Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18].[N-:20]=[C:21]=[S:22]>CCCCC>[CH2:16]([NH:19][C:21]([NH:20][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[S:22])[CH2:17][NH:18][C:14]([NH:13][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[S:15]
Reactant: NCCN
Reactant: [N-]=C=S
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NCCNC(=S)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1

Procedure:
To 10.25 grams (.044 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 10° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 1.73 grams (.0222 moles) of ethylenediamine. The reaction mixture became viscous, pentane was added and the reaction mixture stirred for 6 hours at room temperature. The pentane was stripped from the reaction mixture to leave a yellow solid weighing 10.7 grams (90% crude yield). The product melted at 149°-152° C. with decomposition and its infrared spectrum had a strong band at 1530 cm-1 and moderate NH bands at 3350 cm-1 and the isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:19]=[CH:20][C:21]([N:1]=[N+:2]=[N-:3])=[CH:22][CH:23]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N=[N+]=[N-])cc1)C(C)(C)C
Temperature: 120 °C
Yield: 15 %

Procedure:
Sodium azide (37.9 g, 0.58 mol) was added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (6.0 g, 19.4 mmol) in DMF (400 mL), and the mixture heated at 120° C. for 24 hours. The solvent was removed in vacuo and the residual solid taken up in ethyl acetate (200 ml). The organic phase was washed with 1M Na2CO3 (1×400 ml) and brine (1×400 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow solid. Purification by column chromatography (SiO2, 6:1 iso-hexane:ethyl acetate) afforded the title compound as a yellow solid (1.96 g) and [1(S)-(4-Azidobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester as an orange solid (0.97 g) (47% combined yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]([C@@H:51]3[CH2:55][C@H:54]([CH3:56])[CH2:53][NH:52]3)=[N:48][CH:47]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([CH3:56])[CH2:55][C@H:51]1[C:49]1[NH:50][C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)=[CH:47][N:48]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.59 mmol, Preparation 2) and HATU (270 mg, 0.71 mmol) were stirred in DMA (2 mL) for 10 min and then 5-(4-bromo-phenyl)-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazole 2 HCl (224 mg, 0.59 mmol, Preparation 8) and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) were added. The resulting mixture was stirred at RT overnight, diluted with ethyl acetate (50 mL), and washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes)). Fractions with desired product were combined and concentrated to give the title compound (183 mg, 66% yield) (m/z): [M+H]+ calcd for C21H27BrN4O3 463.13, 465.12 found 465.3.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.C([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=O)C.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1.CO>C1COCC1>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:25](=[O:26])[C:24]([OH:23])([CH3:28])[CH3:29])=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C(=O)C(C)(C)O
Reaction time: 2.5 h
Yield: 52 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a (0.22 g) was reacted with 2-acetoxyisobutyryl chloride (1.2 eq) followed by suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per general procedure K. The resulting compound was dissolved in 2 mL THF and 2 mL MeOH followed by the addition of 2 mL 1M liOH and the resulting solution stirred for 2.5 hours. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 80.2 mg of 407 after RP-HPLC purification (52% yield). MS (Q1) 467.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([F:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([Mg]Br)[CH:23]=[CH2:24]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([F:21])[CH2:9][CH2:24][CH:23]=[CH2:22])[CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](F)c2cccc(Br)c2)cc1
Solvent: C1CCOC1
Product: C=CCC[C@H](F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of toluene-4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethyl ester (5 mmol) in THF at room temperature is treated dropwise with a 1M solution of allylmagnesium bromide, stirred at room temperature for 5 h, quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to afford 1-bromo-(S)-3-(1-fluoropent-4-en-1-yl)benzene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:26]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][C:12]([NH:14][C:15]4[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[N:11][CH:10]=3)=[CH:5][CH:4]=2)=[N:2][N:28]=[N:27]1
Reactant: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(-c4nnn[nH]4)cc3)o2)c1
Temperature: 120 °C
Yield: 89.3 %

