Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:29][NH2:30].C(O)C>>[CH3:29][NH:30][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Oc2ccc(NC(=O)Nc3ccc(C(C)(C)C)cc3)cc2)ncn1

Procedure:
Under N2-atmosphere, a solution of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea (319 mg, 0.80 mmol) in methylamine/ethanol (8.03 M; 5 ml) is stirred for 50 min at 40° C. Then the reaction mixture is concentrated in vacuo, the residue re-dissolved in water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo after adding 2 g of SiO2. The resulting powder is put on top of a SiO2-column and eluted with AcOEt/hexane 9:1, yielding the title compound: m.p.: 245-246° C.; 1H-NMR (DMSO-d6): 8.7 (s, HN), 8.6 (s, HN), 8.13 (s, 1H), 7.45 (d, 2H), 7.35 (d, 2H), 7.31 (d, 2H), 7.05 (d, 2H), 6.78 (s, HN), 5.79 (s, 1H), 2.83 (MeN), 1.30 (Me3C).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:24][CH2:25]4)=[CH:13][C:14]([CH:21]=[O:30])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(C2CC2)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-vinylbenzoate (0.22 g) in a mixed solvent of acetone (4.40 ml)-acetonitrile (4.40 mL)-water (4.40 mL) were added osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.65 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.22 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N:22]=[C:21]([C:4]2=[CH:3][CH:2]=1)[N:20]=[C:19]1[C:23]2[C:28]([C:17](=[N:18]1)[N:16]=[C:15]1[C:29]4[C:34]([C:13](=[N:14]1)[N:12]=[C:11]1[C:35]5[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=2.[Cu:41].[Na].[Cl:43][S:44]([OH:47])(=O)=[O:45].S(Cl)([Cl:50])=O>>[CH:38]1[CH:39]=[C:40]2[C:9]3[N:10]=[C:11]([C:35]2=[CH:36][CH:37]=1)[N:12]=[C:13]1[C:34]2[C:29]([C:15](=[N:14]1)[N:16]=[C:17]1[C:28]4[C:23]([C:19](=[N:18]1)[N:20]=[C:21]1[C:4]5[C:5]([C:7](=[N:22]1)[N:8]=3)=[CH:6][CH:1]=[CH:2][CH:3]=5)=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:30][CH:31]=[CH:32][CH:33]=2.[Cu:41].[S:44]([Cl:43])([Cl:50])(=[O:47])=[O:45]
Reactant: O=S(=O)(O)Cl
Reactant: O=S(Cl)Cl
Agent: [Cu]
Agent: [Na]
Agent: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Product: O=S(=O)(Cl)Cl

