Ethyl 3-[5-({[(1S)-1-cyclohexyl-2-(cyclopentyloxy)-2-oxoethyl]amino}methyl)pyridin-2-yl]propanoate (0.9 g, 2.16 mmol) and hydroxylamine hydrochloride (0.6 g, 8.64 mmol) were dissolved in ethanol (10 mL) then cooled to <5° C. Potassium hydroxide (0.97 g, 17.28 mmol) was dissolved in water (2.07 mL) and then charged to the reaction which was stirred at <5° C. for 20 min. The reaction was quenched to pH ˜7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in hot EtOH (2 mL) and water (3 mL) added. On cooling some of the resulting solid (235 mg) was collected by filtration and dried to give cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]ethanoate (147 mg).
Reaction SMILES: [CH2:1]([C:6]1[O:10][N:9]=[C:8]([CH2:11][N:12]2[C:21]3[C:20](=[O:22])[N:18]([CH3:19])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[N:14]=[CH:13]2)[N:7]=1)[CH2:2][C:3](=O)[CH3:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>C1C=CC=CC=1>[CH:25]([NH:28][CH:3]([CH3:4])[CH2:2][CH2:1][C:6]1[O:10][N:9]=[C:8]([CH2:11][N:12]2[C:21]3[C:20](=[O:22])[N:18]([CH3:19])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[N:14]=[CH:13]2)[N:7]=1)([CH3:27])[CH3:26]
Reactant: CC(=O)CCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Reactant: CC(C)N
Solvent: c1ccccc1
Product: CC(C)NC(C)CCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 53 %

Procedure:
3.32 g. of 7-[{5-(butan-3-on-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline prepared according to the previous Example are heated in 80 cm3 benzene with 6 cm3 isopropylamine under pressure at 80° C. for 4 hours. The mixture is evaporated and the residue is dissolved in 80 cm3 methanol and reduced with 0.8 g. of sodium tetrahydroborate. 2.0 g. (53% yield) of 7-[{5-(3-isopropylamino-butan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline are obtained. M.p.: 55°-61° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:12](OC(OCC)OCC)C.CC(O)=O>C(Cl)Cl>[Cl:9][C:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]2[N:1]=[CH:12][NH:8][C:7]=2[CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nc(Cl)cc(N)c1N
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1nc(Cl)cc2[nH]cnc12

Procedure:
A mixture of 3,4-diamino-6-chloropicolinonitrile (3.2 g), triethylorthoformate (16 ml) and AcOH (5.4 ml) was heated to 150° C. in DCM (16 ml) in a microwave for 15 minutes. Solvent was evaporated, residue was dissolved in EtOAc (250 mL) and washed with water (150 mL). Organic layer was dried over sodium sulphate. Solvent was evaporated under reduced pressure to yield 6-chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]#[C:10][CH2:11][OH:12]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]#[C:10][CH2:11][OH:12])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCC#CCCl
Solvent: Cc1ccccc1
Product: OCC#CCN1CCOCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a solution of morpholine (4.36 g) in toluene (15 mL) was added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The solution was stirred at 85° C. for 3 hours. After cooling, the solid was filtered off. The filtrate was subjected to vacuum distillation to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>Cl.O1CCOCC1.CC(O)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(F)cccc3C(=O)NC)n2)cc1CCC(N)=O
Temperature: 120 °C

