Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([C:24]2[C:29]([O:30][CH3:31])=[N:28][C:27]([P:32]([CH3:35])([CH3:34])=[O:33])=[CH:26][N:25]=2)[N:15]=1>>[CH3:35][P:32]([C:27]1[N:28]=[C:29]([O:30][CH3:31])[C:24]([C:16]2[N:17]=[C:18]([N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:14][N:15]=2)=[N:25][CH:26]=1)([CH3:34])=[O:33]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(N2CCN(c3ccccc3)CC2)n1

Procedure:
This compound can be prepared by reacting 1-Phenylpiperazine with 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine as described in Example 36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)(=[O:10])=[O:9].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an atmosphere of argon, (2S,4R)-1-tert-butyl 2-methyl 4-(2-chlorophenylsulfonyl)pyrrolidine-1,2-dicarboxylate (5.76 g, 14.3 mmol, Eq: 1.00) was combined with dichloromethane (35.0 ml) to give a light yellow solution. At 0° C., 2,2,2-trifluoroacetic acid (24.4 g, 16.5 ml, 214 mmol, Eq: 15.0) was added dropwise. The reaction was warmed up to room temperature and stirred for 3 h. The reaction mixture was evaporated to dryness. The crude material was dissolved in 100 ml dichloromethane, then extracted with 50 ml satd. Na2CO3 solution and 50 ml H2O. The aqueous layers were washed with 40 ml dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The title compound was obtained as a orange viscous oil (4.02 g, 92.8%, MS (m/e)=304.2 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(F)c(Cl)c2)CCNC1
Reaction time: 5 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3-chloro-4-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (0.87 g, 2.77 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 5 h. Yield: 0.31 g. MS m/z (rel. intensity, 70 eV) 215 (M+, 72), 157 (bp), 133 (53), 130 (62), 129 (98).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[H][H]>CO.[Pd]=O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:3]([N:2]([CH3:16])[CH3:1])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CO
Product: CN(C)S(=O)(=O)Cc1ccc(N)cc1

Procedure:
A suspension of N,N-dimethyl-4-nitrobenzenemethanesulphonamide (4.2 g) in methanol (300 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (1 g) at atmospheric pressure and temperature. Hydrogen uptake was complete in 1 h. The catalyst was filtered off (Hyflo), washed with ethyl acetate (400 ml), the solvent evaporated and the title compound obtained as a cream solid (3.3 g), m.p. 151°-2°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=3)[C:8]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S1(=O)CCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: O=S1(=O)CCc2nc(-c3cccc(Cl)c3)nc(Nc3ccc(CCO)cc3)c21
Yield: 65.6 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.095 g, 0.22 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.036 g, 0.26 mmol) to afford the title compound (0.060 g, 65%) as a white solid. MW=415.89. 1H NMR (DMSO-d6, 500 MHz) δ 9.51 (s, 1H), 8.24-8.17 (m, 2H), 7.64-7.60 (m, 1H), 7.58-7.53 (m, 3H), 7.27 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.72 (t, J=7.0 Hz, 2H), 3.67-3.62 (m, 2H), 3.44-3.38 (m, 2H), 2.76 (t, J=7.0 Hz, 2H); APCI MS m/z 416 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][C:16](O)=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41]>O1CCCC1.O>[S:41]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:16]1[CH2:15][CH2:14][CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCCc1nc2ccccc2s1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 25.5 %

Procedure:
5.0 g (19.9 mmol) of 4-[1-(benzyloxy)-N-methylformamido]butyric acid are dissolved in 175 ml of tetrahydrofuran. To the solution, cooled to -20°, are added 2.95 ml (2.1 g; 24 mmol) of triethylamine and 2.95 ml (22 mmol) of isobutyl chloroformate. The reaction mixture is thereafter stirred at this temperature for 1 hour. 2.45 g (19.6 mmol) of 2-aminothiophenol are then added and the reaction mixture is stirred at room temperature for 20 hours. Thereupon, 250 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. After chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane there are obtained 1.7 g (25.1%) of benzyl [3-(2-benzthiazolyl)propyl]methylcarbamate as an oil, MS: M+ 340.
Reaction SMILES: [NH3:1].[CH3:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:11](=[O:12])[C:9](=[O:10])[C:8]=1OCCCC>CCOCC>[NH2:1][C:8]1[C:9](=[O:10])[C:11](=[O:12])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: N
Solvent: CCOCC
Product: CCCCOc1c(N)c(=O)c1=O
Reaction time: 3 h
Yield: 92.9 %

