Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3cccs3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3cccs3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the resulting crystals were recrystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(2-thienyl)-1(2H)-isoquinolinone hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18]C(O)=O)([C:15]([OH:17])=[O:16])=[O:14].[OH-].[K+].Cl>>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:18][C:13](=[O:14])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: O=C(O)CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
Phenyl pyruvic acid (5.0 g, 30.5 mmol) and 12.1 g (91.4 mmol) of oxaloacetic acid were added to 25 mL of aqueous solution in which 13.8 g of potassium hydroxide (purity 85%) had been dissolved, and reacted at room temperature for 72 hours. A pH value of the reaction mixture was adjusted to 2.2 using concentrated hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. An organic layer was washed with saturated aqueous NaCl solution, dried on magnesium sulfate anhydrate, and then concentrated to yield residue. The residue was recrystallized from ethyl acetate and toluene to yield 2.8 g (11.3 mmol) of 4-phenylmethyl-4-hydroxy-2-ketoglutaric acid as crystal.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:23]1([C:29]2[N:30]=[C:31]([NH2:34])[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1nc(-c2ccccc2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-phenylthiazol-2-amine (43 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-phenylthiazol-2-yl)benzamide as a white solid. Yield: 43 mg, (37%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H), 7.78-7.73 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.47-7.42 (t, J=7.5 Hz, 2H), 7.36-7.32 (m, 1H), 7.24-7.08 (m, 3H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.C(O)COCCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: OCCOCCO
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 84.6 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of diethylene glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.8 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](OC)=[O:8])[C@H:4]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccsc2)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl (+−)-trans-4-methylene-2-(3-thienyl)cyclopentanoate (6.0 g, 27 mmol) prepared as in Step B in THF (70 mL) under nitrogen and cooled to −10° C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) in THF (54 mL). After 1 h, the bath was removed and the reaction was stirred at rt for 3 h. The reaction was cooled in an ice/methanol bath and the excess LAH was quenched by dropwise addition of water/1N potassium hydroxide/water and the salts were removed by filtration through celite. The filtrate was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated to afford the crude title product (4.09 g).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29]Br)[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1.C(OCC)(=O)C>C(O)C>[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29][NH:2][CH3:1])[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CN
Reactant: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Temperature: 25 °C

Procedure:
Methylamine (2 ml of a 33% solution in ethanol) was added to a stirred suspension of N-(3-trifluoromethylphenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.5 g) in ethanol. Stirring was maintained at room temperature for 1 hour. The solution was diluted (ethyl acetate), washed (water), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with methanol/hexane to give N-(3-trifluoromethylphenyl)-2-(2,3-dihydro-6-methylaminomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 105, 0.21 g) as an orange gum, NMR (CDCl3)δ 1.6(s,6H), 2.25(s,3H), 3.25(s,2H), 5.3(s,2H), 7.1-7.3(m,8H), 7.55(m,1H), 7.75(s,1H), 8.45(s,1H);
Reaction SMILES: [CH3:1][C:2]1([CH2:17][CH2:18][O:19]C2CCCCO2)[C:14](=[O:15])[N:5]2[CH2:6][CH:7]=[CH:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:4]2[C:3]1=[O:16]>Cl.CO>[OH:19][CH2:18][CH2:17][C:2]1([CH3:1])[C:14](=[O:15])[N:5]2[CH2:6][CH:7]=[CH:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:4]2[C:3]1=[O:16]
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCOC3CCCCO3)C(=O)N12
Agent: Cl
Solvent: CO
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCO)C(=O)N12
Yield: 96.9 %

Procedure:
A solution of 3.52 g (0.01 mol) of methyl 2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-2[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in 50 ml of 1M hydrochloric acid and 50 ml of methanol was stirred at room temperature for 1.5 hours. The solvent was removed by evaporation in vacuo. The solid residue was taken up in dichloromethane, dried over magnesium sulfate and evaporated to give 2.6 g (97%) of methyl 2,3,5,8-tetrahydro-2-(2-hydroxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 97°-99° C. (from diethyl ether).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]4[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:43]=[CH:42][C:33]2[O:34][C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=3[C:32]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:41][C:38]1[CH:39]=[CH:40][C:35]2[O:34][C:33]3[CH:42]=[CH:43][C:30]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[C:16]6[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=6[C:22]6[C:27]5=[CH:26][CH:25]=[CH:24][CH:23]=6)=[CH:13][CH:14]=4)=[CH:31][C:32]=3[C:36]=2[CH:37]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: CC1(C)OB(c2ccc(-n3c4ccccc4c4ccccc43)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)cc3c2c1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 70.5 %