Procedure:
N-(3-((5-(4-cyanophenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 7 (0.12 g, 0.338 mmol) was dissolved in anhydrous DMF (10 mL), Sodium azide (0.088 g, 1.35 mmol) and ammonium chloride (0.072 g, 1.35 mmol) were added to above solution. Resulting suspension was heated at 120° C. for overnight (14 hours). Reaction was cooled down and water was added. Resulting (precipitated) solid was filtered, washed with water, methanol, and water. This was further purified by dissolving into DMSO and re-precipitated with addition of water. Resulting solid was filtered, washed with water, methanol and dried under high vacuum to yield N-(3-((5-(4-(1H-tetrazol-5-yl)phenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 41 (0.12 g, 90%) as a white solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:15][CH2:16][CH2:17][CH3:18])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH:19]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20]1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:19]1([NH:22][C:23](=[O:24])[O:14][C:11]2[CH:10]=[CH:9][C:8]([S:7][CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1
Reactant: CCCOC(CSc1ccc(O)cc1)OCCC
Reactant: O=C=NC1CC1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCOC(CSc1ccc(OC(=O)NC2CC2)cc1)OCCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dipropoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Cyclopropylisocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dipropoxyethylthio)phenyl] N-cyclopropylcarbamate as the residue.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:28])=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:28])=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:19]=1
Reactant: CON(C)C(=O)C=Cc1cc(Br)ccc1F
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cc(Br)ccc1F)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 40.6 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (15.3 mL, 13.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (8.9 mL, 13.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then 3-(5-bromo-2-fluoro-phenyl)-N-methoxy-N-methylacrylamide (1.3 g, 4.4 mmol, in tetrahydrofuran 10.0 mL) prepared in Step 3 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 620.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[C:37]([NH:56][CH2:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:60]([CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:67])([CH3:69])[CH3:68])[CH2:59][CH2:58][CH2:57][NH:56][C:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)N(CCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 87.7 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)pyrazol-4-yl]carbamate (423 mg) and tert-butyl 2-{[3-(tritylamino)propyl]amino}ethylcarbamate (410 mg) in dehydrated chloroform (2.5 ml) was added N-ethyldiisopropylamine (0.152 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added ethyl acetate, and the solution was washed successively with water, 5% aqueous citric acid solution, 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/methylene chloride to give tert-butyl (2-{N-({[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}carbonyl)-N-[3-(tritylamino)propyl]amino}-ethyl)carbamate (657 mg) as a solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:13])[CH:6]=1.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)(=O)C>[C:1]([C:14]1([NH:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:13])[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)#[N:2]
Reactant: [C-]#N
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(N)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(NC2(C#N)CCCC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
Sodium cyanide (0.74 g, 15 mmol) was added to a mixture of 4-amino-2-fluorobenzonitrile (1.36 g, 10 mmol) and cyclopentanone (1.26 g, 15 mmol) in 90% acetic acid (10 ml). The reaction mixture was stirred at room temperature for 3 hours and then the medium was hearted to 80° C. and stirred for an additional 5 hours. The medium was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 97:3) to yield 4-(1-cyanocyclopentylamino)-2-fluorobenzonitrile (54b) (2.07 g, 9.03 mmol, 90%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.69-1.91 (m, 4H), 2.13-2.18 (m, 2H), 2.37-2.42 (m, 2H), 5.08 (bs, 1H), 6.54-6.62 (m, 2H), 7.39 (t, J=7.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 23.7, 39.8, 56.8, 89.6 (d, J=15.8 Hz), 101.2 (d, J=23.8 Hz), 110.9, 115.2, 120.8, 134.1 (d, J=2.4 Hz), 150.3 (d, J=11.2 Hz), 164.5 (d, J=254.1 Hz).
Reaction SMILES: NC1C(NC)=[C:4]([CH:9]=[C:10]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:21]([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)(N1C=CN=C1)=O.[O:33]1CCCC1>>[CH3:18][C:13]1[C:12]([C:10]2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:32]3[N:28]([CH3:21])[C:29](=[O:33])[NH:30][C:31]=3[CH:11]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: C1CCOC1
Reactant: CNc1c(N)cc(-c2c(C)noc2C)cc1C(=O)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COC(=O)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)n(C)c12
Temperature: 100 °C
Yield: 35 %

