Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[C:10]([CH3:19])([CH3:18])[C:9]2=[O:20])[CH:7]=1.[F-].[Cs+].[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29](B(O)O)=[CH:28][CH:27]=1>ClCCl.O>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:2]2[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]3[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[C:11](=[O:17])[C:10]([CH3:19])([CH3:18])[C:9]3=[O:20])[CH:7]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(Cl)ccc1B(O)O
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)nc2C)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 6-(5-bromo-2-ethylphenyl)-2,2,4,4-tetramethylcyclohexane-1,3,5-trione (0.19 g, 0.5 mmol), cesium fluoride (0.24 g, 1.6 mmol), 6-chloro-2-methylpyridin-3-ylboronic acid (0.13 g, 0.8 mmol) and degassed 1,2-dimethoxyethane (1.7 ml) is stirred under nitrogen at room temperature for 30 minutes. [1,1′-Bis-(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.034 g, 0.042 mmol) is added and the mixture is stirred at room temperature for 10 minutes and then heated at 80° C. overnight. After cooling to room temperature the reaction mixture is diluted with dichloromethane (5 ml) and water and filtered through diatomaceous earth. The filtrate is acidified with 2M aqueous hydrochloric acid, and the organic phase is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (approximately 1 ml) and purified by preparative reverse phase HPLC to afford 6-[5-(6-chloro-2-methylpyridin-3-yl)-2-ethylphenyl]-2,2,4,4-tetramethylcyclohexane-1,3,5-trione as a pale brown solid (75.3 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[N:36]=[CH:35]2>CC(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[N:36]=[CH:35]2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 95 °C
Yield: 58.8 %

Procedure:
A mixture of 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate (3.14 g, 7.42 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.85 g, 7.93 mmol) in IPA (180 mL) was heated at 95° C. for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (SiO2, CH2Cl2/MeOH) to give the desired compound tert-butyl 5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.70 g, 4.36 mmol, 59%). MS 620.4 (M+1). HPLC retention time 8.10 mins (5-95-13 method).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].O.O.[Sn](Cl)Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of 5-(4-chloro-3-(trifluoromethyl)phenoxy)-2-nitropyridine (8 g, 25.1 mmol) in ethanol (100 mL) was added tin (II) chloride dihydrate (56.7 g, 251 mmol). The reaction mixture was stirred at 80° C. for 2 hr. and poured into 500 mL of H2O and adjusted to basic with 10% NaHCO3. Then, the reaction mixture was extracted with 500 mL of EtOAc. The organic layer was separated, and then dried over Na2SO4, and concentrated under reduced pressure to give 5-(4-chloro-3-(trifluoromethyl)-phenoxy)pyridin-2-amine (6 g, 72.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:24]=[CH:23]1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]2[N:24]=[CH:23][N:22]([C:2]3[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:7]=3)[CH:26]=2)[CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1cncc(-c2c[nH]cn2)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available 3-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-85-1] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.11 g, 49%). MS (ISP) 436.1 [(M)+]; mp 200.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(#N)C>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: NC(=O)C(c1ccc(-c2ccc(F)cc2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 64.4 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.341 mmol) in dry 1,4-dioxane (1.5 mL) was treated with (4-fluorophenyl)boronic acid (0.375 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol) and 2M aq potassium carbonate (1.022 mmol). The solution was degassed with a stream of nitrogen for three minutes, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with ethyl acetate. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) and by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v aq ammonium hydroxide. This mixture was concentrated to a minimal volume in vacuo and was then extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization of the product from water (w/25% acetonitrile) afforded the title compound as a white solid (100 mg, 61% yield). MS(ES)+m/e 456.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C)C=O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: Cc1c(Cl)nn2ccnc2c1C
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ccnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
0.59 g of 60% oily sodium hydride was suspended in 21 ml of dimethylformamide. To this suspension, 1.18 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 1 hour. To this mixture was added 1.28 g of 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine, followed by stirring at 60° C. for 40 minutes. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid andthen extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The fraction containing the desired product was concentrated and recrystallized from ethanol to yield 0.866 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][C:20](=[O:22])[NH:21][C:14]=23)=[CH:4][CH:3]=1.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[C:24]=[O:25]>>[O:22]=[C:20]1[NH:19][C:15]2=[N:16][CH:17]=[CH:18][C:13]([O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([NH:1][C:24]([NH:23][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)=[O:25])=[CH:3][CH:4]=3)=[C:14]2[NH:21]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Yield: 64.7 %

