Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 3-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]>>[CH2:10]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH3:9])[C:2]=3[Cl:1])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]
Reactant: CCOCCOCCOc1ccc(C2CCC(N)CC2)cc1
Reactant: Cc1nccc(Cl)c1Cl
Product: CCOCCOCCOc1ccc(C2CCC(Nc3ccnc(C)c3Cl)CC2)cc1
Reaction time: 4.5 h
Yield: 28 %

Procedure:
Preparation was carried out analogously to Example 35 from 3,4-dichloro-2-methylpyridine and 4-(4-(3,6-dioxaoctyloxy)phenyl)cyclohexylamine. After 4.5 hours the mixture is worked up. Yield: 28%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:11]1[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: COc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccccc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 55.7 %

Procedure:
A mixture of 7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.40 g), aminoguanidine hydrochloride (0.17 g), concentrated hydrochloric acid (0.22 ml), water (0.22 ml) and ethanol (40 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 67) (0.3 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[Cl-:10].[Li+]>CN(C)C=O.O.[Cu](Cl)Cl>[Cl:10][CH:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7](=[O:9])[CH3:8]
Reactant: [Cl-]
Reactant: COCCCCC(C)=O
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCC(Cl)C(C)=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
1.5 mol of 6-methoxyhexan-2-one [29006-00-6] are added to a mixture of 3.6 mol of copper(II) chloride hydrate and 1.8 mol of lithium chloride in 900 ml of N,N-dimethylformamide at 80° C. The reaction mixture is stirred at 80-90° C. for 1 hour. 900 g of ice are added, and the precipitate is dissolved by adding N,N-dimethylformamide. Extraction with pentane (6×) is carried out. The combined organic phases are washed with water, dried over sodium sulphate and fractionated in vacuo. The title compound is identified by means of the Rf.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1.N12CCCN=C1CCC[CH2:42][CH2:41]2.ICC>CN(C)C=O>[CH2:41]([O:33][C:32](=[O:34])[CH2:31][CH2:30][C:4]1([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:3][C:2](=[O:1])[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5]1)[CH3:42]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)OCC)CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the titled product of Example 43 (676 mg, 1.25 mmol) in 5 ml of dimethylformamide (DMF) was added 190 mg (1.25 mmol) of 1,8-diazabicyclo (5.4.0)undec-7-ene followed by 585 mg (3.75 mmol) of iodoethane. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2. The solution was then washed with 3N hydrochloric acid, dried (Na2SO4), filtered, and the solvent removed on a rotary evaporator. The residue was chromatographed on a silica gel column. Elution with 35% ethyl acetate/61.5% hexane/2.5% acetic acid as eluent produced the title product which was crystallized from 3:1 hexane:ethyl acetate to give 183 mg, m.p. 83.5°-84.5° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20].Cl.C([O-])(=O)C.[Na+]>O.N1C=CC=CC=1>[CH3:18][N:19]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:20]1
Reactant: CNN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 80 °C
Yield: 94 %

Procedure:
545.0 Grams (2.43 moles) of dibenzoylmethane and 533 ml. of pyridine are stirred together and heated to 80° C. 112 Grams (2.43 moles) of methylhydrazine are then slowly added to the mixture and a strong exothermic reaction ensues necessitating cooling of the mixture with a water bath. When addition is complete, the mixture is heated to reflux and maintained in this condition for 40 minutes. The mixture is then cooled to 30° C., poured into 19 liters of 3N HCl, filtered, and the solid collected. This is reslurried in 198 grams (2.43 moles) of sodium acetate dissolved in 19 liters of water. The mixture is filtered, water washed and air dried to give 535 grams of product, 94.5% yield, having melting point 58° C. to 59° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]O)[CH3:2].N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:36]I>CC#N.CCOCC>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][I:36])[CH3:2]
Reactant: II
Reactant: CCc1ccccc1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CCc1ccccc1CCI
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
Into a 50-mL round-bottom flask was placed ether (10 mL), CH3CN (5 mL) and 2-(2-ethylphenyl)ethan-1-ol (900 mg, 5.99 mmol, 1.00 equiv). Then imidazole (570 mg, 8.38 mmol, 1.40 equiv), PPh3 (2.20 g, 8.39 mmol, 1.40 equiv) and I2 (1.98 g, 7.80 mmol, 1.30 equiv) were added at 0° C. The resulting solution was stirred for 6 h at room temperature. The reaction was then quenched by the addition of 10 mL of saturated Na2SO3 solution. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 1.16 g (74%) of 1-ethyl-2-(2-iodoethyl)benzene as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(Br)Br
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][O:10][CH2:11][C:12]1[O:17][CH2:16][CH2:15][CH2:14][CH:13]=1.[OH-:31].[Na+].OO>O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][O:10][CH2:11][C@H:12]1[C@H:13]([OH:31])[CH2:14][CH2:15][CH2:16][O:17]1
Reactant: C1=C(COCC(CCCCCCOC2CCCCO2)OC2CCCCO2)OCCC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1CCCO[C@H]1COCC(CCCCCCOC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1.46 ml of a 1M borane-tetrahydrofuran complex was added dropwise, whist ice-cooling, to a solution of 0.934 g of 6-[2,8-bis(tetrahydropyran-2-yloxy)octyloxymethyl]-3,4-dihydro-2H-pyran (prepared as described in Preparation 73) in 3 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 4.5 hours. At the end of this time, 0.80 ml of a 10% w/v aqueous solution of sodium hydroxide and 0.60 ml of a 30% v/v aqueous solution of hydrogen peroxide were added, in turn, to the mixture at 30° to 40° C., and then the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was then diluted with 50 ml of water and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give a residue, which was purified by column chromatography through 20 g of silica gel and by medium pressure liquid chromatography using a Lobar B column. 0.615 g of the title compound was obtained, as a colorless oil, from the fractions euted with a 7:3 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH:9]([OH:11])[CH2:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1.CCOC(C)=O>C(Cl)Cl>[CH:1]12[CH2:13][CH2:12][CH:8]([C:9](=[O:11])[CH2:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CC2CCC1c1ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CC2CCC1c1ccccc12
Yield: 88.5 %

