Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:26][C:27]([CH3:32])([CH2:30]N)[CH2:28][NH2:29].[S]>CCO>[CH3:26][C:27]1([CH3:32])[CH2:28][NH:29][C:22]([C:20]2[CH:19]=[N:18][C:14]3[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[C:13]=3[CH:21]=2)=[N:23][CH2:30]1
Reactant: N#Cc1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: CC(C)(CN)CN
Agent: [S]
Solvent: CCO
Product: CC1(C)CN=C(c2cnc3c(c2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCO3)NC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (30 mg, 0.081 mmol) in EtOH (2 mL) was added 2,2-dimethylpropane-1,3-diamine (41.5 mg, 0.406 mmol) and sulfur (41.7 mg, 0.162 mmol). The reaction was heated to 80° C. and stirred at that temperature for 6 h. LCMS analysis identified the product as the predominant component of the reaction mixture. The reaction mixture was concentrated in vacuo and the resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 20-100% EtOAc to provide 7-(5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (18.7 mg, 0.039 mmol, 48.1% yield) as an off white solid. LCMS (+ESI) m/z=455.1 [M+H]+; 1H-NMR (CD3OD) δ 8.51 (d, 1H), 8.26 (d, 1H), 8.01 (d, 2H), 7.90 (d, 2H), 3.98 (s, 4H), 3.15 (s, 4H), 1.05 (s, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:24]([O:30][C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Reactant: CCCCCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCCCOc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 150 °C
Yield: 18.9 %

Procedure:
To a solution of N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0536 mmol, 1 eq.) in 3 ml of toluene were added hexanol (0.071 g, 0.697 mmol, 1.3 eq.), Cs2CO3 (0.227 g, 0.697 mmol, 1.3 eq.), Pd(OAc)2 (0.002 g, 0.011 mmol, 0.02 eq.) and 2-(Di-t-butylphosphino)-1,1′-binapthyl (0.005 g, 0.013 mmol, 0.025 eq.). The vessel was purged with argon and sealed. The reaction was heated in microwave at 150° C. for 600 s (abs-normal fixed-hold) and diluted with 50 ml of EtOAc, filtered through a “celite” pad. The filtrate was evaporated and the residue was purified by chromatography on silica gel to give N-{[6-(hexyloxy)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.04 g, 17% yield) as a viscous pale brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[P:7]([O:14][C@H:15]1[CH2:19][O:18][C@@H:17]2[C@H:20]([O:23][N+:24]([O-:26])=[O:25])[CH2:21][O:22][C@H:16]12)([O:12][CH3:13])([O:9][CH2:10]Cl)=[O:8].[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:33]([C:37]([OH:39])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:33]([C:37]([O:39][CH2:10][O:9][P:7]([O:12][CH3:13])([O:14][C@H:15]2[CH2:19][O:18][C@@H:17]3[C@H:20]([O:23][N+:24]([O-:26])=[O:25])[CH2:21][O:22][C@H:16]23)=[O:8])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COP(=O)(OCCl)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OCOP(=O)(OC)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (29.3 mg, 0,090 mmol) was added to a stirred, room temperature mixture of chloromethyl methyl (3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl phosphate (30 mg, 0.090 mmol) and 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 61.1 mg, 0.090 mmol) in N,N-dimethylformamide and the mixture was stirred at room temperature for overnight. The reaction was cooled, quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered and concentrated in vacua. Chromatography over silica, eluting with 40-100% ethyl acetate/hexane afforded the separated diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: N=C(N)NN
Reactant: O=C(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 161.8 %

Procedure:
To a solution of (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (Example 73) (65 mg, 0.25 mmol) in ethanol (5 mL) was added aminoguanidine hydrochloride (55 mg, 0.85 mmol) and 6 N HCl (0.2 mL). The reaction mixture was heated to reflux under N2. After 2 h, heating was terminated and the reaction mixture was cooled to room temperature forming a white precipitate. The precipitate was collected by filtration and dried under vacuum to provide [[(5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methylene]amino]guanidine dihydrochloride (78 mg, 100%) as a white solid: mp 274-278° C.; 1H NMR (300 MHz, CD3OD) δ 6.62 (1H, s), 7.49-7.58 (2H, m), 7.68-7.79 (4H, m), 8.04 (1H, s), 8.98 (1H, s); ESI MS m/z 313 [C15H13ClN6+H]+; HPLC (Method A) >99% (AUC) tR=16.5 min.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([N:16]([CH2:18][C:19]1[CH:24]=[C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]=[CH:21][C:20]=1[C:33](=[CH2:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:17])=[O:15])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([N:16]([CH2:18][C:19]1[CH:24]=[C:23]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:22]=[CH:21][C:20]=1[C:33]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:39]1)[CH3:17])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C=C(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)cc2CN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.019 g, 0.473 mmol) in DMSO (2.5 mL), was added trimethylsulfoxonium iodide (0.284 g, 1.291 mmol). The mixture was stirred at rt for 2 h. To the solution was added 15E (0.187 g, 0.430 mmol) in DMSO (2.5 mL) to give a yellow solution. The mixture was stirred at rt for 1 h, quenched with sat. NH4Cl (10 mL), extracted with EtOAc (4×15 mL). Combined organic phase was washed with water (2×10 mL), brine (1×10 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15F (0.173 g, 90% yield) as a colorless syrup. MS (ESI) m/z: 449.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.34-7.50 (1H, m), 7.20 (1H, d, J=8.08 Hz), 6.83-6.96 (1H, m), 6.44 (1H, br. s.), 4.51 (2H, br. s.), 4.07 (2H, q, J=7.16 Hz), 2.82 (3H, br. s.), 1.35-1.72 (22H, m), 1.15 (3H, t, J=7.07 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](Cl)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:31])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138°-139° C.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9](Br)[CH:10]=3)[CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[CH2:16][C:14]([C:13]=2[C:12]=34)=[CH:15][CH:2]=1
Reactant: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 25 °C

