Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
The title compound was prepared by condensing 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 222–224° C., 60% yield. 1H-NMR (DMSO-d6) δ 8.75 (s, 1H), 8.38–8.40 (m, 1H), 8.18 (d, J=9 Hz, 2H), 7.99–8.08 (m, 4H), 7.83 (d, J=15 Hz, 1H), 7.28–7.33 (m, 1H), 6.91 (s, 1H), 4.11 (s, 3H), 4.04 (s, 3H). MS m/z=430 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:29]=[CH:28][C:15]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:29]=[CH:28][C:15]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:30][CH:31]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 1-[4-(4-methoxycarbonylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.5 g) in methanol (20 ml) is added 5% aqueous sodium hydroxide solution (10 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted aqueous hydrochloric acid solution. The precipitated crystal is collected by filtration to give 1-[4-(4-carboxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. >300° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:13]=[C:14]([C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:20]=1)[C:15](O)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[O:5]([C:12]1[CH:13]=[C:14]([C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:20]=1)[C:15]([Cl:3])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)Cl

Procedure:
To thionyl chloride (3 ml), a mixture of 2-phenoxy-5-ethoxycarbonylethylisonicotinic acid (1.0 g) and dimethylformamide (a small amount) is added, and the resultant mixture is stirred at room temperature for 20 minutes. The reaction mixture is evaporated under reduced pressure to remove the thionyl chloride. The residue is mixed with dry benzene and evaporated again. The residue is dissolved in anhydrous ether, and the insoluble part is filtered off. The ether solution is evaporated to give 2-phenoxy-5-ethoxycarbonylethylisonicotinoyl chloride (1.05 g). IR (CHCl3): 1775, 1735 cm-1.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([OH:22])=[O:21].C(=O)(O)[O-].[K+:27]>O>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([O-:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([O-:22])=[O:21].[K+:27].[K+:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1C2=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C([O-])c1ccc2c(c1)C(=O)c1ccc(C(=O)[O-])cc1C2=O

Procedure:
Anthraquinone-2,6-dicarboxylic acid (1.00g) was dissolved in the minimum quantity of water (20 ml) containing one equivalent of potassium bicarbonate (0.68 g) at the boil. The solution was filtered whilst hot and allowed to crystallise. The product which separated was filtered off, dried at 100°C, and analysed for the dihydrate. Analysis: Required Carbon 47.06, Hydrogen 2.47 percent; Found Carbon 47.09, Hydrogen 2.48 percent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[I:12]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(I)cc1N
Temperature: 50 °C
Reaction time: 45 h

Procedure:
To a suspension of 5-chloro-4-iodo-2-nitroaniline (36.5 g, 122 mmol) in EtOH (800 mL) and water (150 mL) was added iron powder (38 g, 673 mmol) and NH4Cl (16 g, 306 mmol). The mixture was heated under nitrogen at 50° C. overnight. Additional iron powder (38 g, 673 mmol) and NH4Cl (16 g, 306 mmol) were added and heating was continued for 45 h. The reaction mixture was cooled, filtered and concentrated. The resulting residue was re-dissolved in ethyl acetate and washed with sodium bicarbonate solution. The organic phase was concentrated to afford the desired product as a gray solid, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([S:21][C:22]#N)[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([O-:3])=[O:2].[BH4-].[Na+].CI.O>CO>[N+:1]([C:4]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: O
Product: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Yield: 47 %