Procedure:
To a solution of 5.6 g of tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-ol in 30 mL of DCM were added 110 mL of a 15% DMP solution in DCM. After stirring overnight 300 mL of EtOAc/Hept (1:1) were added, the obtained suspension was filtered over a pad of celite and the filtrated was concentrated in vacuo. The residue was treated again with EtOAc/Hept (1:1) and filtered over celite. This procedure was repeated twice to obtain 4.9 g of the desired compound as yellow oil.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:6]=2[O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([NH2:22])(=[S:21])[CH3:20]>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[C:2]3[S:21][C:19]([CH3:20])=[N:22][C:8]=3[C:7]=2[CH:10]=1
Reactant: O=C1c2cc(F)ccc2Oc2ccccc2C1Br
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)-c1ccccc1Oc1ccc(F)cc1-2
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 11-bromo-8-fluoro-11H-dibenzo[b,f]oxepin-10-one (2.34 mmoles) in dry N,N-dimethylformamide (12 ml), thioacetamide (2.8 mmoles) was added. The reaction mixture was heated under stirring at 90° C. for 3 hours. Then the solvent was evaporated under reduced pressure and the remaining oily product was dissolved in ethyl acetate and water. After extraction the organic layers were washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous sodium chloride solution. After purification by chromatography on a silica gel column, a crystalline product was isolated.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>>[NH2:10][CH:9]1[NH:1][CH:2]=[N:3][C:4]2[N:5]([CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[N:7][C:8]1=2
Reactant: C=CC(=O)OCC
Reactant: Nc1ncnc2nc[nH]c12
Product: CCOC(=O)CCn1cnc2c1N=CNC2N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
Adenine (10.00 g., 74.00 mmol) was placed into a clean, dry 500 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser, and a CaCl2 drying tube. Absolute ethanol (360 ml) was added and the solution was stirred. To the suspension was added a small piece of Sodium (approximately 75 mg). When the Sodium had completely reacted, 22.2 g (0.222 mol) ethyl acrylate was added to the suspension and the mixture was brought to reflux. Reflux was continued overnight for approximately 18 hours and the resulting lime colored homogeneous solution was allowed to cool slowly to room temperature. Crystals were allowed to form at 4° C. The solution was filtered by Buchner vacuum filtration and the solid was washed with anhydrous ether. Upon drying, 15.2 g (64.6 mmol) of 3-(1,6-dihydro-6-amino-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0026) was obtained. Yield: 87%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.Cl>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([C:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=2)[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 64 h
Yield: 29 %

Procedure:
A mixture consisting of 36.1 g (0.20 mol) of 3-tert-butyl-4-hydroxyanisol, 19.6 g (0.20 mol) of cyclohexanone and 10 ml of acetic acid is placed in a reactor and saturated, with stirring, with hydrochloric acid gas at room temperature. After standing for 64 hours at room temperature, the mixture is again saturated with hydrochloric acid gas and stirred for another 5 hours at 40° C. The reaction mixture is diluted with hexane and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system ethyl acetate/hexane=1:49, giving 15.1 g (29%) of 2-tert-butyl-6-cyclohexen-1-yl-4-methoxyphenol as a yellowish thick oil, 1H--NMR (CDCl3), δ(ppm): 3.75 (s, 3H, OCH3), 5.87 (m, 1H, cyclohexenyl--H), (compound (111), Table 1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH:25][C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OC)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 4-chloro-7.8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile (150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline (160 mg, 0.83 mmol) and pyridine hydrochloride (70 mg, 0.60 mmol) in 15 mL of 2-ethoxyethanol is heated at reflux for 25 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant bright orange solid is collected to provide 86 mg (38%) of 4-(2,4-dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 297° C. dec.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:39]=[CH:40][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][C:34]=1[CH3:37]
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1C
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1C

Procedure:
4-{4-[5-(3,4-Dimethyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3,4-dimethyl-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O3 [M+H]+: 431.2078. Found: 431.2078.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][N:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[N:4][CH:5]=2)=[N:13]1
Reactant: CC1(C)COC(c2ccc(Cl)nc2)=N1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Yield: 67 %

Procedure:
2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridine hydrochloride was transformed into its free base by dissolving 8.0 g (32 mmol) in saturated sodium bicarbonate solution and extracting the base into dichloromethane. The solvent was evaporated and the residue was dissolved in toluene. After addition of 11.35 g (113 mmol) N-methylpiperazine, the mixture was refluxed for 36 h. After cooling to room temperature water (50 ml) and ethyl acetate (150 ml) were added and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were extracted two times with 1 N hydrochloric acid, the acidic aqueous layer was made alkaline with 28% sodium hydroxide solution and extracted two times with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 6.0 g (67%) of a white crystalline compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([OH:15])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([O:15][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2c(c1)OCO2
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
410 mg (1.95 mmol) of 7-Hydroxy-benzo[1,3]dioxole-5-carboxylic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 410 mg (2.15 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 1.9 g (equivalent to 5.85 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.0 g (5.85 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H](CC1CC1)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](CC2CC2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.33 g) in dimethyl sulfoxide (20 mL) were added 3-cyclopropyl-L-alanine (1.00 g) and cesium carbonate (3.28 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 2.05 g, 100%).