Procedure:
A mixture of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (40 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (50 mg), and 2 drops of 4 N HCl/dioxane in IPA (3 mL) were microwave-heated at 120° C. for 1.5 hours. The mixture was concentrated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide. The crude mixture was stirred for 4 hours in TFA and concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (45.7 mg) as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.3 (s, 1H), 7.7-7.5 (m, 3H), 7.65 (s, 1H, slowly exchanging NH), 7.4 (d, 1H), 7.32 (d, 1H), 7.28 (dd, 1H), 3.0 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 1.8 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16](C=O)[CH:15]=[N:14]1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21].[C:42]1([CH3:48])C=CC=C[CH:43]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:43]=[CH:42][CH:48]=[O:21])[CH:15]=[N:14]1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: Cc1ccccc1
Product: O=CC=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (2 g) and formylmethylene triphenylphosphorane (1.9 g) were heated under reflux in toluene for 4 hours. After removal of the solvent at reduced pressure the resulting residue was purified by column chromatography to give 3-[(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]-2-propenal, m.p. 68°-69°. This compound (1.8 g) was then stirred with diaminomaleonitrile (0.6 g) in methanol containing a trace of p-toluenesulphonic acid for 4 hours. Removal of the solvent at reduced pressure and column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[3-(2-amino-1,2-dicyanoethenylimino)-2-propenyl]-2H-1,2,3-triazole, m.p. 207°-209°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29](=[O:31])[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:27]2[CH2:28][C:29](=[O:31])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(C2=CC(=O)OC(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 2,2-dimethyl-6-(3-methoxy-phenyl)-[1,3]dioxin-4-one (Example J11) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,4-diphenylpiperidine (Matrix, 0.24 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.308 g, 1.00 mmol), under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.34 (m, 20H), 4.23 (s, 2H), 3.68-3.73 (m, 2H), 3.45-3.52 (m, 4H), 2.60-2.66 (m, 2H), 2.37-2.45 (m, 4H), 1.78-1.88 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>FC(F)(F)C(O)=O>[F:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 5 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a suspension of 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione (837 mg, 4.23 mmol) in trifluoracetic acid (30 mL) was added KNO3 (512 mg, 5.07 mmol). The mixture was stirred at 55° C. for 20 h at the end of this time, 256 mg (2.50 mmol) of KNO3 was added and the reaction mixture was stirred at 5° C. for 20 h, then another 256 mg (2.50 mmol) of KNO3 was added and the mixture was stirred at 55° C. for 20 h. The reaction mixture was then rota-evaporated to dryness. To the residual solid was added ice-cold water (about 15 mL), the solid was collected by vacuum filtration, washed with ice-cold water (5×5 mL), and dried at 40° C. under 1 mm Hg for 14 h, giving 700 mg (68%) of the title compound as a yellow powder. Mp 288°-90° C. (dec.). IR (KBr) 3424, 3226, 1752, 1717, 1554, 1356, 1304 cm-1. 1H NMR (DMSO-d6): 12.249 (s, 1H), 11.864 (bs, 1H), 7.330 (dd, 1H, J=10.5, 7.8 Hz). Analysis for C8H3F2N3O4, calcd: C, 39.50, H, 1.24, N, 17.29; found: C, 39.42, H, 1.26, N, 17.08.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccsc3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccsc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(3-thienylmethoxy)benzyl]-3-pyrrolyl]propionate (624 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 5 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(3-thienylmethoxy)benzyl]-3-pyrrolyl]propionic acid (421 mg, yield: 72%). This was recrystallized from ethyl acetate-hexane. Melting point: 118–119° C.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11].[CH2:12]([OH:15])[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][O:15][C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCO
Agent: [Na]
Product: Cc1c(OCCO)cc[n+]([O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4.60 g (0.2 mol) of metallic sodium was dissolved in 80 ml of ethylene glycol under cooling with ice to obtain a solution. This solution was stirred in a nitrogen atmosphere at 100° C. for one hour, followed by the addition of 15.76 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide at a room temperature. The obtained mixture was stirred at 120° C. for 2 hours. After the completion of the reaction, the reaction mixture was distilled to dryness to remove the ethylene glycol. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol 19:1) to obtain 13.28 g of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-chlorostyryl benzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDC13) δ4.55 (2H, s), 6.66 (1H, d, JH,H=12.12), 7.16-7.65 (9H aromatic+1H ethylenic).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+].C(O)(C)(C)C.[OH2:30]>>[C:1]([C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1)([OH:20])=[O:30]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Oc2cc(Cl)ccc2C(=O)O)cc1
Reactant: O
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(Oc2cc(Cl)ccc2C(=O)O)cc1

