Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:59]=[C:50]3[CH2:51][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:53][CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:38]2[CH:39]=[C:40]([NH:46][C:47]3[CH:59]=[C:50]4[CH2:51][N:52]([CH:55]5[CH2:58][O:57][CH2:56]5)[CH2:53][CH2:54][N:49]4[N:48]=3)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:34])([CH3:35])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 75.8 %

Procedure:
A sealed tube was charged with the mixture of (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b (300 mg, 0.584 mmol), 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 252a (222 mg, 0.584 mmol), Pd(dppf)Cl2 (48 mg, 0.0584 mmol), K3PO4.3H2O (311 mg, 1.168 mmol), and NaOAc (96 mg, 1.168 mmol) in CH3CN (20 mL). The system was evacuated and then refilled with N2. And the reaction mixture was heated at 110° C. for 2 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 318a as a yellow solid (304 mg, 74%). MS: [M+H]+ 687.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=1)[CH3:9]
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of diisopropylamine (0.603 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (2.56 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (490 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.510 mL) was added dropwise at −78° C., and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) and further purified by basic silica gel chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 66.5 mg, 13%).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C\CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(/C=C\CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(1.00 g, 19.2 mmol) was slowly added to a stirring solution of cis-2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (2.00 g, 6.4 mmol) in EtOH (100 mL) and the solution was heated to reflux for 5h. The resulting mixture was made acidic (pH <2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc (2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O (3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 800 mg, 70%: 1H NMR (300 MHz, CDCl3) δ 1.26 (s, 2H, br), 3.421 (m, 2H), 3.78 (s, 3H), 5.81 (m, 1H), 6.40 (d, J=11.0 Hz, 1H), 6.62 (m, 2H), 6.90 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Cl)[C:26](=[CH2:28])[CH3:27]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[O:22][CH2:27][C:26]([CH3:28])=[CH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CC(C)(C)C(=O)Oc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(C)(C)C)c(OC(=O)C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under a nitrogen stream, a solution of 0.50 g of 2,5-di-t-butyl-4-trimethylacetoxyphenol in 3 ml of dimethylformamide was added dropwise into a suspension of 0.08 g of oily sodium hydride in 3 ml of dimethylformamide. After stirring for 30 minutes, 0.19 ml of methallyl chloride was added dropwise and the mixture was stirred for 3 hours and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the mixture was extracted with water and n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 0.48 g of 2,5-di-t-butyl-4-trimethylacetoxy-1-(2-methyl-2-propenyloxy)benzene as a colorless oil (yield 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][N:37]1[CH:41]=[C:40]([C:42](Cl)=[O:43])[CH:39]=[N:38]1>>[CH3:36][N:37]1[CH:41]=[C:40]([C:42]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:43])[CH:39]=[N:38]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: Cn1cc(C(=O)N2CCC(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)CC2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-methyl-1H-pyrazole-4-carbonyl chloride (Maybridge, Cat. No. CC77402). LCMS (M+H)+: m/z=593.2.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=[O:47]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[C@@H:14]([OH:47])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C

Procedure:
Methyl chenodeoxycholate (27 g, 61.5 mmol) is dissolved in 100 mL dichloromethane (DCM), pyridine (20 mL). Dimethylaminopyridine (DMAP) (1.22 g, 10 mmol) is then added. The reaction mixture is chilled to 0° C., and methanesul-fonyl chloride (7.5 mL, 11.0 g, 96.7 mmol) is added dropwise. The reaction mixture is heated at 60° C. for 3 h, cooled to r.t., washed with 5% HCl, water, sodium bicarbonate, brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure (1 mm Hg, 80° C. in a bath) to give mesylate 1 as a thick oil, weight 27 g (90%). This material is used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[N:13][CH:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[C-:15]#[N:16].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C(#N)C>[C:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[N:13][CH:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)#[N:16]
Reactant: [C-]#N
Reactant: ClCCCCc1cccc2cncn12
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCCc1cccc2cncn12

Procedure:
A solution of 5-(4-chlorobutyl)imidazo[1,5-a]pyridine (5.73 g), potassium cyanide (7.18 g) and 1.0 g of dibenzo-18-crown-6 in 190 ml of acetonitrile is heated at reflux for 18 hours, cooled and evaporated to a residual oil which is partitioned between water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The resulting solid is dissolved in ethyl acetate and filtered through 60.0 g of silica gel to yield 5-(4-cyanobutyl)-imidazo[1,5-a]pyridine m.p. 72°-75°.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(O)(=O)C>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[C:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
Following a procedure similar to that of Example 1C but using 64.9 g. of 2-(2-oxocyclohexyl)acetophenone and 37 g. of 4-methoxyaniline in 180 ml. glacial acetic acid there was obtained 80.9 g. of 1-(4-methoxyphenol)-2-phenol-4,5,6,7-tetrahydroindole; m.p. 132°-133°C. (isopropyl alcohol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([F:29])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[C:20]3[N:19]=[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:9][CH2:10][CH2:11]5)=[CH:17][CH:16]=4)[C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:30][N:21]3[N:22]=2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 38.2 %