Procedure:
A mixture of Compound 11 (2.00 g, 4.56 mmol), 2,8-dibromodibenzo[b,d]furan (2.60 g, 7.98 mmol), tetrakis(triphenylphosphine) palladium(0) (0.26 g, 0.23 mmol), potassium carbonate (1.892 g, 13.70 mmol), 1,4-dioxane (60.00 mL), and water (12.00 mL) was degassed with bubbling argon for 1 hour. The reaction mixture was then heated to 80° C. and was stirred overnight (16.5 hours), maintaining an argon atmosphere. Consumption of the starting material was confirmed by thin-layer chromatography and the reaction was cooled to room temperature. The product was extracted with dichloromethane, dried, and purified by silica gel column chromatography with dichloromethane in hexanes as the eluent. The product fractions were then dried and the product was collected to yield Compound 13 (1.57 g, 70%). Confirmed by LCMS (APCI): calculated for C30H18BrNO (M+H): 488. Found: 488.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1>O>[CH2:1]([O:8][C:11]1[N:16]=[C:15]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(Cl)nc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: CCc1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of benzyl alcohol (80 ml) in water bath, was added sodium metal (2.17 g, 94.6 mmol) under nitrogen atmosphere. After complete reaction of sodium metal, the mixture was cooled in an ice bath and 2,4,6-Trichloro-5-ethyl-pyrimidine (10.5 g, 49.6 mmol) was added portionwise. After stirring for 30 min in an ice bath, the reaction mixture was stirred at room temperature for overnight. Excess benzyl alcohol was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (4:96)) to give 14 g (80%) of a white solid; m.p. 53-54° C.; 1H NMR (200 MHz, CDCl3) δ: 1.14 (3H, t, J=7.4 Hz), 2.70 (2H, q, J=7.4 Hz), 5.41 (2H, s), 5.45 (2H, s), 7.34-7.53 (10H, m); m/z (EI): 354 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[CH2:13]/[CH:14]=[CH:15]/[Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:25]([Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])/[CH:15]=[CH:14]/[CH2:13][O:10][CH2:9][CH:7]1[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]1)[CH2:26][CH2:27][CH3:28]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](/C=C/COCC1COC(C)(C)O1)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Sodium hydride (215 mg) was added to a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (644 mg) in dry DMF (25 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (1.00 g) was added to the reaction mixture after 10 min. The reaction mixture was stirred for 20 h at 20° C. and then quenched with saturated NH4Cl (aq.). Extraction with EtOAc and drying (Na2SO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:22])[CH3:21]
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12
Reaction time: 16 h

Procedure:
A solution of 25.5 g (0.1 mole) of the title compound of Example 1 and 11 ml (ca. 0.11 mole) of acetic anhydride in 150 ml of pyridine was allowed to stand for about 16 hours at room temperature. Approximately half of the solution was separated and concentrated in vacuo to dryness and chromatographed on silica gel, giving the title compound, m.p. 181°-182°.
Reaction SMILES: IC.[C:3]([O:7][C:8](=[O:17])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:18](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:3]([O:7][C:8](=[O:17])[N:9]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)[CH3:18])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 18 h