Procedure:
Method H2 was used with 7-(4-aminonaphthalen-1-yl-oxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (30 mg, 0.10 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (21 mg, 0.11 mmol) to afford the title compound as a brown solid (31 mg, 65%). 1H-NMR (δ, ppm, DMSO-d6): 6.21 (d, 1H, HPy,5, J=5.5 Hz), 7.32 (m, 2H, Harom,Naph), 7.53-7.71 (m, 5H, Harom,naph+Ph′), 7.96 (t, 2H, Harom,naph), 8.09 (s, 1H, Harom,Ph), 8.19 (d, 1H, HPy,6, J=5.5 Hz), 8.96 and 9.46 (bs, 2H, NHurea) 11.39 (s, NH, NHPy), 11.44 (s, NH, NHPy). LC-MS (m/z): 480 (M+H, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH3:22])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 185 °C
Reaction time: 6 h
Yield: 6.1 %

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 10.0 g (0.054 mol) of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 185° C. for one hour then at 135°-140° C. for sixteen hours and finally at 195° C. for six hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 350°-354° C. after recrystallization from pyridine.
Reaction SMILES: C(OC([N:8]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH:35]3[CH2:37][CH2:36]3)[CH:33]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2([CH2:27][CH3:28])[CH2:26][CH2:25]2)[C:9]1=[O:38])=O)(C)(C)C>Cl>[CH:35]1([C:32]2[CH:33]=[C:34]3[NH:8][C:9](=[O:38])[C:10]4([CH:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=5)[CH2:14][C:13](=[O:23])[NH:12][CH:11]4[C:24]4([CH2:27][CH3:28])[CH2:25][CH2:26]4)[C:29]3=[CH:30][CH:31]=2)[CH2:36][CH2:37]1
Reactant: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)N(C(=O)OC(C)(C)C)c2cc(C4CC4)ccc23)CC1
Agent: Cl
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(C4CC4)ccc23)CC1
Reaction time: 0.17 h

Procedure:
Racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (10 mg, 0.019 mmol) was dissolved in a methanolic solution of HCl (6 M, 10 mL). After 10 min, the solution was concentrated to obtain racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield, 5.9 mg, 72%)
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:13][N:14]([CH3:40])[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][C:25]2[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][C:28]=3[NH:27][CH:26]=2)(O)[CH2:17][CH2:16]1>ClCCl>[CH3:13][N:14]([CH3:40])[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:20][CH2:19][C:18]2([C:26]3[NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[C:25]=3[CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(CCCc3c2[nH]c2ccncc32)CC1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
Trifluoromethane sulphonic acid trimethylsilyl ester (409 mg, 334 μL, 1.84 mmol) was added to a solution of 4-dimethylamino-4-phenyl-1-[3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propyl]-cyclohexanol (172 mg, 0.39 mmol) in anhydrous dichloromethane (30 mL) and stirred for 10 d at room temperature. The reaction mixture was then diluted with dichloromethane (10 mL), firstly washed with 1 N sodium carbonate solution (2×10 mL) and then with water and saturated sodium chloride solution (10 mL each), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (131 mg) was taken up in methanol (15 mL) and stirred overnight at room temperature and then concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(O)=[O:2].S(Cl)(Cl)=O.[NH:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]([OH:30])=[O:29])[CH:23]1[C:31]([OH:33])=[O:32].[OH-].[Na+].Cl>C1C=CC=CC=1.O1CCOCC1>[CH:5]1[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][C:4]=1[C:1]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([OH:30])=[O:29])[C@@H:23]1[C:31]([OH:33])=[O:32])=[O:2]
Reactant: O=C(O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=C(O)C1NCCNC1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=C(O)[C@H]1NCCN(C(=O)c2ccc3c(ccc4ccccc43)c2)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 11.3 %