Procedure:
The compound 2 (0.65 g, 1.747 mmol), bis(4-biphenyl)amine (TCI Corp.) (1.40 g, 4.37 mmol), sodium tert-butoxide (0.51 g, 0.5 mmol), Pd2(dba)3 [(tris(dibenzylidene acetone)dipalladium(0))] (0.08 g, 0.087 mmol), and tri(tert-butyl)phosphine (0.017 g, 0.087 mmol) in a 50 ml round bottom flask were dissolved with toluene (10 mL), and the reaction mixture was refluxed for 12 hours. After the reaction was terminated, the reaction solution was cooled to room temperature and extracted with distilled water (100 ml). The combined organic layers were dried over MgSO4, concentrated, and purified by silica gel column chromatography. The eluate was concentrated and dried to give a material 1 represented by Formula 9 (1.1 g, yield: 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([N:25]([CH3:31])[CH2:26][C:27]([O:29]C)=O)[C:22]([N+:32]([O-])=O)=[CH:21][C:20]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:21][C:22]4[NH:32][C:27](=[O:29])[CH2:26][N:25]([CH3:31])[C:23]=4[N:24]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CN(C)c1nc(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CC(=O)Nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Yield: 38.2 %

Procedure:
In a glass autoclave were added methyl 2-((6-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-3-nitro-5-phenylpyridin-2-yl)(methyl)amino)acetate (800 mg, 1.46 mmol) and 10% palladium on carbon (300 mg, 0.28 mmol) in THF (100 ml). The solution was hydrogenated at room temperature under 1.5 atm hydrogen for 20 hours. The reaction mixture was filtered through celite, then concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 100:0 to 0:100) to afford the title compound (270 mg, 38%). 1H NMR (500 MHz, CDCl3): 7.35 (2H, d), 7.20-7.33 (5H, m), 7.15 (2H, d), 6.98 (1H, s), 5.05 (1H, br s), 4.11 (2H, s), 3.18 (3H, s), 2.20-2.70 (4H, br m), 2.00-2.14 (1H, m), 1.77-1.87 (1H, m), 1.10-1.50 (9H, br).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[OH:22].[OH-].[Na+].S(=O)(=O)(O)[OH:26]>O>[CH3:13][C:14]1[C:19]([CH3:20])=[C:18]([OH:26])[C:17]([CH3:21])=[CH:16][C:15]=1[OH:22]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)c(C)c(C)c1O
Temperature: 20 °C
Yield: 93 %

Procedure:
A solution containing 100 mmols of potassium persulfate in one liter of water is added dropwise with stirring, at 20° C., to a solution containing 100 mmols of 2,3,5-trimethylphenol in 100 ml of a 10% solution of sodium hydroxide. After stirring for 20 hours, the reaction mixture is neutralized with concentrated sulfuric acid and the solid formed is filtered. The remaining aqueous solution is acidified by slowly adding 220 ml of concentrated sulfuric acid, and heated for 30 minutes at 80° C. The oil formed is decanted and extracted with ethyl ether. The expected product is obtained after drying the ether phase, evaporating and recrystallizing in ethyl acetate.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([C:8]2[N:4]3[CH2:5][CH2:6][CH2:7][C:2]([O:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=4)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:3]3=[N:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][C:20]([CH3:22])=[N:19][CH:18]=1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2ccc(C(F)(F)F)cc2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.0 g) was added to a mixture of 4-(trifluoromethyl)phenol (408 mg), potassium carbonate (995 mg) and DMF (10 ml) at 90° C., and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (520 mg).
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[CH2:15]1[CH2:20][O:19][CH:18]=[CH:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>>[I:1][C:2]1[N:6]([CH:18]2[CH2:17][CH2:16][CH2:15][CH2:20][O:19]2)[N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CSc1nccc(-c2cnn(C3CCCCO3)c2I)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 60933.3 %

