Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]1([N:12]=[C:13]=S)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)CCl.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23].Cl>CN(C=O)C.C(N(CC)CC)C>[C:3]([C:2](=[C:13]([NH:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[NH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]#[N:5])#[N:4]
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)CCN
Reactant: N#CCC#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)CCNC(Nc1ccccc1)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 47 %

Procedure:
To a solution of malononitrile (0.34 g, 5.15 mmol) in DMF (5 mL) at 0° C. first phenylisothiocyanate (0.60 mL, 5.02 mmol) and then triethylamine (1.4 mL) were added. The resulting mixture was stirred at 0° C. for 25 min, and then a freshly prepared mixture of EDC (2.90 g, 15.1 mmol), 3-methylbutylamine (1.20 mL, 10.3 mmol) and DMF (10 mL) was added. After stirring at room temperature for 2 d the mixture was poured into a mixture of ice-water (50 mL) and conc. HCl (3.0 mL). The product was extracted (2×30 mL ethyl acetate), the combined organic extracts were washed (2×30 mL brine), dried (magnesium sulfate) and concentrated. The remaining oil was mixed with methanol (3 mL), whereby a solid precipitated. After 20 h the solid was filtered off and dried in vacuo. 0.60 g (47%) of the title compound was obtained as slightly yellow crystals. Recrystallization from ethyl acetate/heptane yielded 0.40 g of an analytically pure sample, mp. 183-185° C. LCMS: MH+ calcd.: 255, found: 255. 1H NMR (400 MHz, DMSO-d6): δ=0.83 (d, J=7 Hz, 6H), 1.40 (q, J=7 Hz, 2H), 1.57 (nonett, J=7 Hz, 1H), 3.18 (m, 2H), 7.10 (m, 3H), 7.33 (t, J=8 Hz, 2H), 7,87 (s, br, 1H), 9.33 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ=22.06, 24.90, 35.34, 37.38, 41.92, 118.11, 121.46, 124.16, 129.15, 138.81, 161.43. Anal. Calcd. for C15H18N4 (254.34): C, 70.84; H, 7.13; N, 22.03. Found: C, 70.88; H, 7.28; N, 21.90.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]([CH:14]=[CH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH2:2]([N:9]1[C:13]([CH2:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1cncn1Cc1ccccc1)CC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(Cn2cncc2CCCC(c2ccccc2)c2ccccc2)cc1

Procedure:
1-benzyl-5-(4,4-diphenyl-1-butenyl)-1H-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount of Pd/C (10%) is added. The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloride-methanol mixture. Yield 1,3 g. M.p. of the hydrochloride salt is 200°-202° C.
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]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2[CH:54]=[CH:55]C=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CCC>CN(C=O)C>[CH2:52]([NH:51][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=2)[CH:20]=1)[CH2:53][CH2:54][CH3:55]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCN
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and butylamine (8.19 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.7 mg, 55%). LC-MS m/z 629 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:30]([NH:34][C:35](=[O:56])[CH2:36][N:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=2)[N:39]=[C:38]1[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=1)([CH3:33])([CH3:32])[CH3:31].[CH2:57]([OH:61])[CH2:58][CH:59]=[CH2:60]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[C:30]([NH:34][C:35](=[O:56])[CH2:36][N:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH:60]=[CH:59][CH2:58][CH2:57][OH:61])[CH:44]=2)[N:39]=[C:38]1[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CCCO
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(I)cc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCO)cc2c1=O
Yield: 47.5 %

