Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C@@H:10]([CH:11]([CH3:20])[CH2:12][O:13]C2CCCCO2)[C@H:9]([CH2:21][CH2:22][O:23][O:24][C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:26])[C:8]1=[O:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[N+:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:25]([O:24][O:23][CH2:22][CH2:21][C@H:9]2[C@H:10]([CH:11]([CH3:20])[CH2:12][OH:13])[NH:7][C:8]2=[O:37])=[O:26])=[CH:33][CH:32]=1)([O-:36])=[O:35]
Reactant: CC(COC1CCCCO1)[C@H]1[C@H](CCOOC(=O)Cc2ccc([N+](=O)[O-])cc2)C(=O)N1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(CO)[C@@H]1NC(=O)[C@H]1CCOOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1 M pH 7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone. The cis diastereoisomers are obtained in an analogous manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:23][CH:22]=[C:21]([Cl:25])[Cl:20])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: ClCC=C(Cl)Cl
Reactant: COCOc1c(C)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a mixture of 10 g of 3-chloro-4-methoxymethoxy-5-methylphenol, 7 g of potassium carbonate and 100 ml of N,N-dimethylformamide was added dropwise a solution of 8 g of 1,1,3-trichloro-1-propene dissolved in 30 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water, and extracted with 200 ml of diethyl ether. The combined ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 14.1 g of 3-chloro-4-methoxymethoxy-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (91% yield).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[CH:8]=1.CN([CH:21]=[O:22])C>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([Cl:17])[C:8]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
A 2M n-BuLi solution (5.8 mL, 11.6 mmol) was added to a −78° C. THF solution (60 mL) of 1,3-dichloro-5-(trifluoromethyl)benzene (2.5 g, 11.6 mmol). After 45 min neat DMF (0.39 mL, 5.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([NH:2][NH2:3])=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Hydrazine monohydrate (7.40 mL) was added to a stirred suspension of methyl [(4-cyclohexylphenyl)amino](oxo)acetate (3990 mg) in ethanol (50 mL) at ambient temperature. The reaction was heated to 85° C. and allowed to stir for a further 3 hours. Allowed to cool to ambient temperature overnight. The precipitate was filtered off, washed with Et2O and dried under vacuum, to give the title compound (Intermediate 47, 3750 mg) as a solid; 1H NMR δ10.42 (1H, s), 10.17 (1H, s), 7.68 (2H, d), 7.16 (2H, d), 4.58 (1H, s), 2.48 (1H+DMSO, m), 1.89-1.65 (5H, m), 1.46-1.13 (5H, m); MS m/e M−H− 260.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[N:7]([CH3:11])[C:8](=[O:10])[CH3:9].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:5]2[CH2:6][CH:2]([OH:1])[CH:3]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[CH2:4]2)=[CH:14][CH:15]=1
Reactant: CC(=O)N(C)[C@@H]1CNC[C@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(=O)N(C)C1CN(c2ccc(N)cc2)CC1O

Procedure:
trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(F)c3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 36.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (125 mg, 0.26 mmol) obtained in step 2 and ethanesulfonamide (139 mg, 1.32 mmol), the title compound (53 mg, 36%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Li+].[OH-]>O.CO>[CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCSC(c1ccccc1)C1(OC)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1(C(SCCC(=O)O)c2ccccc2)CCOCC1
Yield: 103.6 %

Procedure:
A solution of methyl 3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl-thio]propionate (Step 1) (0.91 g, 2.8 mmol) and LiOH (0.29 g, 7.01 mmol) in 10% water and methanol (10 mL) was stirred for 18 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). The organic layer was separated and washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 0.9 g of 3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid as a clear, colorless oil: HRMS calcd for C16H22O4S 310.1239, found 310.1241.