Procedure:
A mixture of compound A (75.0 g, 0.235 mmol), DHP (39.6 g, 0.471 mmol) and TsOH.H2O (7.5 g) was stirred at 60° C. for 6 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (EtOAc:petroleum ether=1:15) to give 4-(5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (B) (57.6 g, 60.8%). 1H NMR (400 MHz, CDCl3): δ 8.495 (d, 1H), 8.400 (s, 1H), 7.638 (d, 1H), 5.398 (m, 1H), 4.070 (m, 1H), 3.732 (m, 1H), 2.796 (s, 3H), 2.110 (m, 3H), 1.900 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH2:30]([OH:33])[C:31]#[CH:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:25])([F:26])[F:24])[N:17]=[C:16]2[O:33][CH2:30][C:31]#[CH:32])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C#CCO
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and propargyl alcohol with pyridine there is obtained isopropyl 2-chloro-4-fluoro-5-[6-oxo-4-pentafluoroethyl-2-(2-propynyloxy)-1(6H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz): 7.85 ppm (d,1H), 7.41 ppm (d,1H), 6.71 ppm (s,1H), 5.27 ppm (m,1H), 5.00 ppm (d,2H), 2.53 ppm (t,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C>C(O)C.O>[OH:16][C@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
In a mixed solvent (16 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2R)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (400 mg, 1.62 mmol) and 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 402 mg, 1.62 mmol) and stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 323 mg (40%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[C:6]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:4]=1[OH:5]>[Ag]=O>[CH3:1][O:2][C:3]1[C:4](=[O:5])[C:6]([CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[C:7]([CH3:13])[C:8](=[O:12])[C:9]=1[O:10][CH3:11]
Reactant: COc1c(O)c(C)c(CN2CCOCC2)c(O)c1OC
Agent: O=[Ag]
Product: COC1=C(OC)C(=O)C(CN2CCOCC2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
Silver oxide (15 g) was added to a solution of 2,3-dimethoxy-5-methyl-6-morpholinomethylhydroquinone (9 g) as obtained in Reference Example 8 in ether-dioxane (5:2, 70 ml) and the mixture was stirred at room temperature for 1.5 hours. The filtrate was treated in the conventional manner and the residue was recrystallized from ethyl acetate-hexane to give 2,3-dimethoxy-5-methyl-6-morpholinomethyl-1,4-benzoquinone (4.5 g), melting at 60°-62° C.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22]Cl.O>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]=[C:4]([NH2:3])[S:5][C:6]=2[CH:12]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: Fc1cccc(Cl)c1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2ccc(OCc3c(F)cccc3Cl)cc2s1
Reaction time: 1 h
Yield: 18.2 %

Procedure:
add 337 mg of anhydrous potassium hydroxide to a solution of 1 g of 2-amino-1,3-benzothiazol-6-ol in 5 cm3 of N,N-dimethylformamide. After stirring for one hour at a temperature close to 20° C., a solution of 1.08 g of 1-chloro-2-(chloromethyl)-3-fluorobenzene in 2 cm3 of N,N-dimethylformamide is added dropwise. Stir the resultant mixture for about twenty hours at about 20° C. The reaction mixture is poured into 30 cm3 of water, and extracted three times with 50 cm3 of dichloromethane. The organic phases are combined and washed three times with 50 cm3 of a 0.1N aqueous solution of sodium hydroxide, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up in 10 cm3 of a dichloromethane/methanol mixture (98/2 by volume), drained and then washed twice with 5 cm3 of the same mixture, stove-dried under reduced pressure (0.2 kPa) and at a temperature close to 35° C. We obtain 339 mg of 6-[(2-chloro-6-fluorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a white solid, which has the following characteristics:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[NH2:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:38])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[C:27]([O:36][CH3:37])[CH:26]=2)=[O:23])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2]([NH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:38])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[C:27]([O:36][CH3:37])[CH:26]=2)=[O:23])[CH:17]=[CH:18][CH:19]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)C(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C(=O)Nc2cccc(NS(C)(=O)=O)c2)ccc1-c1cnco1
Reaction time: 18 h
Yield: 105.6 %

Procedure:
12 mg (0.011 mmol) of methanesulphonyl chloride were added to a solution of 50 mg (0.011 mmol) of N-(3-aminophenyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide trifluoroacetate and 32 mg (0.317 mmol) of triethylamine in 0.5 ml of dimethylformamide. The resulting solution was left at room temperature for 18 hours then diluted with ethyl acetate and washed with 10% citric acid solution, saturated sodium bicarbonate and water. The organic phase was dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol (1:1) for the elution. There was obtained 5 mg of N-[3-(methanesulphonamido)phenyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 431.0 [M+H]+.