Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][C:43]([O:51][CH3:52])=[C:44]([O:49][CH3:50])[CH:45]=2)[O:40][C:39]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][C:43]([O:51][CH3:52])=[C:44]([O:49][CH3:50])[CH:45]=4)[O:40][C:39]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1cc2oc(-c3ccccc3)c(I)c(=O)c2cc1OC
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1OC
Yield: 86 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-6,7-dimethoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a white solid (68 mg, 86%). LCMS (Method B): RT=4.81 min, [M+H]+=528.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]([CH3:23])[C@H:4]([N:7](C(OC(C)(C)C)=O)[NH:8]C(OC(C)(C)C)=O)[CH2:5][OH:6].[ClH:26]>C1COCC1>[ClH:26].[F:1][C:2]([F:24])([F:25])[C@@H:3]([CH3:23])[C@H:4]([NH:7][NH2:8])[CH2:5][OH:6]
Reactant: C[C@@H]([C@@H](CO)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H]([C@@H](CO)NN)C(F)(F)F
Temperature: 30 °C
Yield: 90.1 %

Procedure:
Di-tert-butyl 1-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]hydrazine-1,2-dicarboxylate (214.4 g, 0.576 mole) was dissolved in 640 mL THF. The solution was warmed to 30° C. and concentrated HCl (240 mL, 2.87 moles, 5 equivalents) was added drop wise over 20 minutes at 30-50° C. The solution was maintained at 50° C. for 2 hours and the THF was removed with aspirator vacuum at 30-60° C. The HCl solution was washed twice with 300 mL TBME. The aqueous phase was then stripped to a white solid using aspirator and vacuum pump at 50-60° C. The resulting solid was dried at 50° C. under vacuum at <10 mm Hg giving 108.3 g, 90% yield of (2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[C:13]([O:18][CH3:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[N:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O1CCOCC1>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([NH:11][C:12]2[C:13]([O:18][CH3:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[N:3]=1
Reactant: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: COS(=O)(=O)OC
Product: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a vigorously stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (7.25 g, 27.5 mmol, 1.00 eq) and potassium carbonate (7.61 g, 55.1 mmol, 2.00 eq) in 1,4-dioxane (92.0 mL), was added dimethyl sulfate (2.90 mL, 30.3 mmol, 1.10 eq) in a dropwise manner over 3 min. After 4 hr, additional portions of 1,4-dioxane (50.0 mL), potassium carbonate (3.80 g, 27.5 mmol, 1.00 eq), and dimethyl sulfate (1.00 mL, 10.4 mmol, 0.30 eq) were added to the reaction mixture. After a further 16 hr, the reaction mixture was concentrated in vacuo, diluted with water (120 mL), and stirred at ambient temperature for 1 hr. The resulting solids were filtered, washed with water (20 mL), and dried for 16 hr at 60° C. to give the title compound (6.42 g, 84% yield, >95% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: N#Cc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1

Procedure:
A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalladium (0) (83.15 mg, 0.0908 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1% yield).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[CH3:20][NH:21][CH3:22]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[CH2:9]([C:10]1[C:11]([N:21]([CH3:22])[CH3:20])=[N:12][C:13]2[C:18]([C:9]=1[NH2:8])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:18]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNC
Reactant: Clc1cc(NCc2ccccc2)c2ccccc2n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CN(C)c1nc2ccccc2c(N)c1Cc1ccccc1
Yield: 68 %