Procedure:
2-Carboxyphenanthrene (2 g, 0.009 mol) was suspended in dry benzene (50 ml) and heated under reflux in the presence of thionyl chloride (5 ml) for 5 hr. The solvent was removed and the corresponding acid chloride was used without further purification. Piperazine-2,3-dicarboxylic acid (0.508 g, 0.003 mol) was dissolved in a 0.991 M aqueous sodium hydroxide solution (9.4 ml, 0.009 mol), dioxane (10 ml) was added and the solution was cooled to 0° C. A solution of the acid chloride (0.84 g, 0.0035 mol) in dioxane (10 ml) was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 2-3 hr. The reaction mixture was acidified to pH 2-3 with aqueous HCl. The solid was filtered, dissolved in dioxane/ H2O (50:50) and bound to an ion exchange resin (Dowex-AG50 H+ form) chromatography column. It was eluted with dioxane/H2O (50:50) until organic impurities are removed. The column was eluted with 10% aqueous pyridine and the ninhydrin fractions were combined. The solvent was removed and the solid was crystallised from H2O to give a white solid (0.128 g, 12%). m.p.=218.1-221.7 ° C. (dec.); 1H NMR (300 MHz, NaOD/ D2O) 7.7-8.8 (m, 9H, Ar), 5.6 (d, 0.5H, CH—CO2H, JAB=2.6Hz), 4.8 (d, 0.5H, CH—CO2H, JAB=2.6Hz), 4.4 (d, 0.4H, CH—CO2H, JAB=12.0Hz), 3.6 (d, 0.4H, CH—CO2H, JAB=12.0Hz), 2.5-3.8 (m, 4H, N—CH2CH2—NH); Elemental analysis calculated for C21,H18N2O5. 2.3H2O C:60.07, H:5.44, N:6.67. Found C:60.06, H:5.38, N: 6.85. The cis-isomerism was confirmed by COSEY 1H NMR.
Reaction SMILES: C(NC1C(C)=CC(OC)=CC=1C(N)=O)(=O)C1C=CC=CC=1.NC1C(C)=CC(OC)=CC=1C(N)=O.[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][C:57]([OH:59])=O)[CH:52]=3)[N:47]=[C:46]([C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[N:45]=2)[CH:39]=[CH:40][C:41]=1[F:42].[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>>[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][C:57]([N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:59])[CH:52]=3)[N:47]=[C:46]([C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[N:45]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: C1COCCN1
Reactant: O=C(O)CCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: COc1cc(C)c(N)c(C(N)=O)c1
Agent: COc1cc(C)c(NC(=O)c2ccccc2)c(C(N)=O)c1
Product: O=C(CCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1)N1CCOCC1
Yield: 40 %