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:13]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=23)=[CH:20][CH:19]=1
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenol (8) (1 g, 3.55 mmol) was dissolved in 30 ml of THF and after addition of NaH (60% in mineral oil, 0.171 g, 4.27 mmol) the mixture was stirred for 20 min at rt. Then methyl 2-bromoacetate (0.382 ml, 3.91 mmol) was added and the mixture was stirred for 16 h at rt. The mixture was quenched with H2O. The mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and NaCl-solution, dried over Na2 SO4 and evaporated. The crude product was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][SH:7].[F:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[C:13](F)[CH:12]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:3][Si:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][S:7][C:13]1[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[C:11]([F:10])[CH:12]=1
Reactant: C[Si](C)(C)CCS
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (360 mg) in DMF (10 mL) at 0° C. was added 2-(trimethylsilyl)ethanethiol (1.8 mL). After 10 min., a solution of 1,3-difluoro-5-phenylbenzene (1.9 g) in DMF (5 mL) was added and the resulting mixture was heated at 110° C. for 2.5 h. Ethyl acetate was added and the solution was washed with 1N HCl, H2O and brine. Concentration and chromatography (silica gel; hexane/EtOAc (98:2)) provided the title compound as a liquid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:38](=[O:39])[CH2:37][CH2:36][N:35]([CH2:41][CH2:42][OH:43])[C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.000175 mol), N,N-diisopropylethylamine (0.034 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12]>O1CCCC1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: CCC[Mg]Br
Reactant: Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
To a flame-dried flask under an argon atmosphere is added 0.59 mL of commercially available p-tolualdehyde and charged with 15 mL of tetrahydrofuran. The solution is cooled to 0° C. and is treated with 3.0 mL (2.0M in diethyl ether) of propylmagnesium bromide. The reaction mixture is left to warm to room temperature overnight and then quenched by the addition of aqueous ammonium chloride. After dilution with diethyl ether the phases are separated; the organic layer is washed with saturated ammonium chloride, brine, dried (magnesium sulfate) and finally concentrated under reduced pressure. The residue is flash column chromatographed using 20% to 30% diethyl ether in hexane to yield 980 mg of the title product as a clear, colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[C:33]4[C:34]5=[C:35]6[C:30](=[CH:31][CH:32]=4)[CH:29]=[CH:28][CH:27]=[C:26]6[CH:25]=[CH:24][C:23]5=[CH:22][CH:21]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:36]#[N:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:43]CC1>>[O:43]=[C:10]1[C:9]2[C:8]([C:36]#[N:37])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[C:33]4[C:34]5=[C:35]6[C:30](=[CH:31][CH:32]=4)[CH:29]=[CH:28][CH:27]=[C:26]6[CH:25]=[CH:24][C:23]5=[CH:22][CH:21]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 2-(piperidin-1-yl)-4-(pyren-1-yl)-9H-fluorene-1-carbonitrile (474 mg) in THF was added sodium hydride (42 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 180-182° C.; ESMS 489 (M+1); IR (KBr) 2217 (CN), 1713 cm−1 (CO).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[ClH:29].[N:11]1([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
Boc-protected piperazine 9 (4.00 g, 10.30 mmol) was dissolved in methanol (45 mL). The solution was cooled in an ice bath. Ethereal hydrogen chloride (30 mL) was added slowly in three portions. A precipitate formed as the reaction stirred at room temperature for 14 hours. The white solid was collected by vacuum filtration and dried under vacuum to give piperazine dihydrochloride salt 10 (3.35 g, 90%): 1H NMR (500 MHz, DMSO-d6) δ 1.62-1.71 (m, 4H), 3.11-3.17 (m, 5H), 2.39-3.41 (m, 2H), 3.48-3.77 (m, 4H), 7.83-7.91 (m, 4H), 9.33 (br, 2H), 11.54 (br, 1H); ESI MS m/z 288 [C16H21N3O2+H]+.