Procedure:
0.263 mL (1.1 eq.) iodomethane are added dropwise at room temperature to a stirred suspension of 1.1 g (4 mmol) (4-bromo-phenyl)-carbamic acid tert-butyl ester and 2 g (1.6 eq.) cesium carbonate in 15 mL DMF. After stirring for an additional 18 hours, the reaction mixture is extracted with water/ethyl acetate and the combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to yield the desired product as a colorless oil, which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].Br.C(S[C:39]([C:41]1[CH:45]=[CH:44][O:43][CH:42]=1)=[NH:40])C1C=CC=CC=1>>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([C:41]3[CH:45]=[CH:44][O:43][CH:42]=3)=[NH:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: N=C(SCc1ccccc1)c1ccoc1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Agent: Br
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4ccoc4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (108 mg, 0.273 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Furan-3-carboximidothioic acid benzyl ester hydrobromide 9d (171 mg, 0.574 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 20 hours. The solvent was evaporated and the residue partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 11. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow oil 14 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]imidazol-5-yl)furan-3-carboximidamide. Yield: 62.8 mg (50.0%) 1H NMR (DMSO) δ; 0.83 (t, 6H, J=7.0), 1.29 (t, 3H, J=7.0), 2.37-2.50 (2×m, 6H), 3.99 (q, 2H, J=6.9), 4.10 (t, 2H, J=6.8), 4.21 (s, 2H), 5.98-6.09 (br, 1-2H), 6.71 (d, 1H, J=9.6), 6.86 (d, 2H, J=8.7), 6.88-6.92 (m, 1H), 6.96 (br, 1H), 7.18 (d, 2H, J=8.5), 7.33 (d, 1H, J=8.5), 7.68-7.73 (m, 1H), 8.23 (s, 1H). MS (ESI): 460 (MH+, 95%)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.C(N(CC)CC)C.[C:22]([C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])#[N:23]>C(Cl)Cl.O1CCCC1.C(OCC)C>[C:27]([C:26]1[CH:35]=[CH:36][C:37]([NH:38][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:24]([C:22]#[N:23])[CH:25]=1)(=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N#Cc1cc(C(=O)c2ccccc2)ccc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1C#N)C(F)(F)F
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a stirred, cooled solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.15 g) in methylene chloride (10 mL) was added thionyl chloride (0.12 g) and the mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature, triethylamine (0.11 g) added and the mixture stirred at reflux for 0.5 hour. The mixture was again cooled to room temperature, 3-cyano-4-aminobenzophenone (0.19 g) in tetrahydrofuran (2.5 mL) was added and the mixture stirred at reflux overnight. The solvent was evaporated and the residue partioned between ethyl acetate and 3N HCl. The organic layer was washed with water, dried and evaporated to yield a pale yellow oil. Chromatography (eluent methylene chloride then 2% ethyl ether in methylene chloride) gave the title compound (0.11 g) as a white solid; mp 202-204° C. Analysis for C18H13F3N2Ob .0.5 H2O: Calculated: C, 58.22; H, 3.80; N, 7,54; Found: C, 58.03; H, 3.57; N, 7.26.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=[O:28])[CH:23]=1>C(#N)C>[CH3:19][N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=2)[CH:17]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([N:24]3[CH:23]=[CH:22][N:26]=[CH:25]3)=[O:28])[CH:3]=[CH:4][C:5]=2[CH3:21])[C:9]1=[O:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Solvent: CC#N
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)n3ccnc3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (22 mg, 0.08 mmol) in ACN (0.5 mL) was added CDI (16 mg, 0.09 mmol). After stirring at rt for 2 h, solvent was removed and the crude N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-1H-imidazole-1-carboxamide 18 was used without further purification. MS m/z 374.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: CN1CCN(CCCO)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(C)CC1
Yield: 27.8 %

Procedure:
Using an analogous procedure to that described in Example 16, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (0.14 g, 0.9 mmol) to give 4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)cinnoline (80 mg, 28%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 500 ml flask was added 2000 mg of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E, 50 ml of DMF, 1.4 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 953 μl of tert-butyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 800 ml EtAc, 2×200 ml of saturated brine, and 2×200 ml of water. (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 50% EtAc in Hexane) to give 1.8 g of 17.8.A as a white solid.
Reaction SMILES: [NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([O:25]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCCO)C.[NH3:34]>>[NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([NH2:34])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Solvent: CCOCCO
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of Example 64 (129 mg), 2-ethoxyethanol and liquid ammonia was placed in a sealed pressure vessel and heated at 80° C. and 400 p.s.i. for 24 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica, 50% to 100% EtOAc in hexane) to give the title compound (20 mg). δH (CDCl3) 8.75 (1H, brs), 7.36-7.34 (2H, m), 7.16-7.11 (2H, m), 7.03 (1H, d, J 9.7 Hz), 6.99-6.88 (4H, m), 6.17 (1H, d, J 9.7 Hz), 5.47 (2H, br s). LCMS (ES+) RT 2.927 minutes, 368 (M+H)+