Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=2)=[CH:4][N:3]=[CH:2]1>Cl>[NH:1]1[C:5]([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(/C=C/Cc2cnc[nH]2)cc1-c1ccc(F)cc1
Agent: Cl
Product: O=C(O)c1ccc(/C=C/Cc2cnc[nH]2)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (0.6 g; 1.8 mmol) in 1N HCl (15 ml) was refluxed for 20 hours. The mixture was evaporated to dryness to give 4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid as the hydrochloride salt.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-fluoro-2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[C:4]([F:29])[CH:3]=1.I[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[C:4]([F:29])[CH:3]=1
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4F)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 110 above, using compound from Example 141, 3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([O:24]CC3C=CC=CC=3)[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12].C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:9]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12]
Reactant: Nc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 2,6-diamino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-nicotinamide (238 mg, 612 μmol) described in Example 1 was added thioanisole (287 μL, 2.45 mmol) at 0° C., which was stirred at room temperature for 2 hours. To the reaction solution were added sodium bicarbonate and water at 0° C., followed by extraction with ethyl acetate. After washing the organic layer with sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (101 mg, 55%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([I:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(I)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A round bottom flask was charged with 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 0.027 mol), triphenylphosphine (10.5 g, 0.0401 mol), iodine (10.16 g, 0.0401 mol), imidazole (2.72 g, 0.0401 mol), and methylene chloride (90 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the collected solids were washed with methylene chloride. The combined organic layers were concentrated. The resulting crude product was dissolved in ethyl acetate, and the organic phase was washed with water. The ethyl acetate layer was washed with a 3:1 mixture of water and methanol to remove triphenylphosphine oxide. The ethyl acetate layer was then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was loaded onto a 330 gram silica gel column. Flash chromatography afforded 3-iodo-pyrrolidine-1-carboxylic acid tert-butyl ester (6.9 g, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 4.31-4.42 (m, 1H), 3.84 (dd, J=12.60, 6.30 Hz, 1H), 3.67-3.79 (m, 1H), 3.54-3.64 (m, 1H), 3.40-3.49 (m, 1H), 2.20-2.32 (m, 2H), 1.48 (s, 8H). MS cald. for C5H71NO2 [(M-C4H9)+] 241, obsd. 241.7, 282.7 [(M-C4H9+41)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH3:19][C:15]1[CH:14]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Product: Cc1cc(/C(C[C@H](c2ccc(-c3cncnc3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 22, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and pyrimidine-5-boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][OH:14]>[Ag-]=O>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CO
Agent: O=[Ag-]
Product: COCc1cc([N+](=O)[O-])ccc1F
Temperature: 54 °C
Reaction time: 2.5 h

Procedure:
Under argon, 250 g (1.07 mol) of 2-(bromomethyl)-1-fluoro-4-nitrobenzene were introduced as initial charge in 2.5 l of methanol, 371 g (1.60 mol) of silver(I) oxide were added and the mixture was stirred for 2.5 h at 52-56° C. After cooling to RT, suction filtration over kieselguhr was carried out, followed by after-washing with methanol, and the solvent was removed on a rotary evaporator. The crude product was purified by distillation on a short-path evaporator at a jacket temperature of 104° C. and 0.56 mbar. This gave 184.5 g (93%) of the desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH:27]1([C:33]([O:35][CH:36](Cl)[CH3:37])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:26])[C@@H:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:37][CH2:36][O:35][C:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:34])=[O:13])(=[O:6])=[O:7]
Reactant: CC(Cl)OC(=O)C1CCCCC1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Yield: 39.2 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.2 g, 3.3 mmol) dissolved in 10 mL of anhydrous toluene was reacted with 1.9 g (10.0 mmol) of chloroethyl cyclohexanecarboxylate (24) in the presence of 1.4 g (5.0 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9→EtOAc/Hxn=1:5) as eluent to provide 0.69 g (39% yield) of the title compound (44a) as a colorless oil. Rf=0.11 (EtOAc/Hxn=1:9). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.23-1.36 (br. m, 3H), 1.44-1.50 (br. m, 2H), 1.53 (d, J=5.6 Hz, 3H), 1.58-1.68 (br. m, 1H), 1.74-1.80 (br. m, 2H), 1.86-1.97 (br. m, 2H), 2.25-2.39 (m, 3H), 3.21-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.82-3.84 (2s, 1H), 3.96 (d, J=9.2 Hz, 1H), 4.20-4.24 (m, 1H), 4.33-4.37 (2d, J=11.6, 11.6 Hz, 1H), 4.59-4.66 (2d, J=10.8, 11.2 Hz, 1H), 6.91-6.95 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 554.92 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].C(OCC)(=O)C.C(OCC)C.C1(C)C(C)=CC=CC=1.[H+].[B-](F)(F)(F)[F:37]>>[F:37][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1cccc2ncccc12
Reaction time: 1 h
Yield: 55 %