Procedure:
Next, copper phthalocyanine (tri- or tetra-) sulfonic acid (tri- or tetra-) sodium salt was gradually fed to chlorosulfonic acid followed by dropping of thionyl chloride to perform reaction. The reaction liquid was cooled and the deposited crystal was filtered to obtain a wet cake of desired copper phthalocyanine (tri- or tetra-) sulfonyl chloride, which was then stirred and suspended followed by addition of aqueous ammonia, and a compound represented by the following chemical formula (γ) to perform reaction. Then, water and sodium chloride were added to the reaction liquid to deposit crystal. The deposited crystal was filtered, washed with an aqueous sodium chloride solution, filtered/washed again, followed by drying to obtain the color material represented by the chemical formula (3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(COC)OC.O>[C:16]1([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: Nc1ccc(I)c(F)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(C2=CCCCC2)c(F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol). Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100° C. for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.00 (m, 1 H), 6.37 (m, 2 H), 5.84 (s, 1 H), 3.71 (br s, 2 H), 2.32 (m, 2 H), 2.17 (m, 2 H), 1.73 (m, 2 H), 1.65 (m, 2 H); MS (+DCI) m/z (rel abundance) 192 (100, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5)nc34)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
To the solid (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.30 g, 0.525 mmol) was added TFA (10 mL) and the reaction stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and the material was slurried in water (5 mL) with acetonitrile/methanol (10 mL, 1:1) and stirred for 3 hours. The slurry was filtered and the solids were dried in vacuo. The solids were then taken up in water and the water layer was basified with a solution of saturated NaHCO3, and the solids were filtered. The solids were again slurried in water, then filtered and concentrated. The residue was slurried in water/acetonitrile/methanol (30 mL total) and nitrogen was bubbled through the solution to drive complete deprotection. The slurry was filtered and the isolated solids were taken up in acetonitrile (3 mL) and heated to reflux, then cooled. The mixture was filtered and concentrated in vacuo to yield (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.0589 g, 0.133 mmol, 25.4% yield) as the free base. LCMS (APCI+) m/z 442 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30](CC2C=CC(OC)=CC=2OC)[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].Cl>CN(C)C(=O)C.O1CCOCC1.CS(C)=O>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11])#[N:19]
Reactant: FC(F)(F)c1ccccc1S
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Sc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Trifluoromethylthiophenol (0.0615 g, 0.345 mmol) and potassium carbonate (0.100 g, 0.724 mmol) were stirred in N,N-dimethylacetamide (3 mL). After 5 minutes, 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.150 g, 0.345 mmol) was added to the reaction mixture and the mixture stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, followed by brine, then dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was then dissolved in 1,4-dioxane (1 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a residue. The residue was solubilised in dimethylsulfoxide (1 mL) and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: N#N.[N+:3]([C:6]1[NH:10][N:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23]>C(C#N)(C)=O.CC(=O)OCC.O>[N+:3]([C:6]1[CH:7]=[CH:8][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[N:10]=1)([O-:5])=[O:4]
Reactant: CC(=O)CCCCBr
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: CC(=O)C#N
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CCCCn1ccc([N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-nitro-1H-pyrazole (3.69 g, 29.35 mmol) and Cs2CO3 (10.53 g, 32.28 mmol) in AcCN (34.0 mL) was treated with a solution of 6-bromo-hexan-2-one (5.78 g, 32.28 mmol) in AcCN (26.0 mL). The reaction mixture was stirred at 80° C. for 2 h. Water (123 mL) and EA (185 mL) were added to the cooled reaction mixture. The aq. layer was extracted with EA (185 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.21. LC-MS-conditions 02: tR=0.82 min; [M+H]+=212.28.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)C1C=CC=CC=1>[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][O:23][CH3:24])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: COCC[C@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C, except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.280 g, 0.83 mmol) and 10% palladium on carbon (80 mg). The title compound was obtained as an oil (179 mg). NMR (CD3OD, 300 MHz) δ 4.17 (1H, m), 3.81 (1H, dd, J=3, 13 Hz), 3.38 (2H, t, J=6 Hz), 2.82-3.02 (2H, m), 2.77 (2H, ABq, J=4, 13 Hz), 2.59 (1H, dt, J=4, 7 Hz), 2.04 (1H, m), 1.84 (1H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7](O)=O)[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[H-].[Na+].COP([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(OC)=O>C1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH2:10][C@@H:11]2[C@H:6]([CH:5]=1)[C:7](=[CH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:12]2)[CH:2]=[CH2:3]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC(C=CC(=O)O)CC=C
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Allylhepta-2,6-dienoic acid (2.00 g, 12.0 mmol) was dissolved in benzene (5 mL). To the solution, oxalyl chloride (7.01 g, 55.2 mmol) was added under ice cooling, and the mixture was stirred in this state for 1 hour. The mixture was further stirred at room temperature for 30 minutes, then heated to 80° C., and stirred for 1 hour. Then, the solvent was distilled off under reduced pressure. To the residue, toluene was added, and the solvent was distilled off again under reduced pressure. The residue was dissolved in toluene (20 mL). This solution was added dropwise to a toluene solution (30 mL) of triethylamine (4.41 g, 43.68 mmol) heated in advance to reflux, and the mixture was further stirred for 2.5 hours. The reaction solution was allowed to cool, then diluted with saturated saline and ethyl acetate, and filtered through Xelite. The filtrate was separated into aqueous and organic layers. Then, the organic layer was washed with 1 N hydrochloric acid and saturated saline in this order, then dried over anhydrous magnesium sulfate, and then filtered. This filtrate was added to a reaction solution prepared in advance by adding sodium hydride (>65% oil, 457.1 mg, 12 mmol) to a tetrahydrofuran solution (20 mL) of tert-butyl dimethoxyphosphorylacetate (3.03 g, 12 mmol) under ice cooling, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (0.63 g, 16%, E/Z mixture).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8]2)C=C.O.C(OCC)(=O)C.CN(C)[C:27]1[CH:32]=CC=C[CH:28]=1>>[CH2:32]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]([CH3:16])([CH3:17])[C:11]2=[O:15])[CH:27]=[CH2:28]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc2c(c1)CCC(C)(C)C2=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(O)ccc2c1CCC(C)(C)C2=O
Temperature: 25 °C