Procedure:
In a second experiment 420 mg (0.83 mmol) {1-[4-(9-fluoro-3-phenylpyrimido[1,2-b]indazole-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, after dissolution in 5 mL dioxane, were treated with 22 mL 4M hydrogen chloride in dioxane. The reaction mixture was worked up as described for the first experiment. The crude products of both experiments were purified by joint chromatography on amine silicagel (eluents: dichoromethane/methanol) yielding 129.5 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])[CH2:5]2.[ClH:20]>CO>[ClH:20].[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3[NH:19][C:17](=[O:18])[C:13]4[N:12]([CH:16]=[CH:15][N:14]=4)[C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)CC(n1ccnc1C(N)=O)C2=O
Agent: Cl
Solvent: CO
Product: Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12

Procedure:
The procedure is carried out as in Example 1 but starting with 1.8 g of 1-(5-methyl-1-oxo-2-indanyl)imidazole-2-carboxamide, a total of 80 ml of methanol and 22 ml of 12N aqueous hydrochloric acid solution. 1.5 g of 8-methyl-5H, 10H-imidazo [1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride are thus obtained which decompose without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 2.42 (s, 3H: Ar--CH3); 4.05 (s, 2H: --CH2-- in position 10); 7.27 (broad d, J=8 Hz 1H: --H7); 7.48 (broad s, 1H: --H9); 7.83 (d, J=8 Hz, 1H: --H6); 7.97 and 8.25 (2d, J=1.5 Hz, 1H each: --H of imidazole); 13.20 (unresolved complex, 1H: --CONH--)].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].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.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:66][N:67]([CH3:76])[CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([N:73]2[CH2:74][CH2:75][N:70]([CH2:69][CH2:68][N:67]([CH3:76])[CH3:66])[CH2:71][CH2:72]2)[CH:3]=[CH:4][C:5]=1[Cl:13])[CH3:11]
Reactant: CN(C)CCN1CCNCC1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N2CCN(CCN(C)C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
Ethyl 5-bromo-2-chlorobenzoate (0.80 g, 3.04 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.19 g, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.28 g, 0.30 mmol) and cesium carbonate (Cs2CO3) (1.39 g, 4.26 mmol) were placed in a Schlenk tube and purged by repeated nitrogen/vacuum cycles for 30 minutes. Dry toluene (6 mL) and 1-(2-dimethylaminoethyl)piperazine (0.55 mL, 3.65 mmol) were then added. The reaction mixture was stirred for 10 min at room temperature, heated at 85° C. overnight and then cooled to room temperature. The solution was diluted with EtOAc (30 mL), the insoluble material was filtered off and the filtrate was washed with saturated brine (15 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was purified by flash chromatography (eluent gradient: EtOAc, EtOAc:MeOH/1:1, EtOAc:MeOH:NH3 in MeOH (2M)/1:1:0.2) to afford 0.30 g of the title compound (30%). 1H-NMR (400 MHz, DMSO): δ 1.28 (3H, t), 2.12 (6H, s), 2.32-2.42 (4H, m), 2.47-2.51 (4H, m), 3.11-3.14 (4H, m), 4.27 (2H, q), 7.06-7.09 (1H, m), 7.18-7.19 (1H, m), 7.30-7.32 (1H, m).
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC(O)=O>CN(C=O)C>[C:25]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]2[S:37][C:2]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=4)[N:18]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[N:36]=2)[CH2:33][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)N1CCC(C(N)=S)CC1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(C)(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.276 g, 0.699 mmol, Preparation #A.2), 1-tert-butylpiperidine-4-carbothioamide (0.140 g, 0.699 mmol) and HOAc (0.080 mL, 1.40 mmol) were added to DMF (4 mL). The mixture was stirred at ambient temperature for about 1 h then at about 85° C. for about 1.5 h. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 N aqueous NaOH. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to an oil which was then purified by flash chromatography on silica gel using DCM/MeOH with 3% NH4OH (95:5) as an eluent to give the title compound: (0.077 g, 22%): LC/MS (Table 1, Method a) Rt=1.66 min; MS m/z: 497.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][CH3:16])=[O:15]
Reactant: COC[C@H]1CCCN1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.5 mg). Calcd for C16H17ClN2O3: 320.0928, found 320.0924.
Reaction SMILES: C(OCC)(=O)CCC([O:6][C:7]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[N:12][C:11]=2[N:10]([CH3:23])[C:9](=[O:24])[CH:8]=1)=O.OC1C2C=C(C3C=CC=CC=3)N=NC=2N(C)C(=O)C=1.Cl[C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54]CC)=[O:53]>>[OH:6][C:7]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:13]=[N:12][C:11]=2[N:10]([CH3:23])[C:9](=[O:24])[C:8]=1[C:49](=[O:57])[CH2:50][CH2:51][C:52]([OH:54])=[O:53]
Reactant: CCOC(=O)CCC(=O)Oc1cc(=O)n(C)c2nnc(-c3ccccc3)cc12
Reactant: CCOC(=O)CCC(=O)Cl
Agent: Cn1c(=O)cc(O)c2cc(-c3ccccc3)nnc21
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(-c3ccccc3)nnc21