Procedure:
To a suspension of 5-aminoquinoline (50 g, 347 mmol) in 48% HBF4 (200 mL) at 0° C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (500 mL). The resulting suspension was filtered and the solid dried. This solid (82.5 g, 338 mmol) was added portionwise to refluxing xylene (1 L) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue dissolved in 1N hydrochloric acid (600 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (10×500 mL). The extracts were dried over sodium sulfate, filtered and the volatiles removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-20% diethyl ether in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 28.1 g (55%) of the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:30]=[C:14]3[CH:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][CH2:19][N:13]3[N:12]=2)[CH:8]=[CH:7][C:6]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1.CN(C=[O:41])C>>[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:30]=[C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:27])([F:29])[F:28])([OH:41])[CH2:16][CH2:17][CH2:18][CH2:19][N:13]3[N:12]=2)[CH:8]=[CH:7][C:6]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: CN(C)C=O
Reactant: COc1nc(-c2nc3n(n2)CCCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(-c2nc3n(n2)CCCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 96 h

Procedure:
Sodium hydride (60%) was added to a solution of 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-9-(2-trifluoromethylphenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine obtained in Examples 74 and 75 (83 mg) in DMF (5 mL) with stirring under ice-cooling until bubbling was stopped. Thereafter, the mixture was stirred at room temperature in an oxygen atmosphere. After four days, ice water, chloroform and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure. The residue was diluted again with toluene and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with chloroform and then air-dried to obtain 36.8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: O
Product: O=Cc1ccc(C(=O)O)cc1

Procedure:
A process for the production of high purity terephthalic acid comprising the steps of dissolving a crude terephthalic acid in a solvent consisting essentially of water to form an aqueous solution of crude terephthalic acid having a content of 4-carboxybenzaldehyde of at least 1,000 ppm, said crude terephthalic acid being obtained by the oxidation of a paradialkylbenzene, subjecting said aqueous solution of crude terephthalic acid having a content of 4-carboxybenzaldehyde of at least 1,000 ppm to oxidation at a temperature of from 230° to 300° C. and a pressure of 30-100 Kg/cm2 by an oxygen-containing gas at a feed rate of 0.4-10 moles of oxygen per mole of 4-carboxybenzaldehyde contained in the crude terephthalic acid, said oxidation being conducted in the presence of a fixed bed catalyst, to obtain a resultant solution, said aqueous solution of crude terephthalic acid having a concentration of 100-700 g of terephthalic acid per liter of aqueous solution, and subjecting the resultant solution to hydrogenation by hydrogen at a temperature in the range of 270°-300° C. and a hydrogen partial pressure of 5-15 Kg/cm2 in the presence of a catalyst to obtain a high purity terephthalic acid.
Reaction SMILES: N[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.N([O-])=O.[Na+].[I-:23].[K+].S([O-])([O-])=O.[Na+].[Na+]>Cl.O>[C:17]([C:4]1[CH:3]=[C:2]([I:23])[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)#[N:18]
Reactant: N#Cc1cc(N)c2c(c1)ncn2-c1ccccc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
A suspension of 7-Amino-5-cyano-1-phenylbenzimidazole (12.5 g, 53.4 mmol) in hydrochloric acid (90 ml, 25% w/v) was diazotised with a solution of sodium nitrite (3.7 g, 53.4 mmol) in water (20 ml). The resultant mixture was stirred for 30 min at 0° C. whereafter a solution of potassium iodide (14.2 g, 85.5 mmol) in water (40 ml) was added dropwise. Stirring was continued for 10 min at 0° C., and then the temperature was raised to 80° C. for 30 min. After cooling, aqueous sodium sulphite (1M) was added and the resultant mixture was extracted with dichloromethane. Column chromatographic work-up of the dried and concentrated organic extract afforded the title product (6.5 g, 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][CH3:20])[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:28][C:24]1[N:23]=[C:22]([N:19]([CH3:20])[C@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:14]2)[CH:27]=[CH:26][N:25]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(N)n1)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1

Procedure:
A stirred solution of 2-(3,5-dichlorophenylamino)-1-((S)-3-(methylamino)piperidin-1-yl)ethanone (0.3 mg, 1.0 mmol), 4-chloropyrimidin-2-amine (60 mg, 0.5 mmol), DIEA (0.17 mL, 1.9 mmol) in DMF (2 mL) was heated to 100° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound which was purified (silica gel, gradient MeOH in CH2Cl2) to give the (20 mg, 5.2%). 1H NMR (400 MHz, CD3OD): δ 7.77-7.73 (m, 1H), 6.64-6.56 (m, 3H), 6.10-6.00 (m, 1H), 4.58-4.45 (m, 2H), 4.10-3.84 (m, 3H), 2.96 (s, 3H), 2.58-2.81 (m, 1H), 2.03-1.90 (m, 4H), 1.60-1.48 (m, 1H). LC-MS: m/z [M+1]=409 & [M+23]=431.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[OH-:22].[Na+]>O1CCOCC1>[OH:22][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: [OH-]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1

