Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.Cl.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].O1CCOCC1>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[N:29]=[C:28]([NH:30][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC1CCCCN1c1cccc(N)n1
Reactant: Brc1cc(-c2ccccc2)nn2ccnc12
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: CC1CCCCN1c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (125 mg, 0.46 mmol), 6-(2-methylpiperidin-1-yl)pyridin-2-amine (144 mg, 0.75 mmol), Pd2(dba)3 (29 mg, 0.05 mmol), BINAP (125 mg, 0.2 mmol), Cs2CO3 (489 mg, 1.5 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solution was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was 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 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol, three drops of concentrated HCl was added, and the mixture was stirred for 5 minutes, then concentrated in vacuo to give N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (18 mg, 10%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.99 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.05-7.98 (m, 3H), 7.60 (brs, 3H), 7.46-7.28 (m, 2H), 4.12 (brs, 1H), 3.92-3.81 (m, 1H), 3.65-3.56 (m, 1H), 2.07-1.66 (m, 6H), 1.17 (d, 3H, J=5.7 Hz). LC-MS: [M+H]+, 385, tR=2.081 min, HPLC: 99.49% at 214 nm, 99.48% at 254 nm, tR=3.588 min.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(CN)cc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-methylbenzylamine and acetonitrile essentially as described above in example 18. Purity by LC/MS (APCI)=100%, [M+H]+=365.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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]>[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[CH:16][CH:15]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1coc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of ethyl 2-chloro-1,3-oxazole-4-carboxylate (0.59 g, 3.36 mmol) in dioxane was treated with 4-(hydroxymethyl)phenyl boronic acid (0.766 g, 5.04 mmol), K2CO3 (0.929 g, 6.72 mmol), t-Bu3PhBF4 (0.049 g, 0.168 mmol) heated to 80° C. then treated with Pd2(dba)3 (0.154 g 0.168 mmol) and stirred overnight at 90° C. The reaction mixture was diluted with EtOAc, washed with water, saturated sodium chloride, dried over MgSO4 and concentrated in in vacuo. The resultant residue was purified by flash chromatography (silica, EtOAc:hexanes 20→50%) to give the title product in 70% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 248 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][CH2:9][CH2:10][O:11][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: OCCBr
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)OCCBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: C1CSCCN1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCSCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and thiomorpholine are converted to the named compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>C1COCC1>[F:40][C:38]1[CH:37]=[CH:36][C:33]([CH2:34][C@H:3]2[C:2](=[O:1])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4]2)=[C:32]([CH3:31])[CH:39]=1
Reactant: Cc1cc(F)ccc1CBr
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
Step (c) (S)-Di-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (1.15 g, 4.0 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. A solution of LiHMDS (1M in hexanes, 4.4 mL, 4.4 mmol) then was added dropwise under nitrogen. The mixture was cooled at −78° C. for 40 minutes and then a solution of 2-methyl-4-fluorobenzyl bromide (975 mg, 4.8 mmol) in THF (5 mL) was added slowly. The mixture was stirred at −78° C. for 2 hours and then quenched with saturated ammonium chloride (20 mL). The mixture was extracted with diethyl ether (3×70 mL) and the combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified from the residue by flash column (eluted with a 4:1 hexanes/diethyl ether mixture) to give (2S,4R)-di-tert-butyl 4-(4-fluoro-2-methylbenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (810 mg, 2.0 nmol, 49.7%), clean as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[C:7]=1I)[CH3:2].CCN(CC)CC.[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.[Cu]I>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[C:7]=1[C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH3:2]
Reactant: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 93.5 %

Procedure:
A mixture of 3 (18.1 g, 45.9 mmol), Et3N (12.8 mL, 91.9 mmol), Pd(PPh)2Cl2 (1.6 g, 5% mol), CuI (0.7 g, 8% mol), and TMS-acetylene (19.6 mL, 137.8 mmol) in degassed THF (180 mL) is heated at 60° C. overnight. The mixture is cooled to rt, and then partitioned between H2O and EtOAc. This mixture is filtered through Celite to remove the insoluble material. The two layers of the filtrate are separated, and the organic layer is washed H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc as eluant to give 15.6 g (93%) of the product 4 as beige solid. 1H NMR (CDCl3) δ 7.15-7.00 (m, 2H), 6.41 (br s, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.27 (s, 9H); 19F NMR (CDCl3) δ −57.59 (s, 3F), −118.15 (s, 1F); MS 364 (M+1, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:26][CH2:25]2)[CH:16]=1
Reactant: c1cncc(CCCN2CCNCC2)c1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a mixture solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 1.7 g, 1-[3-(3-pyridyl)propyl]piperazine 1.56 g, 1-hydroxy-benzotriazole 1.3 g and N,N-dimethylformamide 20 ml was added dicyclohexylcarbodiimide 1.67 g under ice-cooling, and the mixture stirred overnight at room temperature. Ethyl acetate 50 ml was added, the precipitated dicyclohexylurea filtered off, water 30 ml added to the filtrate, the resultant solution basified with sodium hydrogen carbonate and transferred into a separating funnel. The aqueous layer was washed with ethyl acetate, the washings combined with the ethyl acetate layer, and the resultant ethyl acetate solution washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate - methanol (4:1) to give 860 mg of oily 1-[3-(3-pyridyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. This product was dissolved in ethanol 8 ml and after addition to stand to yield crystals. The crystals were filtered off and dried to give 580 mg of 1-[3-(3-pyridyl)propyl-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine.fumarate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=O)=[CH:6][N:7](C)C)C.Cl.[C:20]([NH:24]N)([CH3:23])([CH3:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[N:7][N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:18]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(C)on1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1-c1cc(C)on1
Temperature: 90 °C
Yield: 101.7 %

Procedure:
A solution of 3-dimethylamino-2-(5-methyl-isoxazole-3-carbonyl)-acrylic acid ethyl ester (27.53 mmol) in absolute ethanol (41.7 mL) was treated with tert-butylhydrazine hydrochloride (3.57 g, 28.63 mmol) and sodium acetate (2.80 g, 34.13 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was diluted with water (200 mL) and was then extracted with dichloromethane (3×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37 g, 96%) as a black solid. The material was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][C:14]=2[OH:32])[CH:10]=[CH:11][CH:12]=1)[CH3:2].IC.[C:36]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:15][C:14]=2[O:32][CH3:36])[CH:8]=1)[CH3:2]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2OC)c1
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 35 (0.23 g, 0.508 mmol, 1.0 eq), iodomethane (0.13 mL, 2.1 mmol, 4.1 eq), and K2CO3 (0.56 g, 4.06 mmol, 8.0 eq) in acetone (5 mL) was heated to 70° C. for 24 hours. LC/MS showed complete conversion. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (neutral aluminum gel, 0-3% methanol in dichloromethane). Yield: 63%, 99% pure. M+1=468
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])[CH:9]=1)[CH3:2].S(OC)(O[CH3:28])(=O)=O>>[CH2:1]([O:3][C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:28])[C:11]2=[O:21])[CH:9]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(5-ethoxy-4-chloro-2-fluorophenyl)-6-trifluoromethyl- 2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(5-ethoxy-4-chloro-2-fluorophenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 118°-121° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:21][N:22]([CH2:28][C:29](OCC)=[O:30])[C:23]=2[C:24]([F:27])([F:26])[F:25])=[CH:15][CH:14]=1>C(Cl)Cl>[C:2]1([NH:1][C:29](=[O:30])[CH2:28][N:22]2[C:23]([C:24]([F:27])([F:25])[F:26])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=3)[C:20]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)Nc3ccccc3)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Aniline (0.07 g, 0.75 mmol) was added to a methylene chloride solution of trimethyl aluminum (0.38 mL, 0.75 mmol, 2.0M in hexanes) at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (Example 8) (0.25 g, 0.5 mmol) was added and the mixture stirred for 24 hours at 25° C. The reaction was quenched with dilute aqueous HCl and extracted with two portions ethyl acetate and the extracts washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.18 g, 68% yield). Elemental analysis for C25H19N3F4SO3 Calc'd: C, 58.02, H, 3.70, N, 8.12, S, 6.20. Found: C, 57.48, H, 3.78, N, 8.03, S, 6.46.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:9]([C:12]1[CH:13]=[C:14]([CH2:23][C:24]([NH2:26])=[O:25])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)[CH:10]=[CH2:11].[OH-].[Na+]>>[CH2:9]([C:12]1[CH:13]=[C:14]([CH2:23][C:24](=[O:25])[NH2:26])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:10]=[CH2:11]