Procedure:
Benzyl-(2-chloroquinolin-4-yl)-amine (100 mg, 0.372 mmole), copper(II)sulphate pentahydrate (92.9 mg, 0.372 mmole) and dimethylamine (1M in MeOH, 3 mL) were stirred at 150° C. in a microwave oven for 5 hrs. The reaction mixture was dissolved with water and extracted with ethyl acetate. The residue obtained from the organic phases was purified using silica gel chromatography, eluting with dichloromethane:methanol 90:10. Precipitation in isopropyl ether gave a yellowish solid (70.0 mg, 68%).
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18]C)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.[Cl-].[Na+].O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
A mixture of 9-fluoro-6-methoxybenzo[g]isoquinoline-5,10-dione (0.072 g) and aluminum trichloride (0.112 g) in dry methylene chloride (40 mL) is stirred at room temperature for 4 hours under a nitrogen atmosphere. An additional portion of aluminum chloride (0.190 g) is added and the mixture is allowed to react at reflux for 1.5 hrs and at room temperature overnight. Following addition of brine (15 mL) the aqueous phase is separated and extracted with methylene chloride (3×5 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solvent is removed by distillation at reduced pressure to give an approximately 1:1 mixture (0.070 g) of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione (slower moving yellow spot on silica gel TLC plate, eluant methylene chloride/ethyl acetate 70/30) and 9-chloro-6-hydroxybenzo[g]isoquinoline-5,10-dione (faster moving yellow spot on the above chromatographic system) which is used without further purification for the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:17]([CH3:27])[C:16]=2[CH:28]=1.I[CH3:30]>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH:22]([CH3:30])[C:23]([O:25][CH3:26])=[O:24])[N:17]([CH3:27])[C:16]=2[CH:28]=1
Reactant: COC(=O)CCCc1nc2ccc(Br)cc2n1C
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CCc1nc2ccc(Br)cc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.6 M in THF, 6.15 ml) was added to a solution of methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)butanoate (1.02 g) in THF (20 ml) at −78° C. After being stirred at −78° C. for 30 min, iodomethane (0.612 ml) was added to the reaction mixture. The mixture was stirred at room temperature under Ar atmosphere for 2 h. The mixture was quenched with saturated NH4Cl solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (440 mg) as a pale yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][C:14]=2[CH:13]=[C:12]([Cl:30])[N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:17]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[C:15]2[C:10]([Cl:9])=[N:11][C:12]([Cl:30])=[CH:13][C:14]=2[N:18]=1
Reactant: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(Cn2c(Br)nc3cc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (352 mg, 1.98 mmol) was added to a solution of 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (200 mg, 0.99 mmol) stirring in degassed chloroform (20 mL) at room temperature. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. MS APCl calc'd. for C14H7BrCl2F3N3 [M+H]+ 426. found 426.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[OH:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:24])[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([C:21]([C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[OH:13])([OH:24])[CH2:22][CH3:23])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(C(F)(F)F)c1)c1ccc(O)cc1O

Procedure:
To a Grignard reactant prepared from 14.6 g. of magnesium turnings and 135 g. of 3-trifluoromethylbromobenzene in 330 ml. of tetrahydrofurane a solution of 16.6 g. of 2',4'-dihydroxy-propiophenone in 83 ml. of tetrahydrofurane is added dropwise, at 50° C., and the mixture is stirred at this temperature for 30 additional minutes. After cooling, the reaction mixture is decomposed with a cold 20% aqueous ammonium chloride solution, with stirring. The phases are separated, the aqueous phase is extracted with tetrahydrofurane, the combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. The residue is decolored with activated carbon in methanol, the solvent is filtered off, and distilled off under reduced pressure. If desired, the product is crystallized from a mixture of ethyl acetate and n-hexane to yield 26.6 g. of the named compound, melting at 137° to 138° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]1(=[O:31])[CH2:30][CH2:29][CH:28]=[CH:27]1>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>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:28]3[CH2:29][CH2:30][C:26](=[O:31])[CH:27]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: O=C1C=CCC1
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
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
A suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (500 mg, 1.268 mmol), 2-cyclopenten-1-one (0.410 mL, 5.07 mmol), 105° C. and bis(tri-tert-butylphosphine)palladium (0) (64.8 mg, 0.127 mmol) in Dioxane (4 mL) was capped, degassed and backfilled with argon. The reaction was heated at 105° C. After 6 h, the reaction was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluant: 40-100% EtOAc/hexane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 396.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:23]=[CH:24][CH2:25][CH3:26]>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH2:25][CH:24]=[CH2:23])[C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C)c(Br)cc1O
Reactant: CCC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCOc1cc(Br)c(C)cc1C
Temperature: 95 °C

Procedure:
A 250-mL round bottomed flask is charged with 5-bromo-2,4-dimethylphenol (3.135 g, 15.6 mmol) and dimethylformamide (DMF) (50 mL). Potassium carbonate (23.7 g, 172 mmol) and bromobutene (15.8 mL, 156 mmol) are added and the reaction mixture is heated to 95° C. for 2 hr. After cooling to room temp, water (200 mL) is added. The product is extracted into ether (2×100 mL), and the combined organic fractions are washed with brine, dried over sodium sulfate and dried in vacuo. Yield=3.63 g (91.3%) of light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 (38 mg, 0.098 mmol) in methanol (3 mL) was added NaBH4 (11 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h. Aqueous NaOH was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organic was then dried over Na2SO4, filtered and concentrated to give a residue that could be purified by silica gel chromatography (eluent: 1/4 hexanes/EtOAc). The desired 3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 was obtained as a white solid (22 mg, 58%). MS m/z 391.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.56 (m, 2H), 0.82 (m, 2H), 2.22 (s, 3H), 2.82 (m, 1H), 4.75 (s, 2H), 5.91 (brs, 2H), 6.75 (brs, 1H), 7.49 (m, 3H), 7.76 (m, 4H), 7.99 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([F:15])[C:3]=1[CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCOC(C)=O.Cl.Cl.[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:70]=[CH:69][C:68]([CH2:71][NH2:72])=[CH:67][CH:66]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:66]=[CH:67][C:68]([CH2:71][NH:72][C:17](=[O:19])[CH:16]([C:3]2[C:4]([F:15])=[CH:5][C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][C:2]=2[F:1])[O:20][CH2:21][CH3:22])=[CH:69][CH:70]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CCOC(C(=O)O)c1c(F)cc(C(=O)NCC(C)C)cc1F
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(C(=O)NCC(C)C)cc1F
Yield: 22.9 %

