Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15].Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C1COCC1.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl) amide (1.0 M solution in tetrahydrofuran, 542 mL, 0.542 mol) was added to a solution of 3,5-difluoroaniline (35 g, 0.271 mol) in THF (60 mL) at 0° C. Isopropyl chloroformate (1M solution in toluene, 406 mL, 0.406 mol) was then added dropwise at 0° C. and the mixture allowed to warm to room temperature over 2 h. The reaction mixture was diluted with ether and washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Solvent was removed under vacuum and the residue was triturated in hexanes to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17](Cl)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:26][C:27]1[O:28][C:29]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[N:30][N:31]=1>CO>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:29]1[O:28][C:27]([NH:26][C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)=[O:18])=[N:31][N:30]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
2-phenyl-4-quinolinecarbonyl chloride (2.00 g, 7.47 mmol) was added in small portions to a pyridine (40 mL) solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (1.69 g, 11.2 mmol), and the mixture was heated with stirring at 60° C. for 6 hours. To the reaction solution, methanol was added, and the solvent was distilled off. The obtained residue was triturated by the addition of water. The deposited crystal was collected by filtration, washed with methanol and then with ethyl acetate, and then recrystallized from DMF-methanol to obtain the title compound (1.23 g, 3.22 mmol) as a light brown powder (yield: 43%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1>>[CH3:27][O:26][C:24]([C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1)=[O:25]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: COC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 58 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (280 mg, 1.0 mmol) was converted, using methyl 2-aminopyridine-4-carboxylate instead of 2-aminopyridine, to the title compound (194 mg, 58%) which was obtained as a yellow foam. MS: m/e=334.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][S:13][CH2:12]1.[H][H].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1.[Ni].C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][S:13][CH2:12]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCSC2)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(N2CCSC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
The 3-(2-fluoro-4-nitrophenyl)thiazolidine (1.485 g, 6.513 mmol) was dissolved in tetrahydrofuran (25 mL) and water (5 mL) and then shaken under 40 psi of hydrogen in the presence of Raney nickel (500 mg) for 5 hours. After this time, the mixture was filtered over diatomaceous earth. The filter pad was washed with methanol and the filtrate was concentrated to an aqueous layer. Water (15 mL) and acetone (25 mL) were added to the aqueous mixture and the mixture was cooled in an ice bath. Solid sodium bicarbonate (2.728 g, 32.47 mmol) was added followed by benzyl chloroformate (3.0 mL, 21.01 mmol). The mixture was allowed to warm to room temperature and stirred over 3 nights. Ethyl acetate was added to the mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to provide 3.925 g crude material as a dark oil. The crude was chromatographed on a silica gel column (27 cm×4.5 cm, 40-63 μ), eluting with 500 mL 40% hexane/methylene chloride, 1L 20% hexane/methylene chloride, 500 mL 10% hexane/methylene chloride, 500 mL methylene chloride and 500 mL 3% methanol/methylene chloride to provide 480 mg of the title compound as yellow solids and 950 mg of the title compound contaminated with benzyl alcohol. In order to remove the benzyl alcohol contaminate, the contaminated material was treated with triethyl amine (0.6 mL, 4.31 mmol), butyric anhydride (0.45 mL, 2.86 mmol) and a small amount of 4-dimethylamino pyridine at 0° C. After 35 minutes the mixture was concentrated and chromatographed on a silica gel column (23.5 cm×2.5 cm, 40-63 μ), eluting with 250 mL 10% ethyl acetate/hexane and 500 mL 15% ethyl acetate/hexane to provide 700 mg of the title compound as light yellow solids. In all, 1.180 g (59%) of the title compound was obtained. Recrystallization from ethyl ether/hexane provided an analytical sample with a melting point of 90°-92° C.