Procedure:
Ethyl 8-methyl-7-oxo-3-phenyl-7,8-dihydropyrido[2,3-c]pyridazin-5-yl succinate. The title compound is prepared by acylation of 5-hydroxy-8-methyl-3-phenylpyrido[2,3-c]pyridazin-7(8H)-one with ethyl 4-chloro-4-oxobutanoate according to that described in Method 4 (step b).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].[C:26]1([S:32]([C:35]2[CH:36]=[C:37](OS(C(F)(F)F)(=O)=O)[C:38](=[O:44])[N:39]3[C:43]=2[CH2:42][CH2:41][CH2:40]3)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]1([S:32]([C:35]2[CH:36]=[C:37]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:38](=[O:44])[N:39]3[C:43]=2[CH2:42][CH2:41][CH2:40]3)(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=c1c(OS(=O)(=O)C(F)(F)F)cc(S(=O)(=O)c2ccccc2)c2n1CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc(S(=O)(=O)c2ccccc2)c2n(c1=O)CCC2
Temperature: 25 °C

Procedure:
Pyridinone derivative (P) can also be derivatized to form pyridinone derivative (W) by the organometallic coupling of (trimethylsilyl)acetylene as shown in Reaction Scheme XIII. A similar result in Reaction Scheme XIII can be obtained for the corresponding derivative of pyridinone (E). wherein Z, R2, R3, and R4 are as defined in Reaction Scheme VI. Reagents for the organometallic coupling include PdCl2(PPh3)2 and Cul or other suitable organometallic reagents. The organometallic coupling is accomplished by combining the halogenated pyridinone derivative with (trimethylsilyl)acetylene and triphenylphosphine, PdCl2(PPh3)2 and Cul and then heating at 120 degrees Celcius for 72 hours. The preparation of pyridinone derivative (W) is illustrated by a procedure described by Padwa A., Sheehan S. M., and Straub C. S., J. Org. Chem. 1999, 64: 8648-8659 for an isomunchnone-based method for the synthesis of highly substituted 2(1H)-pyridones, the entirety of which is hereby incorporated by reference. The authors describe the palladium catalyzed coupling of (trimethylsilyl)acetylene with a triflate to provide a (trimethylsilyl)acetylene substituted compound. The specific preparation procedure employed by the authors involved the addition of Cul, followed by PdCl2(PPh3)2 to a solution containing triphenylphosphine in triethylamine. To this solution was added (trimethylsilyl)acetylene in toluene followed by the addition of trifluoromethanesulfonic acid 8-phenylsulfonyl-5-oxo-1,2,3,5-tetrahydroindolizin-6-yl ester. The mixture was heated at 115 degrees Celcius for 1 hour, cooled to room temperature, poured into ice water, extracted with CH2Cl2, washed with brine, and dried over Na2SO4. The organic extracts were filtered and concentrated under reduced pressure. The crude residue was subjected to flash silica gel chromatography to yield 8-phenylsulfonyl-6-trimethylsilanylethynyl-2,3-dihydro-1H-indolizin-5-one.
Reaction SMILES: C([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([NH:24][CH2:25][CH2:26][NH:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:48]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([N:24]1[CH2:25][CH2:26][N:27]=[C:28]1[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Reactant: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C2=NCCN2C(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 85 °C
Yield: 50 %

Procedure:
A mixture of N-{2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-4-methyl-benzamide (2.8 g, 5.5 mmol) and phosphorus oxychloride (9.4 mL, 100 mmol) in toluene (60 mL) was heated at 85° C. for 7 hours, then heated at reflux for 1 hour. The reaction was concentrated and the residual phosphorus oxychloride removed by toluene azeotrope. The residue was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated. The resultant residue was purified by flash chromatography (0→8% methanol/methylene chloride) to give 1.4 g (50%) of the title compound. MS (ES+) m/e 485 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.[CH3:22][N:23]=[C:24]=[O:25].O>N1C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1)[C:24]([NH:23][CH3:22])=[O:25]
Reactant: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)N(C)c1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 47.7 %

Procedure:
A solution comprising 12.7 g (0.04 mole) of 2-methylamino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole, 3.1 g (0.054 mole) of methyl isocyanate in 40 ml of pyridine was heated at about 45° for 24 hours. The reaction solution was poured into water and the crude product was collected. Two recrystallizations from isopropanolheptane yielded 7.1 g of desired product, m.p. 125°-27°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8 (CH3, doublet), 3.5 (CH3, singlet), 3.8 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=0).