Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C2CCCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 312.2 %

Procedure:
3-Amino-1-N-Boc-piperidine (2.5 g, 12.5 mmol) was added to the solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 34 mL, 11 3 mmol) and heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (20 mL) and potassium carbonate powder (2.2 g, 15.8 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (100 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×, 50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 4.93 g (82% yield) of ethyl 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:8]=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[C:11]([CH3:13])[N:12]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1c(C)cc(Br)nc1C
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
tert-Butyllithium (1.040 mL, 1.77 mmol) was added dropwise to THF (5 mL) at −100° C. under an argon atmosphere. A solution of 6-bromo-3-methoxy-2,4-dimethylpyridine (191 mg, 0.88 mmol) in THF (3 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.74 mmol) in THF (7 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (3.54 mL, 4.42 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified on a silica gel column eluted with 0-10% 0.1 M NH3 in MeOH in DCM to give the title compound (272 mg, 84%). MS (ES+) m/z 440, 442 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(#N)C.ClCCl.Cl>O1CCOCC1>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:16]3[CH:23]=[N:22]2)=[CH:25][CH:26]=1)(=[O:31])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Into a 200 mL round-bottomed flask was placed a stir bar, Compound A1 (1.2 g), anhydrous acetonitrile (50 mL), and dichloromethane (15 mL). 4M HCl in 1,4-dioxane (15 mL) was added under nitrogen and the mixture was stirred at 40° C. for 10 minutes. The solution turned cloudy. The precipitate was isolated and purified by HPLC to give Compound A6. 1H NMR (DMSO-d6, 400 MHz) δ 2.04 (m, 2H), 2.25 (m, 2H), 3.21 (m, 2H), 3.28 (s, 3H), 3.32 (m, 2H), 5.60 (m, 1H), 8.16 (d, 2H), 8.61 (d, 2H), 8.70 (s, 1H), 8.79 (s, 1H). LCMS: calculated for C17H19N5O3S 373.12, observed 374.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[NH:16][CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]([O:39][CH2:40]C)=[O:38]>C(Cl)Cl>[CH3:40][O:39][C:37]([N:16]1[CH2:17][CH:18]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:12]2[N:11]([C:9](=[O:10])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:15][CH2:14][CH:13]12)=[O:38]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Solvent: ClCCl
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution containing crude 49 (229 mg, 0.47 mmol) in DCM (5 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by ethyl chloroformate (73 mg, 0.78 mmol). After 30 min, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1 hexanes/EtOAc to 1:1 hexanes/EtOAc) to afford 226 mg (88%) of 50 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3): δ8.25-8.14 (m, 1H), 8.10 (s, 1H), 7.03-6.97 (m, 1H), 6.95-6.83 (m, 1H), 5.36-5.32 (m, 1H), 4.63 (dd, J=5.4, 19.8 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.22 (m, 1H), 4.09-4.04 (m, 2H), 3.95 (app t, J=5.7 Hz, 1H), 3.80 (s, 3H), 3.53-3.48 (m, 2H), 2.49-2.43 (m, 0.5H), 2.31-2.24 (m, 0.5H), 1.94-1.88 (m, 1H), 1.77-1.65 (m, 6H), 1.44 (s, 9H), 1.29-1.10 (m, 5H) ppm. Mass spectrum, m/z [543.4] (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[F:48][C:49]([F:53])([F:52])[CH:50]=O>CN(C=O)C.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:50]([C:49]([F:53])([F:52])[F:48])=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: O=CC(F)(F)F
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF was combined with 30 mg (0.26 mmol) trifluoroacetaldehyde and 3 drops of TFA and stirred for 2 h at 100° C. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2-(Hydroxyphenyl)acetic acid (50 g) was added to a solution of hydrogen chloride in methanol [prepared from acetyl chloride (25 ml) and methanol (250 ml)]. The solution was stirred at room temperature for three hours and then allowed to stand overnight (fifteen hours). The resulting mixture was concentrated under reduced pressure, and the residue was taken up in ether (250 ml) and washed with an aqueous solution of sodium bicarbonate until effervescence ceased. The ethereal solution was dried and then concentrated under reduced pressure and the resulting solid was recrystallized from ether/petrol to afford methyl (2-hydroxyphenyl)acetate (50 g; 92% yield) as white, powdery crystals, top. 70°-72° C.; infrared max. (nujol mull): 3420, 1715 cm-1 ; 1H nmr (90 MHz): delta 3.70 (2H,s), 3.75 (3H,s), 6.80-6.95 (2H,m), 7.05-7.10 (1H,m), 7.15-7.25 (1H,m), 7.40 (1H, s) ppm.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=O)=O.[C:27]1(C)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:27]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([CH:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(CC)C(CO)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Product: CCN(CC)C(CO)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 90 °C
Yield: 49 %