Procedure:
Ammonia gas was bubbled into a solution of dibutyl squarate (22.6 g, 100 mmol) in ether (500 mL) contained in a 1 L three-necked, round-bottomed flask equipped with a mechanical stirrer and an acidic scrubber. Precipitation of product ceased after 3 hours, so the reaction was halted and the ether solution was filtered. The solid residue was washed with ether and set aside. The filtrate was allowed to stand at room temperature for a further 3 hours, after which time more solid was observed to have been precipitated. This solid was collected by filtration, washed with ether, and combined with the material set aside previously. Drying in vacuo afforded the product as a white solid (15.7 g, 92.9% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@@H:12]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:13]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:43][NH2:44]>C(Cl)Cl>[OH:43][NH:44][C:14](=[O:15])[C@H:13]([CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)[C@@H](CCCCc2ccccc2)[C@@H](CSc2ccccc2)C(=O)O)cc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)[C@@H](CCCCc2ccccc2)[C@@H](CSc2ccccc2)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(±)-(2R*,3S*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid (0.42 g, 0.84 mmol) is dissolved in CH2Cl2 (3 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (1.5 mL, 3 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 1 hour. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (2 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.3 mL, 2.6 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid hydroxyamide (0.37 g, 87%) The material obtained from the reaction is analytically pure: 1H NMR (300 MHz, CD3OD) δ 7.74-7.69 (m, 2H), 7.32-7.17 (m, 1H), 7.15-7.08 (m, 1H), 7.06-7.01 (m, 4H), 3.87 (s, 3H), 3.49 (dd, J=13.8, 5.3 Hz, 1H), 3.39 (q, J=5.3 Hz, 1H), 3.21 (dd, J=13.8, 9.8 Hz, 1H), 2.98-2.85 (m, 1H), 2.43 (t, J=7.3 Hz, 2H), 1.78-1.71 (m, 2H), 1.41-1.10 (m, 4H); MS (FAB) m/e 514 (M+H)+ ; Anal. (C27H31NO5S2) C, H, N.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH2:41][OH:42]>C(OCC)(=O)C.CO>[OH:42][CH2:41][CH2:40][NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29]
Reactant: NCCO
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCCO)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 58 %

Procedure:
Using the method for Example 164, this compound was prepared from 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (159 mg, 0.30 mmol) and 2-aminoethanol (92 mg, 1.50 mmol). The reaction product was extracted into ethyl acetate and purified by a silica column (eluted with dichloromethane-MeOH 20:1) to give a pale yellow solid, 100 mg, 58% yield; mp 241-243° C. (from ethyl acetate-MeOH). NMR was consistent with the structure. Calcd. For C31H31N306S
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[CH:29]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH2:30]>C(O)C>[CH2:29]([S:31]([CH2:34][CH2:35][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: C=CS(=O)(=O)CC
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)(=O)CCON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime was reacted with sodium ethoxide and ethyl vinyl sulfone to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-[2-(ethylsulfonyl)ethyl]oxime, m.p. 144-148° C. Compound 27.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:21][CH2:20][C:13]3(C(=O)CCC3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:23]1CCCC1>>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:21][CH2:20][C:13](=[O:23])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)C12CCC(COCc1ccccc1)CC2
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CCC(COCc2ccccc2)CC1
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of the compound of Example 106 (18.43 g, 70.2 mmol) in tetrahydrofuran (400 ml) was added 50 ml of a 2% aqueous HCl solution and stirred for 24 hours. The mixture was concentrated in vacuo and the residual solution layered with ether. The ether layer was dried (MgSO4), concentrated in vacuo, then chromatographed to give 11.16 g (73% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[N:19]=[CH:18][N:17]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:21]=1
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(=O)(=O)N(C)C)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)-N,N-dimethylmethanesulfonamide (0.107 g, 0.50 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo and the residue was recrystallized from isopropanol to give C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Reference compound 1)
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 53 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.4 g), triethylamine (0,72 mL), 2,6-difluorocinnamic acid (1.0 g), WSC.HCl (1.0 g), and methylene chloride (50 mL), to give the captioned compound (1.1 g, 51%) as an oily product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:14][C:5]1[N:4]=[N:3][C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[N:15]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1cc(-c2ccccc2)c(Cl)nn1
Product: Cc1cc(-c2ccccc2)c(N2CCN(c3ncccn3)CC2)nn1
Reaction time: 168 h
Yield: 40 %