Procedure:
A solution of palladium (II) acetate (82 mg, 0.37 mmol, 10 mol %) and tris (o-tolyl)phosphine (145 mg, 0.48 mmol) in anhydrous acetonitrile (40 mL) was sparged with argon for 5 minutes. Triethylamine (5.10 mL, 36.60 mmol) was added, followed by N-tert-butyl-2-[2-(3-chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]acetamide (INTERMEDIATE IV.12) (1.81 g, 3.66 mmol) and 3-buten-1-ol (1.57 mL, 18.30 mmol). The resultant mixture was heated at reflux temperature for 18 h. The resultant green suspension was concentrated in vacuo, and the residue was treated with ethyl acetate (100 mL) and filtered. The black precipitate was washed with ethyl acetate (2×50 mL), and the combined filtrates were washed with 1N HCl (aq.) (2×100 mL), brine (100 mL), dried (MgSO4) and concentrated to give the crude product as yellow-orange foam. Trituration with ether provided N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-hydroxybut-1-enyl)-4-oxo-4H-quinazolin-3-yl]acetamide (766 mg, 1.74 mmol, 48%) as an off-white powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:34]3[C:35]4[C:31](=[CH:30][CH:29]=[C:28]([C:27]([F:26])([F:38])[F:37])[CH:36]=4)[CH:32]=[N:33]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(C(F)(F)F)cc43)nc12
Temperature: 125 °C
Yield: 49.1 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (180 mg, 421 μmol) and 6-(trifluoromethyl)-1H-indazole (78.4 mg, 421 μmol) in dioxane (2 mL) was added sodium tert-butoxide (89.0 mg, 927 μmol) and bis(tri-tert-butylphosphine)palladium(0) (21.5 mg, 42.1 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-Butyl-2-(6-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 49%). 1H NMR (CDCl3) δ: 9.05 (s, 1H), 8.74 (d, J=0.5 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J=1.0 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 5.74 (s, 2H), 3.57-3.62 (m, 2H), 1.53 (s, 9H), 0.93-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:33][CH:34](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:35]>CN(C=O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:35][CH2:34][Cl:33])=[C:3]([O:25][CH3:26])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cl)cc1
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the DMF solution (10 mL) of tert-butyl 4-(7-hydroxy-6-methoxyquinazolin-4-yl)piperazinecarboxylate (1.8 g, 5 mmol), Cs2CO3 (3.3 g, 10 mmol) added 1-chloroethyl-tosylate (1.8 mL, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the crude residue was purified by RP-HPLC (reverse-phase high performance liquid chromatography) to afford the intermediate tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate as the desired product (850 mg, 40%). MS(ES) 423 (M+H)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.57 g (10.0 mmol) 5-bromo-nicotinic acid chloride hydrochloride, 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. with stirring for 1.5 h. After cooling to RT the mixture was mixed with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [FH:1].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:35](O)([CH3:37])[CH3:36])[CH:31]=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:35]([F:1])([CH3:37])[CH3:36])[CH:31]=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(F)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
XtalFluor® (66.19 mg, 0.29 mmol) was transferred to a flask and put under nitrogen, then DCM (2 mL) was added via syringe. The reaction was cooled to 0° C. in an ice bath then triethylamine trihydrofluoride (62.76 μl, 0.39 mmol) and triethylamine (26.7 μL, 0.19 mmol) were added via syringe. The reaction was stirred until all solids dissolved completely then was cooled to −78° C. in a dry ice/acetone bath. A solution of 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol (Example 27, 60 mg, 0.19 mmol) in DCM (1 mL) was added via syringe then the reaction was warmed to 0° C. and allowed to stir for 1 hour. Upon completion, a solution of NaHCO3 (sat aq.) and EtOAc was added. The combined organics were separated and washed with a 50% aq. bleach solution. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 0-25%, EtOAc/Hexanes), and a second purification with preparative HPLC (Shimadzu SCL-10 VP, ACN/H2O, 25-90% (0.1% TFA)) afforded the title compound as a pure solid (18.2 mg, 22%). 1H NMR (400 MHz, CDCl3) δ 9.08 (d, J=1.8 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.53 (dd, J=5.4, 8.4 Hz, 2H), 7.43 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 7.12 (t, J=8.7 Hz, 2H), 5.35 (s, 2H), 1.99-1.63 (m, 6H). [M+H]=314.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:9]2[CH3:23])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:24][C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:23])[C:10]=1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: Cn1c(CCc2ccc(F)cc2)cc(=O)n1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClCCl
Product: Cn1c(CCc2ccc(F)cc2)c(Br)c(=O)n1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 84.3 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.296 g) in methylene chloride (5 mL) was added N-bromosuccinimide (0.168 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-bromo-2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.312 g) as a white solid. MS (ESI+): 395.0 ([M+H]+).
Reaction SMILES: [OH-].[Na+:2].C(O)C.[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@@H:34]1[O:36][C@H:35]1[C:37]([O:39]CC)=[O:38])=[O:33])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:14][CH2:13]1)=[O:11]>C(O)C>[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@@H:34]1[O:36][C@H:35]1[C:37]([O-:39])=[O:38])=[O:33])[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:16][CH2:17]1)=[O:11].[Na+:2]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(Cc2ccc(OC)c(OC)c2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)[C@@H]3O[C@H]3C(=O)[O-])CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
Under cooling with ice, a 0.48N sodium hydroxide-ethanol solution (9.48 ml) was added to an ethanol solution (20 ml) of ethyl trans-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate (2.38 g) obtained above, and the mixture was stirred at room temperature for 2.5 hours. After removal of ethanol by distillation under reduced pressure, water was added, and any insoluble matters were removed by filtration using sellaite. The filtrate was concentrated and dried under reduced pressure to yield 2.31 g of sodium trans-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate as a light yellow powder (yield: 98%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][C:26]#[N:27]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[C:25](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([O:1][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)/[C:26]#[N:27])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COCCOCCl
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 37 %