Procedure:
0.1 g (0.254 mmol) of 2-trifluoromethanesulfonyloxy-8-(1-diethylamino-2-hydroxyethyl)quinoline, 3 ml of toluene, 62 mg (0.51 mmol) of of phenylboronic acid, 53 mg (0.38 mmol) of potassium carbonate and 17.6 mg (0.0152 mmol) of tetrakis(triphenylphosphine)palladium are placed in a 20 ml three-necked flask. The mixture is heated with an oil bath at 90° C. for 2 h and 10 ml of water are added. Extraction is carried out with ethyl acetate and the organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: dichloromethane/methanol 95/5) to provide 40 mg of 2-phenyl-8-(1-diethylamino-2-hydroxyethyl)quinoline in the form of a colorless oil. (Yield: 49%)
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([Br:28])=[CH:20][C:19]=1[C:29]([OH:31])=O.[Cl:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1>O1CCCC1>[Br:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([O:17][CH3:16])=[C:19]([C:29]([NH:48][CH2:47][CH2:46][N:43]2[CH2:42][CH2:41][N:40]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([Cl:39])[C:33]=3[Cl:32])[CH2:45][CH2:44]2)=[O:31])[CH:20]=1
Reactant: NCCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: COc1c(C(=O)O)cc(Br)c2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
Triethylamine (1.24 mL, 8.87 mmol) and isobutyl chloroformate (0.50 mL, 3.9 mmol) are added to 1-methoxy-4-bromo-2-naphthoic acid (European Published Patent Application EP 0 539 281A1) (1.0 g, 3.55 mmol) in dry tetrahydrofuran (20 mL) at 0° C. and allowed to stir for 1 hour. To this mixed anhydride is added 4-(2,3-dichlorophenyl)-l-piperazineethanamine (0.97 g, 3.55 mmol) in dry tetrahydrofuran (5 mL) and stirring continued for 18 hours, gradually allowing the mixture to warm to room temperature. The reaction mixture is washed with saturated sodium chloride (NaCl), dried (sodium sulfate), and concentrated to give 0.27 g of the title compound as a white solid; mp 137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:46])[N:14]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:45])[CH3:44])[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[O:34])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25]C(=O)C(F)(F)F)[CH:20]=2)[CH:17]=1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C:16]1[CH:17]=[C:12]([NH:11][C:9]([O:8][CH3:1])=[O:10])[C:13](=[O:46])[N:14]([CH2:32][C:33]([NH:35][CH:36]([CH:43]([CH3:45])[CH3:44])[C:37](=[O:42])[C:38]([F:39])([F:40])[F:41])=[O:34])[CH:15]=1
Reactant: CC(C)C(NC(=O)Cn1cc(Cc2cccc(NC(=O)C(F)(F)F)c2)cc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1cc(Cc2cccc(N)c2)cn(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Reaction time: 6 h
Yield: 50 %

