Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH3:14])[N:6]=1)=[O:4].O1CCOCC1.S(=O)(=O)(O)O>O>[CH3:13][O:12][C:10]([C:8]1[N:7]([CH3:14])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)OC)n(C)n1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
1-Methyl-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (640, 3.7 g, 19.0 mmol) was combined with 1,4-dioxane (20 mL) and water (60 mL). Concentrated sulfuric acid (1.0 mL) in 2 mL of water was added to the solution. After the reaction was stirred at reflux overnight, it was cooled to room temperature and concentrated until precipitation began. The obtained mixture was left standing overnight. The resulting solid was filtered and dried under reduced pressure. The collected aqueous fractions were extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and concentrated. Additional solid was crystallized from ethyl acetate to give the desired compound (641, 2.33 g, 68%). MS (ESI) [M+H+]+=185.0, melting point 175° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCc3ccccc32)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Yield: 50 %

Procedure:
Prepared by coupling 2k and benzene boronic acid, (R6-Ph)B(OH)2 where R6=H, in accordance with the general method described in Example VI. Yield 50%; APcI m/z: 408 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([NH2:12])=[CH:7][N:6]=1>CO.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([NH2:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
Sodium methoxide (0.5M in methanol, 3.7 mL, 1.829 mmol) was added to a solution of 2,4-dichloropyrimidin-5-amine (0.2 g, 1.220 mmol) in MeOH (2.5 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title product as a brown solid (177 mg, 91%). 1H NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 5.31 (br s, 2H), 7.73 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.6 min, 160 [M+H]+
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34]CC)=[O:33])[N:31]=3)=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:37])[CH2:7]1)[CH:4]=[CH2:5].CO.Cl>O1CCOCC1>[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][CH:29]=[C:30]([C:32]([OH:34])=[O:33])[N:31]=3)=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:37])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(-c3nc(C(=O)OCC)cs3)cc2)c2cccc(O)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(-c3nc(C(=O)O)cs3)cc2)c2cccc(O)c2)C[C@H]1C

Procedure:
Aqueous sodium hydroxide solution (3 ml, 2N) was added to a solution of the compound from Example 37 (580 mg), in dioxan (6 ml) and methanol (3 ml) and the reaction stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 5 using 2N hydrochloric acid then evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel using gradient elution (85/15/2.5-80/20/3 dichloromethane/methanol/ammonium hydroxide). This material was further purified on a polystyrene reverse phase resin using gradient elution (100/0-50/50 water/acetonitrile). The acetonitrile was evaporated in vacuo and the remaining aqueous solution was frozen and lyophilised to afford the title compound, 410 mg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][CH3:17])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CN
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 92.6 %

Procedure:
A mixture of 2.0 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylthio-2-nitroethylene, 1.8 g of 40% aqueous methylamine solution and 20 ml of acetonitrile was refluxed for 3 hours and, then concentrated. The residue was washed with dichloromethane to give 1.73 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylamino-2-nitroethylene. Mp 181°-183° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=1>C(#N)C>[Br:9][C:10]1[C:15]([Br:8])=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(Br)n1
Solvent: CC#N
Product: COc1ccc(Br)c(Br)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
NBS (302 g) was added to the compound of Example 259 (295 g) in acetonitrile (575 mL) and the mixture was stirred at 80 to 90° C. for 1 day in a nitrogen atmosphere. After cooling, the crystallized imide was removed by filtration and the filtrate was concentrated. Purification of the resulting residue by silica gel column chromatography (ether:petroleum ether=1:1) gave a 6:1 mixture of the title compound and 2,5-dibromo form. This product was crystallized from cold petroleum ether to afford the title compound as a colorless powder (223 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([O:20]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>C(O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([NH:23][NH2:24])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
Ethanol (50 ml) was added to a mixture of methyl 3,4-diphenyl-2-furancarboxylate (14.00 g) and hydrazine monohydrate (7.33 ml), and heated at reflux while stirring overnight. After concentrating the reaction solution under reduced pressure and adding ethanol, the thus-precipitated crystals were filtered, thereby giving 13.80 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.C(OCC)(=O)C.CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[CH:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(-c2nnc[nH]2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nncn2C2CCCCO2)ccc1Br
Temperature: 50 °C
Yield: 97.9 %

Procedure:
3-(4-Bromo-3-methylphenyl)-4H-1,2,4-triazole (2.00 g, 8.40 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.80 mL, 42.0 mmol) and methanesulfonic acid (0.027 mL, 0.42 mmol) were added and the resulting mixture heated at 50° C. under a reflux condenser under nitrogen for 20 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (10-30-50% ethyl acetate in hexanes) gave the desired product (2.64 g, 8.22 mmol, 98% yield) as a yellow oil. MS (ESI) m/z 322 [M]+, 324 [M+2]+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([CH:18](O)[CH2:19][C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)=[C:16]([CH3:30])[O:15][N:14]=2)=[N:11][CH:12]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17](/[CH:18]=[CH:19]/[C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)=[C:16]([CH3:30])[O:15][N:14]=2)=[N:11][CH:12]=1
Reactant: Cc1nc(CC(O)c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Temperature: 90 °C