Procedure:
A mixture of 12 g. of 2-(p-methylphenyloxy)-4-chlorobenzoic acid, 72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml. of water is refluxed for 4.5 hours. After this time, the t-butanol is distilled off, and the reaction mixture is filtered. The filtrate is acidified to give 2-(p-carboxyphenyloxy)-4-chlorobenzoic acid which can be recrystallized from benzene:heptane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 1-(3-aminopropyl)pyrrolidin-2-one (35.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a beige solid, 63.5 mg, (65% yield) MS (ES+): 392.2, (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=CC2OCCOC=2C=3)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3cc4c(cc3c2Cl)OCCO4)CC1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
The crude acid (500 mg), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (150 mg, 1 mmol), and triethylamine (0.3 mLs) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-6,7-ethylenedioxyquinoline-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=O)=[O:13])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([Cl:23])(=[O:15])=[O:13])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc2c(Br)cccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a round bottom flask was added 5-bromonaphthalene-2-sulfonic acid (5.00 g, 17.41 mmol), followed by DMF (17.41 mL) to generate a deep green heterogeneous solution. Thionyl chloride (2.54 mL, 34.8 mmol) was added dropwise using a syringe at rt, and the solution turned orange and heat was evolved. The solution became homogeneous. The solution was maintained at rt for 18 h. The resulting orange solution was poured into a separatory funnel containing ice and diluted with DCM (200 mL). When the ice melted, the mixture was shaken and then the resulting layers were separated. The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with water (3×200 mL), then dried over Na2SO4 and concentrated to provide 5-bromonaphthalene-2-sulfonyl chloride (5.00 g, 16.36 mmol) as a brown oil, which was used immediately without further purification.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>C1C=CC=CC=1>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21][CH2:22]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN1CCC(N)CC1
Solvent: c1ccccc1
Product: CN1CCC(NC2c3ccccc3Oc3ccccc32)CC1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 1.9 g. of 4-amino-1-methylpiperidine in 100 ml. of dry benzene was refluxed for 24 hours. The cooled solution was then washed with 5% aqueous sodium carbonate solution and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue crystallized on triturating with hexane and was recrystallized from hexane to give N-(N-methyl-4-piperidinyl)-9-xanthenylamine, m.p. 96.5°-98° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][OH:13])[C:6](=[O:14])[CH:5]=1)[CH3:2].CCN(CC)CC.[CH3:22][N:23]1C(=O)O[C:26](=[O:27])[C:25]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:24]12.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:13][CH2:12][CH2:11][CH2:10][CH:7]1[CH2:8][CH2:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]1=[O:14])=[O:27]
Reactant: CCOC1=CC(=O)C(CCCO)CC1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC1=CC(=O)C(CCCOC(=O)c2ccccc2NC)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Alcohol 3 (180 mg, 0.89 mmol), NEt3 (0.56 mL) and catalytic DMAP were added to a solution of N-methylisatoic anhydride (220 mg, 0.89 mmol) in dry DMF (2.0 mL) at rt. After stirring overnight, the solution was warmed to 65° C. for 3 h. After cooling to rt, water was added and this mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by flash column chromatography to afford 87.0 mg (45% yield) of 4 as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, m), 7.33 (1H, m), 6.56 (2H, m), 5.27 (1H, s), 4.22 (2H, t, J=5.2 Hz), 3.85 (2H, q, J=7.0 Hz), 2.86 (3H, s), 2.39 (2H, t, J=5.3 Hz), 2.04-1.41 (7H, m), 1.31 (3H, t, J=7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 201.1, 176.8, 168.7, 151.7, 134.7, 131.7, 115.0, 111.3, 110.6, 102.5, 101.9, 64.7, 64.5, 64.3, 44.9, 30.0, 28.2, 26.6, 26.5, 26.4, 14.3; ESI MS m/z 354 (M++Na+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[ClH:14].Cl.[CH2:16]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:14].[CH2:16]([N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:4])[CH2:27][CH2:26]1)[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(CCl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1

Procedure:
A mixture of 2-chloro-1-(4-nitrophenyl)ethanone (3.2 mmol), N-phenacyl piperazine dihydrochloride (3 mmol), and K2CO3 (9 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-11), 0.71 g (61%), mp 204-205° C., M+ 367.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([S:9][CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.O>C(Cl)Cl>[C:27]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([S:9]([CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)=[O:41])[CH3:8])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(SCCN1CCOc2c(OCC(=O)O)cccc21)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(c1ccccc1)(c1ccccc1)S(=O)CCN1CCOc2c(OCC(=O)O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid (51 mg) was dissolved in methylene chloride (5 ml), and the resultant solution was stirred at room temperature. m-CPBA (20 mg) was then added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water (20 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by Lober® column chromatography (DIOL, type A, developing solvent: n-hexane/ethyl acetate=1/2) to obtain the object compound (43 mg, yield 81%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1)[CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C/CCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC/C=C/CCCOc1ccc(C(=O)O)cc1
Yield: 85.1 %

Procedure:
The ester 35i (500 mg, 1.7 mmol) was dissolved in 50 ml methanol. Water (approximately 10 ml) was added until the solution remained cloudy, at which time lithium hydroxide monohydrate (723 mg, 17.0 mmol) was added. The reaction mixture was refluxed overnight and acidified with concentrated HCl. Water was added (approximately 30 ml), the mixture was cooled, filtered, washed with water and allowed to air dry yielding 400 mg (84%) of a white powder.