Procedure:
4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl) quinazolin-6-yl)-1-morpholinobutan-1-one was prepared in a manner analogous to that described for 2-benzamido-5-methoxy-3-methylbenzamide in Method D, replacing nicotinic acid and 2-amino-5-methoxy-3-methylbenzamide with 4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl) butanoic acid and morpholine to give 32 mg of xxxv-a in a 40% yield as a beige solid. LCMS m/z=506.2, 508.1 (M+1) (Method 1) (retention time=1.85 min). 1H NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.52 (d, J=1.6 Hz, 1H), 8.69-8.65 (m, 2H), 8.39-8.38 (m, 1H), 8.27 (dd, J=6.8, 2.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.86-7.84 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.52 (m, 2H), 3.56-3.53 (m, 4H), 3.46-3.41 (m, 4H), 2.85 (t, J=8.0 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.6 Hz, 2H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>ClCCl.CN(C)C=O>[C:21]([S:23][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: Cn1nnc(CO)n1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)SCc1nnn(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 mmol) in dry dichloromethane (25 mL) at 0° C. was added methanesulfonyl chloride (1.47 g, 12.9 mmol) followed by triethylamine (1.30 g, 12.9 mmol) added dropwise over five min. The mixture was stirred at 0° C. for 1 h, and then treated with a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry N,N-dimethylformamide (10 mL). The resulting gel was stirred at 0° C. for 3 h. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum and chromatography of the resulting oil over silica gel (2×15 cm, eluting with dichloromethane and dichloromethaneacetone 5%) gave the title compound as a clear oil: 1.31 g (65%); ir (film) νmax : 1696 cm-1 (C=O of thioester); 1Hmr (CDCl3) δ: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).
Reaction SMILES: [NH:1]1[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[C:9]=2[CH:11]=[CH:12][N:13]=3)=[CH:4][CH:3]=[C:2]1[C:14](=O)[C:15]([O:17]C)=O.[C:20]([NH2:23])(=[O:22])[CH3:21]>>[NH:1]1[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[C:9]=2[CH:11]=[CH:12][N:13]=3)=[CH:4][CH:3]=[C:2]1[C:14]1[C:15](=[O:17])[NH:23][C:20](=[O:22])[CH:21]=1
Reactant: COC(=O)C(=O)c1ccc2ccc3nccc3c2[nH]1
Reactant: CC(N)=O
Product: O=C1C=C(c2ccc3ccc4nccc4c3[nH]2)C(=O)N1

Procedure:
In one embodiment, the method of the present invention comprises a step of dissolving methyl pyrroloquinolinyl-oxoacetate and acetamide in an organic solvent and adding the obtained solution to a base, and reacting methylpyrroloquinolinyl-oxoacetate and acetamide to form highly pure pyrroloquinolinyl-pyrrole-2,5-dione. In one embodiment, the base is dissolved or suspended in an organic solvent. In a further embodiment, the base is dissolved or suspended in the same organic solvent as methylpyrroloquinolinyl-oxoacetate and acetamide. In a further embodiment, highly pure pyrroloquinolinyl-pyrrolidine-2,5-dione is formed by reducing pyrroloquinolinyl-pyrrole-2,5-dione.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CN(P(N(C)C)(N(C)C)=O)C>>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Benzyl acrylate (500 g, 3.0 mol) was heated in an oil bath to 100° C. Heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internal temperature below 140° C. Once addition was complete, the mixture was stirred and cooled to room temperature. A slurry of silica (5:1 Hexane/EtOAc) was added and the mixture was placed in a column containing a plug of dry silica. The column was washed with 1:1 Hexane/EtOAc and the fractions were combined and evaporated to give 450 g of clear light golden liquid. The liquid was distilled under high vacuum (200 μHg) at 185° C. to give 212 g (42%) of a clear and colorless liquid.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:23])=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C@H:6]([O:29]C(=O)C(C)(C)C)[C@H:5]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>NC(O)C>[C:17]1([C:16]2[N:11]3[CH:10]=[CH:9][C:8]4[C@@H:7]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C@H:6]([OH:29])[C@@H:5]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[NH:4][C:13]=4[C:12]3=[N:14][C:15]=2[CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCO[C@@H]1c2ccn3c(-c4ccccc4)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: CC(N)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCO[C@@H]1c2ccn3c(-c4ccccc4)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 1.14 g (2.05 mmol) of (7R,8R,9R)-10-acetyl-3,9-diphenyl-7-(2-methoxyethoxy)-2-methyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine and 2.28 g (16.5 mmol) potassium carbonate in aminoethanol is stirred at 60° C. for 4 h. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (diethyl ether/petrol ether: 7/3) to give 0.52 g (1.21 mmol/60%) of the title compound as a colourless solid with a melting point of 190–192° C. (diethyl ether).