Procedure:
2-(4-hydroxy-3-nitrobenzoyl)benzoic acid is prepared as follows: a mixture of 10.0 g of 2-(4-chloro-3-nitrobenzoyl)benzoic acid, 200 ml of aqueous sodium hydroxide (1.5 M) and 20 ml of dioxane is heated at reflux for 12 hours. After cooling, the mixture is added to 200 ml of 1:1 concentrated sulfuric acid-ice water with stirring. The resulting solid is filtered, washed with water to a pH of about 6 and dried to obtain 9.5 g of 2-(4-hydroxy-3-nitrobenzoyl)benzoic acid as a light yellow solid. MS: (EI 70 eV); M+,(%): 287 (36); 197 (31); 166 (100); 149 (75); 120 (34).
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5](O[C@@H]1[C@@H](COC(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)O[C@@H](N2C=CC(=O)NC2=O)[C@@H]1OCOCC(C(F)(F)F)C(F)(F)F)([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[C:66]([NH:69][C:70]1[C:71]2[N:72]=[CH:73][N:74]([C:119]=2[N:120]=[CH:121][N:122]=1)[C@@H:75]1[O:118][C@H:92]([CH2:93][O:94][C:95]([C:112]2[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=2)([C:104]2[CH:109]=[CH:108][C:107]([O:110][CH3:111])=[CH:106][CH:105]=2)[C:96]2[CH:101]=[CH:100][C:99]([O:102][CH3:103])=[CH:98][CH:97]=2)[C@@H:90]([OH:91])[C@H:76]1[O:77][CH2:78][O:79][CH2:80][CH:81]([C:86]([F:89])([F:88])[F:87])[C:82]([F:85])([F:84])[F:83])(=[O:68])[CH3:67]>>[C:1]([CH2:3][CH2:4][PH:5]([O:91][C@@H:90]1[C@@H:92]([CH2:93][O:94][C:95]([C:112]2[CH:113]=[CH:114][CH:115]=[CH:116][CH:117]=2)([C:104]2[CH:109]=[CH:108][C:107]([O:110][CH3:111])=[CH:106][CH:105]=2)[C:96]2[CH:97]=[CH:98][C:99]([O:102][CH3:103])=[CH:100][CH:101]=2)[O:118][C@@H:75]([N:74]2[C:119]3[N:120]=[CH:121][N:122]=[C:70]([NH:69][C:66](=[O:68])[CH3:67])[C:71]=3[N:72]=[CH:73]2)[C@@H:76]1[O:77][CH2:78][O:79][CH2:80][CH:81]([C:82]([F:83])([F:84])[F:85])[C:86]([F:89])([F:88])[F:87])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:9])[CH3:10])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 70 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2a instead of the compound 2u. Yield was 70% (white foam).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.S(OC)(O[CH3:23])(=O)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:23][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(N2CCCCCC2=O)CC1(C)C
Temperature: 80 °C

Procedure:
A solution of 63.0 g (0.25 mole) of N-(2,2,6,6-tetramethylpiperidin-4-yl)-epsilon-caprolactam, prepared in Example 1, in 150 ml of toluene is added to a flask fitted with a reflux condenser, stirrer and thermometer. To this solution is then added a second solution of 28.5 ml (0.30 mole) of dimethyl sulfate in 100 ml of toluene. The mixture is heated for one hour at 80° C. and then 50 ml of concentrated ammonium hydroxide is added.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(C)C>[N:21]1([C:2]2[C:3]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1C
Solvent: CC(C)O
Product: COc1ccc(-c2ccc3ncnc(N4CCNCC4)c3n2)cc1C
Temperature: 80 °C
Yield: 78 %

Procedure:
To a suspension of 4-chloro-6-(3-methyl-4-methoxyphenyl)-pyrido[3,2-d]pyrimidine (0.99 mmole) in isopropanol (40 ml) was added piperazine (1.99 mmole). The reaction mixture was heated at 80° C. for 2 hours. The solvents were evaporated in vacuo. The crude residue was purified by silica gel flash chromatography (the mobile phase being a mixture of methanol and dichloromethane with an 0.5% aqueous NH3 solution (in a ratio gradually ranging from 2:98 to 3:97), resulting in the pure title compound (259 mg, yield 78%) which was characterized by its mass spectrum as follows: MS (m/z): 336 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Cl)nc[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1cnc(Cl)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 6-chloropyrimidin-4(3H)-one (5 g), methyliodide (2.6 mL) and K2CO3 (10.6 g) in acetone (100 mL) is stirred at room temperature over night. The mixture is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and concentrated. The residue is triturated with diisopropylether to give the title compound. Yield: 5.1 g; LC (method 11): tR=0.25 min; Mass spectrum (ESI+): m/z=145 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.ClC1C=C(C=CC=1)C(O)=[O:33]>ClCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:33])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Reaction time: 1.58 h
Yield: 51.8 %

Procedure:
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in CH2 Cl2 at -10° C. 3-Chlorobenzoic acid(4.9 g, 15,67 mmol) was then added and the reaction mixture stirred for 95 minutes. The reaction mixture was taken up in CH2Cl2 and extracted with sodium bisulfite, 10% NaOH. The crude reaction product was purified on silica gel eluting first with 1% and then with 2% MeOH in CH2Cl2 to give the title compound (2.7 g, MH+ 399).