Procedure:
Methyl 3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)benzoate (1.1 g, 4 mmol) and 1,1′-carbonyldiimidazole (1.3 g, 7.99 mmol) were stirred in Tetrahydrofuran (100 ml) in a sealed pressure vessel. Reaction was heated to 100° C. and allowed to react overnight. Next day solvents were removed under reduced pressure. Material was slurried in minimal DCM, sonicated and filtered. Solids were air dried to afford methyl 6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate as an off-white powder (417 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].O>CN1CCN(C)C1=O.CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[NH:29][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCCCN
Solvent: CN1CCN(C)C1=O
Solvent: CC(C)=O
Solvent: O
Product: CCCCNc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
In a sealed tube, a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and butylamine (0.116 ml) in 1,3-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone to give 6-[5-amino-6-(butylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (71 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[N:26]=3)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[N:20]=2)[CH2:10]1.[CH3:35][O:36][C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:38].CCN=C=NCCCN(C)C.C(N(CC)CC)C.CN1C=CN=C1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:17]2[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[N:20]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:43]([C:42]4[CH:46]=[CH:47][C:39]([C:37]([O:36][CH3:35])=[O:38])=[CH:40][CH:41]=4)=[O:44])[CH2:10]3)[CH:16]=2)=[N:26][C:27]=1[O:33][CH3:34]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(Nc2cc(N3CCCC(N)C3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC2CCCN(c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 6-(3-aminopiperidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine trifluoroacetate (350 mg, 0.94 mmol), 4-(methoxycarbonyl)benzoic acid (171 mg, 0.94 mmol), EDCI (725 mg, 3.79 mmol), triethylamine (288 mg, 2.84 mmol) and 1-methyl-1H-imidazole (311 mg, 3.79 mmol) in dichloromethane (15 mL) was stirred at room temperature for 16 h. The residue was concentrated in vacuo then 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 give methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoate (50 mg, 10%) as a white solid. LC-MS: 532 [M+1]+, tR=1.58 min.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[C:20]([F:31])([F:30])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]>CC(C)=O.C(OCC)(=O)C>[F:31][C:20]([F:30])([O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[F:1])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: O=C(NCc1ccco1)C(F)(F)Br
Reactant: Oc1ccc2ccccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(NCc1ccco1)C(F)(F)Oc1ccc2ccccc2c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 112.1 %

Procedure:
To a solution of 1-fluoronaphthalen-2-ol (280 mg, 1.73 mmol) and K2CO3 (1.2 g, 8.65 mmol) in 10 mL of acetone, 2-bromo-2,2-difluoro-N-(furan-2-ylmethyl)acetamide (527 mg, 2.08 mmol) were added. The resulting mixture was stirred at 40° C. overnight. The reaction was cooled at room temperature, diluted with ethyl acetate (30 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2,2-difluoro-2-[(1-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)acetamide as red oil (650 mg) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][S:28]([CH:31](O)[CH3:32])(=[O:30])=[O:29].C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(O)S(C)(=O)=O
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: [Cu+2]
Agent: CC[SiH](CC)CC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCOCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 21 %

Procedure:
To a suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (52 mg, 0.108 mmol) obtained in Step F of Example 1 in methylene chloride (anhydrous, 5 mL) were added copper trifluoromethanesulfonate (20 mg, 0.005 mmol), methanesulfonylethanol (200 μL), and triethylsilane (500 μL, 3.13 mmol) under a nitrogen atmosphere, and the mixture was stirred thoroughly for a whole day and night. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with 2% aqueous EDTA, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-ethoxymethyl)-benzamide (13.3 mg, 21%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)C=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:4]([Si:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[CH:11][C:10]=1[F:19])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 254.7 %

Procedure:
A solution of Intermediate 368.2 (394 mg, 0.50 mmol) and 1 M TBAF (in THF) in THF (10 mL) was stirred for 2 h. The mixture was dilute with EtOAc and washed with H2O (3×50 mL) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 324 mg of Intermediate 368.1. LCMS (2 min gradient) RT=2.06 min, 669.5 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)=O.[ClH:21].C(OCC)(=O)C>[C].[Pd].CO>[ClH:21].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCOc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: O=CO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of ethyl 4-[(3-cyanophenyl)oxy]butanoate obtained in Reference Example 41 (8.50 g, 36.4 mmol), 10% palladium carbon (containing 50% water)(12.8 g), formic acid (98 mL) and methanol (80 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. 4N Hydrogen chloride/ethyl acetate solution (15.0 mL, 60.0 mmol) was added to the obtained residue, and the mixture was stirred, and concentrated under reduced pressure. The residue was crystallized from toluene, and the crude crystals were recrystallized from diethyl ether to give the title compound as a white powder (7.79 g, 78%).