Procedure:
2-[3-Benzyloxycarbonylamino-5-(3-trifluoroacetylaminobenzyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.19 g), and 1N sodium hydroxide (3 mL) were combined in methanol and allowed to stir for 6 h. The methanol was evaporated, the residue was dissolved in ethyl acetate, dried, evaporated, and purified by chromatography, eluting with ethyl acetate:dichloromethane (gradient, 0:100, 5:95), to give the title compound (0.070 g).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[CH3:24][C:16](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCc2c[nH]c(N)n2)nn1
Yield: 43.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.062 g, 0.362) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.075 g, 0.434 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.054 g, 43%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.39 (s, 1H), δ 7.12-7.07 (m, 5H), δ 6.54 (s, 1H), δ 6.36 (s, 1H), δ 5.09 (s, 2H), δ 3.01 (t, 2H), δ 2.76 (t, 2H), δ 1.60 (s, 3H) ppm; 13C; 147.7, 143.1, 136.3, 132.7, 129.9, 128.9, 128.6, 128.5, 128.2, 127.4, 127.1, 124.9, 109.9, 61.2, 23.0, 22.3, 14.7 ppm; HRMS (ESI) calcd for C16H20N6(M+) 308.1749. found 308.1742.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:21](=[O:22])[C:20]3[CH:19]=[C:18](Br)[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[N:41]=[C:40]([O:42][CH3:43])[C:39](B(O)O)=[CH:38][N:37]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:21](=[O:22])[C:20]3[CH:19]=[C:18]([C:39]4[C:40]([O:42][CH3:43])=[N:41][C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate AI) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white foam. tR=5.79 min (HPLC 4); ESI-MS: tR=1.26 min, [M+H]+ 596/598 (LC-MS 1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[CH:13]=[O:14]
Reactant: CSc1cc(CO)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of [3-(methylthio)-5-(trifluoromethyl)phenyl]methanol (200 mg, 0.99 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and then Dess-Martin periodinane (573 mg, 1.35 mmol) was added. The reaction was slowly warmed to room temperature. After stirring at room temperature for twenty minutes, the reaction was poured into 1N NaOH (25 mL). The mixture was extracted with EtOAc (75 mL). The organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 1% to 10% EtOAc/hexanes afforded 3-(methylthio)-5-(trifluoromethyl)benzaldehyde. Rf=0.55 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.02 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 2.58 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:13]S(O)(=O)=O.OO>>[OH:13][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: OO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-Benzodioxan-6-carboxaldehyde (5.20 g) was dissolved in MeCH (60 mL) containing conc. H2SO4 (0.6 mL). At 0° C. an aqueous solution of 30% H2O2 (4.7 mL) was added to the mixture over 5 minutes. The mixture was warmed to room temperature, stirred an additional 18 h and evaporated. The residue was taken up with H2O and extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 3:1) to give 6-hydroxy-1,4-benzodioxan (3.85 g). ESMS: m/z 153 MH+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: Nc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
In ethanol (100 ml) was dissolved 1-(3-nitrobenzyl)piperidine (32.2 g), and to the mixture was added dried 10% palladium on carbon (1.61 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from diisopropylether-hexane to give 1-(3-aminobenzyl)piperidine (15.8 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.CCCCCC.[C:28](OCC)(=[O:30])C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:30][CH3:28])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(-c2cccc(F)c2)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: COc1cc(-c2cccc(F)c2)cnc1C#N
Temperature: 25 °C

Procedure:
To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet is charged 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine, 8, (9.28 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction solution is heated to reflux for 20 hours. The reaction can be determined to be complete due to the disappearance of 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture is cooled to room temperature and combined with water (500 mL). The mixture is cooled to 0° C. to 5° C. and stirred for 3 hours. The resulting solid is collected by filtration and washed with water, then hexane. The resulting cake is then dried in vacuo at 40° C. to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[CH:47][CH:46]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:50]([CH2:49][C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:58][CH:57]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CNc2ccccn2)cc1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
To a suspension containing a mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 5A (1.2 g, 3.68 mmol) was added N-(4-methoxybenzyl)pyridin-2-amine (1.183 g, 5.52 mmol) in THF (36.8 mL) at 0° C. This mixture was charged with a 1M solution of potassium tert-butoxide (7.36 mL, 7.36 mmol), slowly via syringe. The dark suspension was stirred for 20 min at room temperature. Volatiles were removed in vacuo and the resulting residue was triturated with MeOH and cooled to 0° C. Filtration, with cold MeOH washes afforded a tan solid which was dissolved in THF and azeotroped with PhMe to remove residual MeOH, then dried in vacuo overnight, which afforded 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (1.31 g, 68.5% yield) as a tan solid. LC/MS, m/z 504.0 (M+1). HPLC Rt=4.265 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (1H, d, J=2.27 Hz), 8.62 (1H, d, J=2.27 Hz), 8.35-8.48 (4H, m), 8.23 (1H, s), 7.67-7.83 (1H, m), 7.32 (2H, dd, J=8.56, 2.27 Hz), 7.24 (1H, dd, J=7.05, 5.29 Hz), 7.00 (1H, s), 6.79-6.89 (2H, m), 5.60 (2H, s), 3.62-3.72 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][CH2:16][CH2:17][CH2:18][NH2:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=1)=[O:29]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2nccc(OCCCN)c2cc1OC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(OCCCNC(=O)Nc3ccc(F)cc3)c2cc1OC
Reaction time: 0.25 h

Procedure:
6,7-Dimethoxy-4-(3-aminopropoxy)quinoline 150 mg (0.57 mM) and ethyl acetate (20 ml) were stirred at room temperature, and then 4-fluorophenyl isocyanate (0.078 ml, 0.68 mM) was added and the mixture was further stirred for 15 minutes. The precipitated solid was filtered out to obtain the target substance (92 mg) as a white solid.