Procedure:
(RS)-(2,6-Difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid (71 mg) was dissolved in DMF (3.5 ml) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (88 mg), disopropylamine (114 mg) and 2-(1H-benzotriazole-1-yl) 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (80 mg) were subsequently added. After 30 min stirring at rt AcOEt (10 ml) was added and the organic layer was washed with 1 N HCl (2×10 ml), H2O (10 ml) and brine. The aqueous layers were extracted with more AcOEt (10 ml). After drying (MgSO4) the solvent was evaporated and the crude product was purified by HPLC to obtain 30 mg (23%) of (RS)-[(4-{[2-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White solid. MS 581.4 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH2:33][NH:32][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)NCCO)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminoethanol (8 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration in vacuo, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(2-hydroxyethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (6 mg, 10%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.18 (dd, 1H, J1=6.6 Hz, J2=1.8 Hz), 8.08 (d, 1H, J=2.1 Hz), 8.04-8.01 (m, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.60-7.55 (m, 1H), 6.39 (d, 1H, J=7.5 Hz), 6.29 (d, 1H, J=8.7 Hz), 4.30-4.26 (m, 1H), 3.78-3.69 (m, 3H), 3.58-3.49 (m, 3H), 2.21-2.08 (m, 3H), 1.81-1.78 (m, 1H), 1.19 (d, 3H, J=5.1 Hz). LC-MS: [M+H]+, 458, tR=1.52 min, HPLC: 96.29% at 214 nm, 96.47% at 254 nm, tR=5.332 min.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][NH:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:8])=[O:7].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]([CH2:3][C:2]([CH3:16])([CH3:15])[CH3:1])[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(C)(C)CN[C@@H](C(N)=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CN([C@@H](C(N)=O)c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 3 %

Procedure:
(R)-2-(2,2-Dimethyl-propylamino)-2-phenyl-acetamide (700 mg, 3.2 mmol) was dissolved in dichloromethane (15 mL) and chilled in an ice bath. The solution was treated with triethylamine (553 uL, 4.0 mmol) followed by 4-chlorobenzenesulfonyl chloride (671 mg, 3.2 mmol). After heating at 50° C. for 18 h, the mixture was cooled, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to an oil. Purification on a silica gel flash column (40% EtOAc in hexanes, eluent) afforded the title compound in 3% yield. 13CNMR (100 MHz, CDCl3) 28.6, 33.2, 62.7, 70.0, 128.8, 129.0, 121.1, 129.2, 130.7, 133.6, 138.7, 139.0, 172.7. MS 395.1 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:27]=[C:26]([NH2:28])[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)CC(=O)c2cccnc2)cc1Cl
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc(-c2cc(-c3cccnc3)nc(N)n2)cc1Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
4-(3-Chloro-4-methoxy-phenyl)-6-pyridin-3-yl-pyrimidin-2-yl amine was prepared by treateing 1-(3-chloro-4-methoxy-phenyl)-3-pyridin-3-yl-propane-1,3-dione (0.3 g, 1.0 mmol) with guanidine carbonate (0.21 g, 1.1 mmol) in dowtherm (7 mL) at 180° C. for 30 minutes. The mixture was cooled to temperature in the range of 20-40° C. and diluted with petroleum ether (25 mL). The mixture was stirred for 1 hour. The solid was filtered and dried to give the desired product.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: NC1CCCc2nccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2nccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoxalin-5-ylamine (313 mg, 2.09 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3,-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (227.8 mg, 1.05 mmol) followed by sodium triacetoxyborohydride (444 mg, 2.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2:MeOH:NH4OH) to provide the product as a clear oil (298 mg, 81%): 1H NMR (CDCl3): δ 1.56-1.66 (m, 2H), 1.70-1.95 (m, 4H), 2.04-2.22 (m, 4H), 2.71-2.85 (m, 2H), 2.87-3.05 (m, 2H), 7.69-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.34 (br s, 2H).