Procedure:
To a solution of 2′-Nitro-4′-thiocyano-p-toluenesulfonanilide (5.0 g (14.3 mmol) in methanol (20 ml), sodium borohydride (2.80 g (66.7 mmol)) was added under cooling with ice and with stirring. After 30 minutes' stirring, to the resulting mixture, methyl iodide (3.67 ml (59.0 mmol)) was added dropwise under cooling with ice and the mixture was then stirred at room temperature for 20 hours. Then, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:4) as eluent. The resulting crystals were recrystallized from ethyl acetate to give 2.27 g (47%) of 2′-nitro-4′-methylthio-p-toluenesulfonanilide as orange crystals.
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:19]4[C:24]([CH2:25][CH3:26])=[CH:23][C:22]([C:27]([O:29]C)=[O:28])=[C:21]([O:31]C)[N:20]=4)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>>[CH2:25]([C:24]1[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21](=[O:31])[NH:20][C:19]=1[C:15]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:33][CH2:34][NH:8][CH2:9][C:10]3=[CH:18][C:17]=2[CH:16]=1)[CH3:26]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)cc1n2CCNC1
Temperature: 80 °C
Yield: 59.3 %

Procedure:
To tert-butyl-8-(3-ethyl-6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (50 mg, 0.11 mmol) was added 6M HCl (1 mL) and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was then cooled to room temperature and concentrated to afford a crude residue that was triturated with Et2O. The precipitate was filtered and rinsed with Et2O to afford the title compound as a brown solid (22 mg, 50%).
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[C:10](Cl)[C:9](Cl)=[C:8]2[C:3]=1[C:4]([C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)([N:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:5][C:6]2=[O:7].C(N(CC)C1C=CC(C2(N(C3C=CC(OCC)=CC=3)C3C=CC=CC=3)C3C(=CC=CC=3)C(=O)O2)=C(C)C=1)C.CN(C)C1C=CC(C2(N(C3C=CC(CCCCCCCC)=CC=3)C3C=CC(CCCCCCCC)=CC=3)C3C(=CC=CC=3)C(=O)O2)=CC=1.C(OC1C=CC(N(C2C=CC=CC=2)C2C3C(=CC=CC=3)C(=O)O2)=CC=1)C.CN(C)C1C=CC(C2(N(C3C=CC=CC=3)C3C=CC=CC=3)C3C(=CC=CC=3)C(=O)O2)=CC=1.C(C1C=CC(N(C2C=CC(CCCCCCCC)=CC=2)C2C3C(=CC=CC=3)C(=O)O2)=CC=1)CCCCCCC.C(N(CC1C=CC=CC=1)C1C=CC(C2(N(C3C=CC(OCC)=CC=3)C3C=CC=CC=3)C3C(=CC=CC=3)C(=O)O2)=CC=1)C.C(N(CC)C1C=CC(C2(N(C3C=CC(N(C)C)=CC=3)C3C=CC(N(C)C)=CC=3)C3C(=CC=CC=3)C(=O)O2)=C(C)C=1)C>>[CH3:38][N:37]([CH3:39])[C:34]1[CH:33]=[CH:32][C:31]([C:4]2([N:15]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=3)[C:6](=[O:7])[O:5]2)=[CH:36][CH:35]=1
Reactant: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Agent: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)cc1
Agent: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2OC(=O)c3ccccc32)cc1
Agent: CCN(CC)c1ccc(C2(N(c3ccc(N(C)C)cc3)c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)c(C)c1
Product: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)cc1

Procedure:
3-[4-(dimethylamino)phenyl]-3-[(4-(isopropoxyphenyl)-phenylamino]phthalide; 4,5,6,7-tetrachloro-3-[4-(dimethylamino)-phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide; 3-[4-(diethylamino)-2-methylphenyl]-3-[(4-ethoxyphenyl)phenylamino]-phthalide; 3-[4-(dimethylamino)phenyl]-3-[bis(4-octylphenyl)-amino]phthalide; 6-(dimethylamino)-3-[4-dimethylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide; 3-[4-(dimethylamino)-phenyl]-3-(diphenylamino)phthalide; 6-(dimethylamino)-3-[4-dimethylamino)phenyl]-3-[bis(4-octylphenyl)amino]phthalide; 3-[4-(ethylbenzylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]-phthalide and 3-[4-(diethylamino)-2-methylphenyl]-3-{bis[4-(dimethylamino)phenyl]amino}phthalide.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].C(=O)([O-])[O-:21].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(C#N)c(NC2CCCC2)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(N)=O)c(NC2CCCC2)c1
Temperature: 25 °C
Yield: 334.7 %