Procedure:
The hydroxyl group of 4-hydroxy-3-nitrobenzaldehyde (500 mg) was protected by use of 2-methoxyethoxymethyl chloride (374 mg) in accordance with (production process 1), to thereby produce an MEM form (605 mg, yield: 70%). The resultant MEM form (255 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-3-nitro-phenyl]-acrylonitrile (153 mg, yield: 40%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-3-nitro-phenyl]-acrylonitrile (140 mg) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (72 mg, yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]([OH:25])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]([NH2:26])=[O:25])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: O=C(O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
N,N′-carbonyldiimidazole are added to 1.13 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 15 ml of tetrahydrofuran and the reaction mixture is stirred for 45 minutes at 60° C. Then ammonia gas is piped in at ambient temperature over a period of 25 minutes. The dark reaction solution is evaporated down using the rotary evaporator and the solid residue is stirred with water. Then it is acidified with 1 N hydrochloric acid and the precipitate formed is suction filtered, washed with water and dried in vacuo in the desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)C(OC)=O)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Li].CC[O:36][CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:9]2[CH2:10][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:37]([CH3:38])([OH:36])[CH3:32])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1
Reactant: CCOCC
Reactant: [Li]C
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.044 g (0.1 mmol) of methyl {1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetate in 5 mL dry ether was cooled to −78° C. under nitrogen. To this was added 0.45 mL of a 1M solution of methyllithium and the solution was stirred at −78° C. for 30 minutes. A second aliquot of 0.45 mL of a 1M solution of methyllithium was added, and the solution was allowed to warm to −60° C. After 1 h, the reaction was quenched by addition of 5 mL water and the layers were separated. The aqueous layer was washed with three 10 mL portions of ethyl acetate and the organic extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound; 1NMR (CDCl3) δ 1.37 (s, 6H), 3.52 (m, 2H), 4.12 (m, 21), 4.50 (s, 1H), 6.68-6.76 (m, 3H), 7.22-7.42 (m, 9H); Mass Spectrum: m/e=440 (M+1 35Cl and 442 (M+1 37Cl).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:17]([F:30])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C([Cl:34])(=O)C>>[ClH:34].[NH2:20][CH2:19][C:18]1[CH:28]=[CH:29][C:15]([C:12]2[N:10]3[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]3=[N:14][CH:13]=2)=[CH:16][C:17]=1[F:30]
Reactant: CC(=O)Cl
Reactant: CCCCNc1ccc2ncc(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)n2n1
Product: CCCCNc1ccc2ncc(-c3ccc(CN)c(F)c3)n2n1
Product: Cl
Temperature: 25 °C
Yield: 97.4 %

Procedure:
The solution of tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzylcarbamate (91 mg, 0.22 mmol) was cooled to 0° C. and treated with acetyl chloride (518 mg, 6.6 mmol). The reaction was maintained at room temperature for overnight. The resulting solution was concentrated under reduced pressure to afford 3-(4-(aminomethyl)-3-fluorophenyl)-N-butylimidazo[1,2-b]pyridazin-6-amine HCl salt (75 mg, 88% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.38 (s, 1H), 8.23 (d, J=11.4 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.00 (d, J=9.9 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.9 Hz, 1H), 4.31 (s, 2H), 3.43 (t, J=7.1 Hz, 2H), 1.65-1.84 (m, 2H), 1.42-1.59 (m, 2H), 1.01 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 314.4 [(M+H)+, calcd for C17H21FN5 314.2].
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH:42]C(OC(C)(C)C)=O)=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>ClCCl.O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH2:42])=[CH:29][CH:30]=4)=[O:24])(=[O:20])=[O:21])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Reaction time: 4 h

Procedure:
A room temperature solution of Example 49A (19 mg, 0.03 mmol) in dichloromethane (1 mL) was treated with 4M HCl in dioxane, stirred for 4 hours, and concentrated to provide the desired product. MS (ESI(+)) m/e 650 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ9.12 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.95 (dd, 1H), 7.94 (m, 3H), 7.65 (br s, 3H), 7.50-7.35 (m, 4H), 7.15 (dt, 1H), 3.18 (d, 2H), 2.75 (s, 6H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).