Procedure:
1.69 g of 6-(allyloxy)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one was dissolved in 10 ml of N,N-dimethylaniline, and the obtained mixture was heated to reflux under nitrogen atmosphere for 7 hours. The reaction solution was cooled to a room temperature. Water and ethyl acetate were added to the reaction solution, so as to obtain an organic layer. The obtained organic layer was successively washed with 5 N hydrochloric acid (3 times), water (4 times), and a saturated sodium chloride solution. The resultant product was then dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. Hexane was added to the residue, and the precipitate was then collected by filtration, so as to obtain 1.06 g of the subject compound.
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])/[C:4](=[CH:8]\[CH3:9])/[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])/[C:4](=[CH:8]\[CH3:9])/[C:5]([NH:47][CH2:46][C:44]1[CH:43]=[CH:42][N:41]=[C:40]([C:37]2[CH:36]=[CH:35][C:34]([O:33][C:32]([F:49])([F:31])[F:48])=[CH:39][CH:38]=2)[CH:45]=1)=[O:7])[CH3:2]
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: C/C=C(/C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C/C=C(/C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Acid 11B (574 mg, 2 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.3 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 590 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded 195 mg of a white solid. Yield=18% 1HNMR (DMSO, 200 MHz) δ 1.00 (3H, t, J=7.2 Hz), 1.46 (3H, d J=7.4 Hz), 3.43 (2H, q, J=7 Hz), 4.40 (2H, d, J=6 Hz), 6.83 (1H, q, J=7 Hz), 7.25 (1H, dd, J=6.4 Hz), 7.42 (4H, m), 7.85 (3H, m), 8.18 (2H, d, J=8.2 Hz), 8.60 (1H, d, J=5 Hz), 8.74 (1H, bt) [M+1] 538.1 (C25H23F4N3O4S requires 537.53).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].S([O-])([O-])(=O)=O.[Na+].[Na+]>[Ag]=O>[CH3:10][O:9][C:5]1[C:6](=[NH:8])[CH:7]=[C:2]([CH3:1])[C:3](=[NH:11])[CH:4]=1
Reactant: COc1cc(N)c(C)cc1N
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC1=CC(=N)C(C)=CC1=N
Reaction time: 2 h
Yield: 69 %

Procedure:
0.056 mole (8.56 g) 2-methyl 5-methoxy paraphenylenediamine is introduced into 850 cc isopropyl anhydrous ether to which there have been added 0.085 mole (19.7 g) silver oxide and 55 g anhydrous sodium sulfate. The mixture is agitated for two hours, maintaining the temperature thereof between 30° and 40°. After cooling, the sodium sulfate and the silver arc separated from the reaction mixture by filtration, and the resulting filtrate is evaporated to dryness under vacuum. The dry residue, after recrystallization from a mixture of benzene-hexane, furnishes 5.8 g 2-methoxy-5-methyl benzoquinone diimine, which has a melting point of 96°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(C=O)nc2ccc(I)cn12
Yield: 69.2 %

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g) in DCM (40 ml) was added diisobutylaluminum hydride (1.0 M solution in toluene, 8 ml) at −78° C., and the resultant mixture was stirred at same temperature for 3 h. The reaction mixture was quenched with MeOH (10 ml) and 2 M HCl (15 ml), and basified with saturated aqueous NaHCO3 solution (20 ml) at 0° C. The mixture was extracted with DCM, washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (1.2 g) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 25.3 %

Procedure:
A stirred suspension of sodium hydride (1.6 g, 53 mmol, 80% oil dispersion) in dry tetrahydrofuran is treated with a solution of 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline (10.24 g, 41.80 mmol) in dry tetrahydrofuran dropwise via addition funnel. After addition is complete and effervescence subsides, ethyl 4-bromocrotonate (12.9 g, 50.1 mmol, 75% technical grade) is added to the reaction mixture at once. The resulting mixture is stirred at room temperature under nitrogen for 19 hours. After this period, the reaction mixture is partitioned between water and ether. The layers are separated, and the organic layer is dried over magnesium sulfate, decolorized with activated charcoal, vacuum filtered through diatomaceous earth, and concentrated in vacuo to obtain a dark brown oil. The oil is purified by flash chromatography (2:1 hexanes/ethyl acetate eluent) to give the title product as a pale orange oil (3.78 g, 25%).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10]
Reactant: N#Cc1cncc(I)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cncc(I)c1Cl
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and POCl3 (200 mL) was heated at 100° C. for 2 hours, cooled to room temperature and evaporated to remove excess POCl3. The residue was cooled in an ice-water bath, adjusted to pH 8-9 with aqueous 10 N NaOH and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate and concentrated. The resulting solid residue was washed with a minimum amount of methanol and methylene chloride to give 46.5 g (75%) of 4-chloro-5-iodonicotinonitrile as a tan solid. Melting range: 120-122° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[S:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:25]2[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=2)[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1csc(-c2ccc(-n3nc(-c4c(F)cccc4-c4cc(C)cs4)[nH]c3=O)cc2)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol), (4-methylthiophen-2-yl)boronic acid (0.059 g, 0.407 mmol), K2CO3 (0.112 g, 0.81 mmol), tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol) and DMSO (3.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 6.86 (s, 1H), 6.91 (s, 2H), 7.13 (s, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.48-7.55 (m, 1H), 7.61 (d, J=8.1 Hz, 211), 7.92 (d, J=9.0 Hz, 2H), 9.27 (br s, 1H). MS (m/z): 384.88 (M−H)−.