Procedure:
Concentrated sulfuric acid (9.3 mL) was added to 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid (574 mg, 1.58 mmol) then the mixture was heated at 90° C. for 10 min. After cooling to room temperature the mixture was poured into ice (100 g) and the precipitate was filtered off and dried to give the title product. (471 mg, 86%) as a yellow solid. MS: m/e=344.1 [M−H]−.
Reaction SMILES: [NH2:1][CH:2]([C:16](=[O:34])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][N:27]=1)[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[CH3:15].[CH2:35]=[O:36]>C(O)(=O)C>[CH:35]([NH:1][CH:2]([C:16](=[O:34])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][N:27]=1)[CH2:3][C:4]1[C:5]([CH3:15])=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:36]
Reactant: C=O
Reactant: CC(=O)Oc1cc(C)c(CC(N)C(=O)N2CCCCC2c2ncc(-c3ccccc3)[nH]2)c(C)c1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(C)c(CC(NC=O)C(=O)N2CCCCC2c2ncc(-c3ccccc3)[nH]2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 0.7 mmol of acetic acid 4-{2-amino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenyl ester and 0.8 mL of formaldehyde, cooled in an ice bath under argon, was added 0.5 mL of acetic acid. The resulting mixture was allowed to slowly return to room temperature and stir overnight. The mixture was then extracted with ethyl acetate. The ethyl acetate was washed with water, dried over magnesium sulfate and concentrated to 0.39 g of an orange-yellow oil which was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:16]3[N:17]=[C:18]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]4[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 19.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (150 mg, 0.30 mmol) in DCM (10 mL) was added 1,4′-bipiperidine (152 mg, 0.90 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (35 mg, 19%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.37 (m, 2H), 1.51 (m, 2H), 1.65 (m, 4H), 1.81 (m, 2H), 2.33 (s, 3H), 2.63 (m, 5H), 2.70 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 4.50 (m, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.C[N:37](C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:37])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
In a solution of 0.80 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methoxymethyl benzoic acid in 30 mL of dichloromethane, 0.23 g of oxalyl chloride and 0.06 g of N,N-dimethylforamide were added, and stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 5 mL of tetrahydrofuran, and a solution of 1.50 g of concentrated ammonia water in 10 mL of tetrahydrofuran was added dropwise at room temperature with stirring. After the completion of the addition dropwise, it was continued to stir further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of water was added in the residue, and extracted with ethyl acetate (20 mL×1). The organic phase was washed with 10 mL of 2N hydrochloric acid, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:1) to obtain 0.34 g of the aimed product as white crystal.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[C:18]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:26][CH2:25]1)=[N:17][N:16]=[CH:15]2>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[C:18]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][N:32]([CH3:33])[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[CH2:26][CH2:25]1)=[N:17][N:16]=[CH:15]2
Reactant: O=C=NC1CCCCC1
Reactant: CNCCC1CCN(c2nncc3cc(OC)c(OC)cc23)CC1
Solvent: ClC(Cl)Cl
Product: COc1cc2cnnc(N3CCC(CCN(C)C(=O)NC4CCCCC4)CC3)c2cc1OC
Temperature: 0 °C

Procedure:
Cyclohexyl isocyanate (0.5 g.) in dry chloroform (5 ml.) was added dropwise to 6,7-dimethoxy-1-[4-[2-(methylamino)ethyl]piperidino]phthalazine (1.0 g.) in dry chloroform (10 ml.) with stirring and ice-water cooling. After further stirring at room temperature (20°) for 1 hour the mixture was concentrated in vacuo, triturated with minimum quantity of ethyl acetate and filtered. The resultant solid was dissolved in methylene chloride (10 ml.), filtered, treated with ethyl acetate (20 ml.) and gently distilled to remove methylene chloride. The residual ethyl acetate solution was left standing in the refrigerator overnight to precipitate crystalline 6,7-dimethoxy-1-[4-[2-(3-cyclohexyl-1-methylureido)ethyl]piperidino]phthalazine (820 mg.), m.p. 204°-206° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20].O>CO>[F:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]([C:15]([F:17])([F:16])[F:18])[C:5]=1[CH2:19][OH:20]
Reactant: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
To a solution of 1.6 g (41.0 mmoles) of sodium borohydride dissolved in 300 ml of methanol was added, with ice-cooling, a solution of 26.5 g (102.5 mmoles) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 28.5 g (yield: 100%) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20](O)=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:32]>C(Cl)Cl.Cl>[N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20]([F:32])=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C(=O)F)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core C) (500 mg, 1.6 mmol) and pyridine (0.25 mL, 3.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (400 mg, 3.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 482 mg (98%) of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid fluoride Core D. MS found: (M+H)+=312.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[SH:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1cc(Br)ccc1Br
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 2,5-dibromo-thiophenol.
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34]/[C:3](=[C:10]3\[C:11](=[O:22])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=4)/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:35][CH:36]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Product: O=C1Nc2cc3c(cc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1)OCO3

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [F:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[F:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Product: O=C(O)c1ccc(F)c(C(=O)O)c1

Procedure:
4-fluoro-isophthalic acid was synthesized from 2-fluoro-5-methylbenzoic acid following the procedure described for 5-fluoro-isophthalic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:47]2[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=2)[CH2:50][Cl:51])[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:67].Cl>>[ClH:51].[ClH:67].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[C:47]([C:39]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH:48]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1

Procedure:
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[NH:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:25][C:26](=[O:28])[CH3:27])[CH:13]=[N:12][C:11]=3[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CCCC2)c(=O)n1CC1CCCC1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCCC1)c(=O)n2CC1CCCC1

Procedure:
1,3-Di-cyclopentylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclopentylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 144° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25].[CH3:26][O-:27].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:27][CH3:26])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25]
Reactant: C[O-]
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccc(OC(F)(F)F)cc3)c(Cl)nc12
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1ccc(OC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-2,4-dichloro-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline (1.97 g, 4.367 mmol, Intermediate 58, step c) and sodium methoxide (1.18 g, 21.837 mmol) in toluene (20 mL) was heated in a sealed tube at 110° C. for 24 hours, cooled to RT, diluted with DCM, stirred at room temperature for 30 min, and filtered through Celite® rinsing several times with DCM. The solvents were removed under reduced pressure and the off-white solid product precipitated from MeOH, filtered and dried to provide the title compound.