Procedure:
A solution of ethyl 4-cyano-3-(cyclopentylamino)benzoate (363 mg, 1.41 mmol), potassium carbonate (50 mg, 0.36 mmol), and 30% aqueous hydrogen peroxide (0.25 mL) in DMSO (1.5 mL) was stirred at 60° C. for 1 h. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(aminocarbonyl)-3-(cyclopentylamino)benzoate (333 mg, 86% yield). MS (EI) for C15H20N2O3: 277 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:17]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([NH:26][C:18]2[N:17]=[C:16]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:9]3([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]3)[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][N:19]=2)=[CH:32][CH:31]=1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.120 g, 0.648 mmol), 4-chloro-N-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine A68 (0.197 g, 0.648 mmol), CuI (0.012 g, 0.065 mmol), t-Bu3PHBF4 (0.019 g, 0.065 mmol) and PdCl2(PPh3)2 (0.023 g, 0.032 mmol) in DMF (3 mL) was bubbled with N2 for 5 minutes. Et3N (1 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for 15 minutes. The volatiles were removed in vacuo and the black residue was adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A73 as a yellow solid (0.229 g, 78%). LCMS-D: rt 3.47 min; m/z 454 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:22]#[CH:23]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][C:3]=2[Cl:20])[CH2:26][CH2:25]1)[C:22]#[CH:23]
Reactant: C#CCN1CCNCC1
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCN1CCN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Temperature: 160 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 3.2 g of 1-propargylpiperazine and 25 ml of HMPTA was heated with stirring at 160° C. for 5 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 ml of water and insoluble substances were removed by filtration. The aqueous fraction was extracted with 200 ml of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate. After concentration, the concentrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyako Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 1.2 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 211° to 213° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Si]([O:33][K])(C)(C)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2](=[O:33])[NH:7][N:6]3[C:8]([C:11]([F:13])([F:12])[F:14])=[N:9][N:10]=[C:5]3[C:4]=2[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)O[K]
Reactant: FC(F)(F)c1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Product: O=c1[nH]n2c(C(F)(F)F)nnc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized by reacting 6-chloro-7,8-bis(4-chlorophenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with TMSOK using the procedures described above. 1HNMR (DMSO, 400 Hz): 7.48 (2H, d), 7.38-7.7.42 (4H, m), 7.25 (2H, d). 13CNMR (DMSO, 400 Hz) 160.88, 145.91, 137.00, 135.11, 133.90, 132.94, 132.10, 131.07, 129.98, 128.00 127.13, 118.30(q).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[N:5]([CH3:17])[C:4]=2[CH:3]=1.[CH3:18][S-:19].[Na+]>CN(C)C=O>[CH3:16][C:14]1[CH:15]=[C:6]2[N:5]([CH3:17])[C:4]3[CH:3]=[C:2]([S:19][CH3:18])[N:11]=[CH:10][C:9]=3[C:8](=[O:12])[N:7]2[N:13]=1
Reactant: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(cn1)c(=O)n1nc(C)cc1n2C
Reaction time: 10 h
Yield: 73 %

Procedure:
0.1 mole of 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 5 is suspended in 100 ml. of dimethylformamide. 0.15 mole of sodium methyl mercaptide is added and the mixture is heated at reflux temperature with stirring for 10 hours. After this time, the precipitated sodium chloride is filtered off and 100 ml. of water are added. 2,4-dimethyl-6-(methylthio)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one crystallizes and is filtered off, yield: 73%; m.p. >300° (butyl alcohol).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)o2)cc1
Yield: 79.7 %

Procedure:
A suspension of 1-(4-n-Hexyloxybenzoyl)-2-(4-methoxycarbonylbenzoyl)hydrazine (1.00 g) in phosphorus oxychloride (5 ml) was refluxed for 1 hour. After cooling, the solution was concentrated under reduced pressure. The residue was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give Methyl 4-[5-(4-n-hexyloxyphenyl)-1,3,4-oxadiazole-2-yl]benzoate (761 mg).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18](Br)=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4].O>CS(C)=O>[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18]([NH:2][CH3:1])=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CCOCn1c(NC)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 70 °C