Reaction SMILES: [CH2:1]([CH2:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[C:11]([NH:10][C:8](=[S:9])[CH2:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: NC(=S)CCc1ccco1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(=S)CCc1ccco1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
8.56 g (0.05 mol) of 2-furfurylthioacetamide, 5.61 g (0.055 mol) of acetic anhydride, and 6.11 g (0.05 mol) of N,N-dimethyl-aminopyridine were dissolved in 50 ml of pyridine. The mixture was stirred at 80° C. for 16 hours. The solvent was distilled away from the reaction mixture, and the residue thus obtained was added to ethyl acetate and washed successively with water, 1N hydrochloric acid, water three times, and brine. A resultant organic extract layer was dried, and the solvent was distilled away therefrom, so that N-acetyl-2-furfurylthioacetamide was obtained in a yield of 7.11 g (60%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>CN(C)C=O>[Br:1][C:2]1[N:10]([CH2:23][O:22][CH2:20][CH3:21])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (7.06 g, 28.8 mmol) and potassium carbonate (3.98 g, 28.8 mmol) in dimethylformamide (DMF) (150 ml) was added chloromethyl ethyl ether (2.72 g, 28.8 mmol). After stirring overnight at room temperature, the reaction mixture was poured into ice-cold water (650 ml). After stirring at 0-5° C. for 1 hour, the solid was filtered, washed with water (3×15 ml) and dried under vacuum to provide 8-bromo-7-ethoxymethyl-3-methylxanthine (6.15 g, 70% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][OH:30]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: COCCCO
Product: COCCCOc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 9 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro cyclohexyl methyl)-amide and 3-methoxy-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.79-8.82 (m, 1H), 7.95 (d, J=9.11 Hz, 1H), 7.79 (d, J=9.01 Hz, 1H), 7.70 (d, J=9.01 Hz, 1H), 7.12 (d, J=9.12 Hz, 1H), 4.45 (t, J=13.2 Hz, 2H), 3.49 (t, J=12.61 Hz, 2H), 3.25 (s, 5H), 1.97-2.04 (m, 4H), 1.80-1.86 (m, 3H), 1.73-1.76 (m, 2H), 1.23-1.32 (m, 2H). m/z: 427.0 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>N1C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[C:12]([CH3:11])=[N:13][O:14][C:15]=4[CH3:29])=[CH:24][CH:23]=3)(=[O:26])=[O:27])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cnc(C2CC2)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2cnc(C3CC3)nc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of 2-cyclopropylpyrimidin-5-amine (50 mg, 0.370 mmol) in pyridine (1 mL) stirred in air at room temperature was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (123 mg, 0.407 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, to ensure dissolution and then left to stand overnight. The solvent was evaporated in vacuo to give the crude product which was purified by mass directed autoprep (formic acid modifier) to give the title product (74.5 mg). LCMS (2 min, formic) Rt 0.94 min, m/z (ES+) 401 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.S(OCC)(O[CH2:27][CH3:28])(=O)=O.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:27][CH3:28])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(CC)CCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 1 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate and 2.37 g. of diethyl sulfate is stirred at 130° C. for 3 hours. The mixture is then diluted with 10 ml. of dichloromethane and 10 ml. of water and adjusted to pH 11 with 10N sodium hydroxide. The dichloromethane layer is drawn off and saved. The aqueous layer is extracted with two 10 ml. portions of dichloromethane. The organic layers are combined, washed with 10 ml. of water, dried over anhydrous magnesium sulfate and evaported to an oil. This oil is chromatographed on a silica gel column, eluting with chloroform:hexane (1:3) giving a colorless liquid which is distilled, giving the desired product as a liquid, boiling point 160° C. (14 mm.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)(C)(C)C.C(Cl)[Cl:22]>CO>[ClH:22].[ClH:22].[N:15]1([C:14]2[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1-n1cncn1
Reactant: ClCCl
Solvent: CO
Product: Cl
Product: NCc1ncccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Through a solution of (3-[1,2,4]Triazol-1-yl-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (4.08 g) in CH2Cl2 (100 ml) and MeOH (20 ml) cooled to 0° C. is bubbled HCl (g) for 10 min. The flask is sealed and the reaction mixture is stirred at room temperature for 18 h. Nitrogen is bubbled through the reaction mixture for 5 min and the reaction mixture is concentrated to give C-(3-[1,2,4]Triazol-1-yl-pyridin-2-yl)-methylamine di hydrochloride as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.67 (s, 1H); 8.85 (d, J=5.3 Hz, 1 H); 8.72 (s, 1H); 8.18 (d, J=8 Hz, 1 H); 7.7 (dd, J=5.3, 8 Hz, 1 H); 4.45 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1(OCC)[CH:7]=[CH:6][C:5](O)=[CH:4][CH2:3]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:30]1CC[CH2:32][CH2:31]1>O>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:30][CH2:31][CH2:32][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CCOC1(Br)C=CC(O)=CC1
Reactant: C1=COCCC1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Brc1ccc(CCOC2CCCCO2)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
A mixture of 15.67 g of 4-bromophenetyl alcohol, 6.88 g of 3,4-dihydro-2H-pyran, a catalytic amount of p-toluenesulfonic acid monohydrate, and 100 ml of tetrahydrofuran was stirred. at room temperature for 24 hours. The reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, which afforded 21.5 g (yield, 97%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene, m.p., 93.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13](Cl)=[O:14])=[CH:7][CH:6]=1.CS.N1C=CC=CC=1.CC[O:39]CC>O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13]([OH:39])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOCC
Reactant: COC(=CC(=O)Cl)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: CS
Solvent: O
Solvent: c1ccncc1
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoyl chloride (10 mm.) and ether (10 ml.) is added methyl mercaptan (12 mm.) and pyridine (1 ml.) at about -20°. The mixture is stirred for about 30 minutes and then allowed to rise to about 0° and stand for about 2 hours. The mixture is then diluted with ether and water and the ether phase separated, washed, dried and solvent removed to give the methylthiol ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C(OCC)C>CN(C)C=O.C1CCCCC1>[C:1]([O:5][C:6](=[O:15])[CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
29.3 mmol (6.56 mL) of malonic acid di-tert-butyl ester and 29.3 mmol (1.28 g) of sodium hydride in mineral oil (55% (w/w)) were reacted in 120 mL of anhydrous dimethylformamide for 50 min at room temperature according to general procedure B2. 45.4 mmol (23.0 g) of 4′ were added to the mixture and the reaction mixture was stirred for 1 h at 75° C. bath temperature and at room temperature o/n. Additional 16.2 mmol (708 mg) of sodium hydride in mineral oil (55% (w/w)) were added and the reaction mixture was further stirred at room temperature for 7 h. The work-up was performed as described (general procedure B) with diethyl ether. Column chromatography (cyclohexane→cyclohexane/acetone 9:1) gave 5c′ with 67% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:22])[S:12][C:13]=2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:22][C:11]1[S:12][C:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:29]
Reactant: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CCc2ccccc2)cc1
Yield: 76.4 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-phenylethyl-thiazol-2-ylamine prepared in Example 57 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 76.4%, mp: 74-75 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.02 (2H, t, J=7.60 Hz, CH2), 3.19 (2H, t, J=7.60 Hz, CH2), 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.96 (3H, s, OCH3), 9.85˜7.95 (3H, m, ArH), 7.15˜7.37 (7H, m, ArH), 7.51 (2H, s, ArH), 10.48 (1H, br, CONH); EI-MS m/e (%): 474.1 (M+, 21), 383.0 (58), 165.0 (100); HREI-MS Calcd. for C27H26N2O4S: 474.1613. found: 474.1613.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](F)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2CN)[CH:33]=[CH:34][CH:35]=1.O>CC(N(C)C)=O>[O:18]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[N:2]([CH2:19][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:45])[F:44])[CH:31]=2)[CH:3]=[C:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NCc1ccccc1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2-c2cccc(C(F)(F)F)c2)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a brown solution of (Z)-ethyl 3-(dimethylamino)-2-(3-fluoropicolinoyl)acrylate (31) (200 mg, 0.751 mmol) in DMA (dimethylacetamide) (8 mL) in a 20 mL vial were added a solid powder of tribasic potassium phosphate (399 mg, 1.88 mmol) and (3′-(trifluoromethyl)biphenyl-2-yl)methanamine (208 mg, 0.826 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL), but no solids precipitated. Then, the organic compound was extracted with dichloromethane and the combined extracts were washed with water and brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude brown oil which was purified using ISCO (120 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 4-oxo-1-((3′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (32) (126 mg, 37% yield) as a light brown solid.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[C:17]3[CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19][CH2:18]3)[C:5]=2[CH:4]=1)#N.C[Mg]Br.Cl.[CH3:31][CH2:32][O:33]CC>C1C=CC=CC=1>[C:32]([C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[C:17]3[CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19][CH2:18]3)[C:5]=2[CH:4]=1)(=[O:33])[CH3:31]
Reactant: CCOCC
Reactant: N#Cc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Agent: C[Mg]Br
Agent: Cl
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Temperature: 10 °C

Procedure:
A solution of 3.42 g. (0.01 mole) of 3-(2-cyanothioxanthen-9-ylidene)quinolizidine in 50 ml. of benzene is added to a stirred solution of 0.013 mole of methyl magnesium bromide in 5 ml. of ether and 50 ml. of benzene. The stirred mixture is heated at reflux temperature for two hours, then it is cooled to 10° C. and added slowly to 250 ml. of vigorously stirred ice-water. Excess 3 N hydrochloric acid is added to the stirred mixture. The aqueous layer is separated and then it is made alkaline with 2.5 N sodium hydroxide. The mixture is extracted with ethyl acetate. After being dried over magnesium sulfate, the extracts are concentrated. The residue is chromatographed on an alumina column using ether as the eluate. Evaporation of the appropriate fractional eluant gives 3-(2-acetylthioxanthen-9-ylidene)quinolizidine which is converted to a fumarate salt by treatment with a molar equivalent of fumaric acid in methanol.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[O:3]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[NH:35][N:36]=[CH:37][C:30]=12.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH:35]1[C:31]2=[N:32][CH:33]=[N:34][C:29]([NH:20][CH:18]([C:4]3[O:3][C:2](=[O:1])[C:11]4[C:6]([C:5]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:19])=[C:30]2[CH:37]=[N:36]1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2[nH]ncc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 55.6 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Intermediate E1, 141 mg, 0.136 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (42.0 mg, 0.272 mmol) and DIEA (95 μL, 0.543 mmol) were stirred at 80° C. for 3 hrs in tert-butanol (800 μL). The reaction was quenched by the addition of 1 mL of 1M HClaqueous and the resulting crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (29 mg, 56%).