Reactant: C=CCc1cc(CC(N)=O)ccc1OCC1CO1
Reactant: CCOC(=O)CCN
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(CC(N)=O)ccc1OCC(O)CNCCC(=O)OCC

Procedure:
This compound was prepared in accordance with Example 1 using 10.8 g of thehydrochloride of ethyl 3-aminopropanoate, 11.6 g of 3-allyl-4-(2,3-epoxypropoxy)phenylacetamide, and 2.84 g NaOH. The crude product was crystallized from ethyl acetate. Yield 1.7 g. Melting point 98° C. (base). The structure was determined using NMR and equivalent weight.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:9][C:10]1[CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1cc(-c2ccsc2)ncn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Thiophene-3-boronic acid (2.6 g, 20 mmol) was combined with 4,6-dichloropyrimidine (3.6 g, 24 mmol, 1.2 eq), bis(triphenylphosphine)palladium(II)dichloride (200 mg), and 3.0 g sodium carbonate in a resealable pressure flask. Sixty mL of a mixed solvent (N,N-dimethyl formamide/dimethyl ether/methanol/water 1:1:0.3:0.4 mL) was added, and the solution was purged with nitrogen prior to sealing. The reaction mixture was heated at 130° C. for three hours. The crude reaction mixture was cooled, partitioned between water and ethyl acetate. The organic material was washed with brine and dried over sodium sulfate. After concentrating to half-volume in vacuo, the resultant slurry was allowed to stand overnight, and then filtered to collect a white solid, which was washed with a small volume of ethyl acetate. The combined organic filtrates were chromatographed on silica gel (eluting with a gradient of 0%->5%->20% ethyl acetate in hexanes) to produce a second crop of solid material. The combined yield for the two batches was 1.83 g (46% yield).
Reaction SMILES: C1COCC1.Br[C:7]1[C:15]2[O:14][C:13]([F:17])([F:16])[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[N:18]1[O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1>[F:16][C:13]1([F:17])[O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C@:22]34[CH2:23][O:24][CH2:25][CH2:26][C@H:21]3[CH2:20][O:19][NH:18]4)[C:15]=2[O:14]1
Reactant: C1CC2CON=C2CO1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC1(F)Oc2cccc([C@]34COCC[C@H]3CON4)c2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:9]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH2:3]1.[Sn](Cl)Cl>C(O)C.Cl>[NH2:17][C:15]1[CH:14]=[CH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=3)[C:9]=2[CH:16]=1
Reactant: CN1CC=C(c2csc3ccc([N+](=O)[O-])cc23)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CN1CC=C(c2csc3ccc(N)cc23)CC1
Yield: 74.6 %

Procedure:
A stirred solution of 3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-5-nitrobenzo[b]thiophene (D13, 470 mg, 1.7 mmole) in ethanol (35 ml) at 60° C. under argon was treated over 5 minutes with a solution of tin (II) chloride (2.0 g, 10.5 mmole) in concentrated HCl acid (4 ml) and the mixture then heated at reflux for 1.5 hours. The reaction mixture was allowed to cool and the precipitate filtered off, washed with ethanol and dried. This was then shaken well with 10% Na2CO3 solution (50 ml) and dichloromethane (100 ml), and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (310 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])#[CH:13].N>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: ON=C(Cl)c1ccc(Cl)nc1
Reactant: C#Cc1ccc(F)cc1F
Agent: N
Product: Fc1ccc(-c2cc(-c3ccc(Cl)nc3)no2)c(F)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 95B (79 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, CDCl3) δ 6.93-7.14 (m, 3H), 7.47 (d, J=7.5 Hz, 1H), 8.02 (td, J=8.6, 6.3 Hz, 1H), 8.18 (dd, J=8.1, 2.7 Hz, 1H), 8.86 (dd, J=2.5, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:11]2[NH:15][C:14](=[O:16])[O:13][N:12]=2)[N:6]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CC#N.CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:11]2[N:15]([CH3:23])[C:14](=[O:16])[O:13][N:12]=2)[N:6]=1
Reactant: Nc1nc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)cs1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(/C(=N\OCc2csc(N)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (2.89 g, 50% purity, 4.56 mmol, 1 eq.) in MeCN (50 ml) and DMF (10 ml) was added potassium carbonate (757 mg, 5.48 mmol, 1.2 eq.) followed by iodomethane (778 mg, 5.48 mmol, 1.2 eq.). The reaction was stirred at room temperature overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (930 mg, 61% yield) has a white solid.