Reaction SMILES: [Cl-].[Li+].[CH2:3](C([Sn])=C(CCCC)CCCC)[CH2:4]CC.[C:18]1([C:24]2[C:33]([CH3:34])=[CH:32][C:31]3[C:26](=[C:27](OS(C(F)(F)F)(=O)=O)[CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([C:24]2[C:33]([CH3:34])=[CH:32][C:31]3[C:26](=[C:27]([CH:3]=[CH2:4])[CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc2cccc(OS(=O)(=O)C(F)(F)F)c2nc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cccc2cc(C)c(-c3ccccc3)nc12
Temperature: 110 °C
Yield: 96 %

Procedure:
6.3 g (150 mmol) of lithium chloride, 16.8 ml (57 mmol) of tributylvinyltin and 1.6 g (1.5 mmol) of Pd(PPh3)4 are added sequentially at ambient temperature to a solution of 17.7 g (48 mmol) of 2-phenyl-3-methyl-8-trifluoromethanesulfonyloxyquinoline in 250 ml of dioxane, degassed beforehand using a stream of nitrogen. The reaction medium is then heated at 110° C. for 16 hours. After evaporating the dioxane, the residue is taken up in 200 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to provide 11.3 g of 2-phenyl-3-methyl-8-vinylquinoline in the form of a colorless oil. (Yield: 96%)
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br.C1C=CC=CC=1>C(OCC)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 70 °C

Procedure:
30 g (0.153 mol) of 4-methylbenzophenone are introduced into a 250 ml three-necked flask equipped with a reflux condenser and a dropping funnel containing 8.7 ml (0.168 mol) of bromine. In a first step, the reaction medium is heated to 70° C. and then, after complete dissolution of the solid, to 150° C. The bromine is then added dropwise over a period of 3 hours. The reaction is exothermic. The initially colorless solution becomes orange-yellow. Heating is maintained at 150° C. for 15 hours. At the end of the reaction, the temperature of the reaction medium is allowed to return to room temperature. The solution is brown in color. 75 ml of benzene and 35 ml of diethyl ether are added. Washing is carried out with a saturated Na2CO3 solution, then with a saturated Na2S2O3 solution and finally with a saturated NaCl solution, in order to remove the salts formed and to bring the solution to a pH of the order of 6-7. The organic phase is recovered and the solvents are evaporated. A caramel-colored paste is obtained. It is recrystallized from 100 ml of ethanol. The cream-colored crystals are collected and dried under vacuum. The mother liquors are collected and a second crystallization is carried out. The crystals obtained are dried under vacuum. The yield of expected product is 50%, m=20.81 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (93.2 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:23])[N:7]([CH3:24])[C:6]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C:8](=[O:23])[N:7]([CH3:24])[C:6]3[CH:25]=[C:2]([O:1][CH:33]([CH3:35])[CH3:34])[CH:3]=[CH:4][C:5]=3[S:10]2(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CN1C(=O)N(c2ccc(C(F)(F)F)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(C(F)(F)F)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A suspension of 6-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (124 mg), potassium carbonate (55 mg) and 2-iodopropane (68 mg) in N,N-dimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-trifluoromethylphenyl)-4-methyl-6-isopropoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (78 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[NH:29][C:28]1=[O:35]>>[F:25][C:4]1[CH:3]=[C:2]([N:29]2[C:30]([CH3:34])([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]2=[O:35])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)nc1C
Yield: 13.9 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 128 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (26 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:32])[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[C:28]([F:31])([F:30])[F:29])[CH2:16][CH2:15]3)=[N:10][N:9]2[CH:33]=1)=O)C.[CH2:34]([NH2:39])[CH2:35][CH:36]([CH3:38])[CH3:37].[C-]#N.[Na+]>>[CH3:37][CH:36]([CH3:38])[CH2:35][CH2:34][NH:39][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:32])[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[C:28]([F:31])([F:30])[F:29])[CH2:18][CH2:19]3)=[N:10][N:9]2[CH:33]=1)=[O:3]
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Reactant: CC(C)CCN
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)CCNC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (0.100 g, 0.215 mmol), isoamylamine (1 mL), and sodium cyanide (0.020 g, 0.408 mmol) was stirred at room temperature over night. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4, concentrated. The residue was purified by column chromatography. The title compound was obtained as a white solid in 85% yield (0.092 g). 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.74-7.7 (m, 1H), 7.65 (d, J=9.9 Hz, 1H), 7.21-7.16 (m, 1H), 6.86 (d, J=9.9 Hz, 1H), 4.02-3.92 (m, 1H), 3.89-3.79 (m, 1H), 3.62-3.54 (m, 2H), 3.49-3.39 (m, 4H), 3.35-3.28 (m, 2H), 1.74-1.6 (m, 1H), 1.53-1.44 (m, 2H), 0.91 (d, J=6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 162.4, 154.7, 138.4, 137.0, 136.9, 135.6, 129.7, 129.6, 129.5, 126.4, 125.1, 123.3, 122.9, 122.4, 121.4, 118.1, 116.8, 116.5, 114.9, 114.6, 111.8, 46.2, 46.1, 45.6, 41.2, 38.5, 37.3, 25.7, 22.4. MS (ES+) m/z 507 (M+1).