Procedure:
A synthetic reaction scheme for the preparation of6-methyl-4-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-7-057) is depicted in FIG. 26, and synthesis was carried out as described herein. A mixture of 3-chloro-6-methyl-4-phenylpyridazine (100 mg, 0.5 mmol), 1-(2-pyrimidyl)piperazine (400 mg, 2.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130 C for 7 days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, then 1:3, Ethyl Acetate: Petroleum ether, dried over filter funnel in vacuo to give, light yellow solid (68 mg, 0.20 mmol, yield 41.7%). Purity>95%; ESI-MS: m/z 333.1 (M+H+). 1H NMR (CDCl3): d 8.310 (d, J=5.0, 2H), 7.678 (d, J=7.5, 2H), 7.476 (m, 3H), 7.119 (s, H), 6.509 (t, J=4.5, 1H), 3.785 (t, J=4.5, J=5.0, 4H), 3.277 J=4.5, J=5.0, 4H), 2.669 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.BrC[CH2:23][CH2:24][CH2:25][C:26]12[CH2:37][CH2:36][CH2:35][C:33]3[C:34]1=[C:29]([CH:30]=[CH:31][CH:32]=3)[NH:28][C:27]2=[O:38].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C.[C].[Pd].O>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([CH2:1][CH2:23][CH2:24][CH2:25][C:26]23[CH2:37][CH2:36][CH2:35][C:33]4[C:34]2=[C:29]([CH:30]=[CH:31][CH:32]=4)[NH:28][C:27]3=[O:38])[CH2:9][CH2:10]1
Reactant: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
1-Benzyl-4-methyl-4-phenylpiperidine (62 mg, 0.24 mmol) was dissolved in ethanol (2 ml). Thereto was added palladium-carbon (10 mg), and the resulting solution was stirred at a room temperature for 17 hours in an atmosphere of argon. The reaction solution was filtered, the solvent was evaporated from the resulting mother liquor under a reduced pressure, and the thus obtained material was dissolved in anhydrous N,N-dimethylformamide (2 ml). The resulting solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (79 mg, 0.26 mmol) and potassium carbonate (51mg, 0.37mmol) and then the mixture was stirred at 60° C. for 3 hours. The reaction solution was mixed with ethyl acetate and water, and the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 50 mg of the title compound (0.12 mmol, 53% in yield).
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([C:20](O)=[O:21])#[C:16][C:17]([OH:19])=[O:18]>>[CH2:10]([N:9]1[C:20](=[O:21])[C:15](=[CH:16][C:17]([OH:19])=[O:18])[S:8][C:7]1=[N:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCNC(=S)NCCCCC
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCC
Yield: 44 %

Procedure:
Prepared by the method described in Example 1 from N,N'-dipentylthiourea (31.4 g, 150 mmoles) and acetylenedicarboxylic acid (17.1 g, 150 mmoles). Recrystallization from acetonitrile gave the product (20.6 g), mp 85°-88° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][C:25]([O:26][CH3:27])=[C:20]([F:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ncc(B(O)O)cc1F
Product: COc1ncc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)cc1F
Yield: 87.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 5-fluoro-6-methoxypyridine-3-boronic acid (159 mg, 0.94 mmol) were reacted. After purification the title compound (146 mg, 88% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.13(d, J=4.9 Hz, 1H), 8.45 (d, J=7.4 Hz, 1H), 8.29 (s, 1H), 8.11 (a d, J=13.8 Hz, 1H), 7.95(a d, J=7.2 Hz, 1H), 7.81 (a t, J=7.8 Hz, 1H), 4.03 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=354.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1O)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1OCc1ccccc1)CCCC2=O

Procedure:
Using a procedure analogous to Example 7 from 4.5 g (0.024 mole) of 5-hydroxy-6-methoxy-1-tetralone, 5.4 g (0.031 mole) of benzyl bromide and 10 g (0.072 mole of K2CO3 in 100 ml of acetone), the title product was obtained (5.13 g) as a white solid by crystallization with ether, mp. 90° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=2[N:10]=[CH:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 80 °C

Procedure:
180 g (1 mol) of 3-ethylxanthine were initially introduced into 1000 ml of dimethylformamide, the mixture was heated to 80° C. with stirring and, after the introduction of 88 g (0.64 mol) of potassium carbonate, treated dropwise with 133 g (1.05 mol) of benzyl chloride in the course of 1 hour. It was then stirred at 100° C. for 2 hours, treated with 1000 ml of water, and the precipitated product was filtered on a suction filter, washed with water until salt-free and dried in a vacuum drying oven at 100° C. If necessary, a further purification can be carried out by reprecipitating from 1 N sodium hydroxide solution using 4 N hydrochloric acid analogously to Example 1a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:24]3[C:33]4[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5cc(Cl)ccc5Cl)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(2,5-dichlorophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(2,5-dichlorophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.