Procedure:
A 40% aqueous solution of methylamine (10 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (0.450 g) in dimethylsulfoxide (20 ml). After heating at 70° C. for 6 hours, the mixture was treated with water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (2x 30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine (0.32 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[O:5])[CH3:2].[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33](Cl)=[O:34])[CH3:29]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:19]([C:33](=[O:34])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1NCc1ccc(F)cc1
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)N(Cc1ccc(F)cc1)n1c(C(=O)OCC)cc2ccc(C(F)(F)F)cc21
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 1-(4-fluoro-benzylamino)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (240 mg, 0.63 mmol) and chlorocarbonyl-acetic acid ethyl ester (105 mg, 0.69 mmol) in dioxane (3 mL) was heated in an 100° C. oil bath for 30 min and concentrated. Crude product was purified by silica gel chromatography (5%-50% EtOAc/DCM) to provide the title compound 162 mg. ESI (m/z): 495.24 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Br:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:15])=[N-].C(O)(=O)C>CCOCC.C(OCC)(=O)C>[CH3:15][O:5][C:4](=[O:6])[C:3]1[C:7]([Br:12])=[CH:8][C:9]([Br:11])=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cc(Br)cc(Br)c1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1c(N)cc(Br)cc1Br
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 2-amino-4,6-dibromo-benzoic acid (17.5 g, 59.3 mmol) in ether (150 mL) and ethyl acetate (15 mL) kept in an ice bath was added a solution of diazomethane (approximately 70.0 mmol, prepared from diazald 118.6 mmol) in ether (500 mL) over 1 hour. The reaction mixture was then stirred in an ice water bath for 2 hours. The resultant was treated with acetic acid 10 mL and washed with 2N NaHCO3 and brine. The organic layer was concentrated in vacuo. The residue was purified by chromatography (hexane:EtOAc=8:1) to give the objective compound (15.3 g, 83%) as brown solid: 1H NMR (200 MHz, CDCl3) δ 3.92 (s, 3H), 4.92 (br s, 2H), 6.80 (d, J=7.73, 2H), 7.11 (d, J=7.73, 1H); MS(EI) m/e 307 [M+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:32]=[C:33]([C:37]3[N:42]=[CH:41][C:40]([C:43]4[CH:44]=[N:45][NH:46][CH:47]=4)=[CH:39][N:38]=3)[CH:34]=[CH:35][CH:36]=2)[CH:28]=[N:27]1>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:45]2[CH:44]=[C:43]([C:40]3[CH:39]=[N:38][C:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([C:29]5[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=5)[CH:32]=4)=[N:42][CH:41]=3)[CH:47]=[N:46]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC5CCN(C(=O)OC(C)(C)C)C5)c4)cn3)c2)cn1
Yield: 57.6 %

Procedure:
A solution of 3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in WO2010100144; 200 mg; 0.64 mmol; 1.0 eq.), cesium carbonate (420 mg; 1.29 mmol; 2.0 eq.) and 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 195 mg; 0.64 mmol; 1.0 eq.) was heated at 100° C. O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as a white foam (179 mg, 57%). MS (ESI+): 486.5.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[CH:9]=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:6]1=[O:22])[CH3:4].[I:23]Cl>C(Cl)(Cl)Cl>[OH:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[C:9]([I:23])=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:6]1=[O:22])[CH3:4]
Reactant: C[C@H](CO)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: ClI
Solvent: ClC(Cl)Cl
Product: C[C@H](CO)n1c(=O)c(I)cn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(1-hydroxypropan-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 102) (1.3 g) in chloroform (20.0 ml) was added iodine chloride (12.4 ml, 1M dichloromethane solution) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-(1-hydroxypropan-2-yl)-5-iodo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (1.4 g).