Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1.CN(C)C=O>O>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 20 °C
Yield: 31.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-dimethylaminobenzoic acid (14.9 g), N,N'-carbonyldiimidazole (14.6 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The crude product obtained by filtration of the reaction mixture (6.4 g; m.p. 248° C.) is dissolved in boiling dimethylformamide (95 cc). After cooling for 2 hours at 20° C., water (95 cc) is added. The crystallized solid is separated by filtration, washed with a dimethylformamide/water (50:50 by volume) mixture (2×10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-dimethylaminobenzamide (6.2 g), m.p. 248° C., is obtained.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1>[OH-].[Na+].C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Oc1nc2c(nc1CCc1ccccc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=c1c(CCc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
Ethylene chlorohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[C:10]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])[CH3:11]>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]([C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7])([OH:12])[CH3:11]
Reactant: Cc1nn(C)c(C)c1Br
Reactant: CC(=O)c1ccco1
Product: Cc1nn(C)c(C)c1C(C)(O)c1ccco1

Procedure:
4-Bromo-1,3,5-trimethylpyrazole was converted into the corresponding 4-lithio compound which was then reacted in situ with 2-acetylfuran.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[C:18]=1[CH3:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C[O-].[Na+].CO.C1COCC1>[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH2:27][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:18]=1[CH3:39])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2nc3ccccc3c(OCc3ccccc3)c2C)cc1
Reactant: CCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCSCc1nc2ccccc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
1-Heptanethiol (250 mg) was dissolved in methanol (5 mL), to which a solution of 28% sodium methoxide in methanol (0.37 mL) was then added, followed by stirring at room temperature for 15 minutes. The reaction mixture was added to a solution of p-toluenesulfonic acid [4-(benzyloxy)-3-methylquinolin-2-yl]methyl ester (464 mg) in methanol-THF (1:1, 10 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the resulting residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (380 mg).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[CH:16][N+:17]([O-])=[O:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1>C(O)(=O)C.O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([C:16]([N+:1]([O-:3])=[O:2])=[N:17][OH:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1
Reactant: O=[N+]([O-])C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite, 5 g (0.072 mole), was added in portions over a period of 5 min to a solution of 20 g (0.06 mole) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine* in 100 ml of glacial acetic acid. Following the addition, the reaction mixture was stirred at room temperature for 15 min. The product, which crystallized partially during this period, was further precipitated by slow addition of 50 ml of water and collected by filtration. The crystals were washed with water, sucked dry and washed with methanol/ether to leave light yellow product. The filtrate was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. Crystallization of the residue from methylene chloride/hexane yielded additional product. The analytical sample was recrystallized from ether to give pale yellow crystals with mp 220°-230° C. dec.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:28][O:27][C:22]1[C:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:5]=[C:6]([N:8]([CH3:15])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[N:20]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3cccnc3O)n2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ncccc1-c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To 3-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridin-2-ol (Intermediate 63, 0.31 mmol) was added DMF (2 mL), potassium carbonate (85 mg, 0.52 mmol) and methyl iodide (19 μL, 0.31 mmol). The resulting mixture was stirred for 2 h, after which time further methyl iodide (40 μL, 0.62 mmol) was added. The reaction was stirred for a further 1.5 h after which time further methyl iodide (60 μL, 0.93 mmol) was added. This sequence was repeated two more times after which the starting material had been consumed. The crude mixture was diluted with ethyl acetate (10 mL), extracted with water (5 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by chromatography on silica eluting with a gradient of 2% to 6% MeOH-DCM and then by trituration with hot methanol (2 mL) to give the title compound (44 mg, 38%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:59]=[CH:58][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31](OCC)=[O:32])[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]4[N:47]=[C:48]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[O:49][C:50]=4[CH3:51])=[CH:40][CH:39]=3)=[N:27]2)=[CH:23][CH:22]=1.O>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]4[N:47]=[C:48]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[O:49][C:50]=4[CH3:51])=[CH:40][CH:39]=3)=[N:27]2)=[CH:58][CH:59]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Lithium aluminium hydride (2.03 g) was added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazole-4-carboxylate (40.00 g) in tetrahydrofuran (150 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]methanol (35.91 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 157–158° C.
Reaction SMILES: N#N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([I:25])C(=O)C1.CCO>CCOC(C)=O>[I:25][C:15]1[N:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=3)=[CH:10][C:11]2=[N:17][CH:16]=1
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Reactant: O=C1CCC(=O)N1I
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Ic1cnc2cc(-c3ccncc3)ccn12

Procedure:
Charge a 250 μL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, with 7-pyridin-4-yl-imidazo[1,2-a]pyridine (3.35 g, 17.2 mmol), NIS (3.8 g, 16.8 mmol), EtOH (3A). Heat the reaction to 65° C. for 1 hour. This can be followed by SiO2 TLC (100% EtOAc). Add more NIS (3.8 g, 16.8 mmol) and heat the reaction to 65° C. for 1 hour. Mix the reaction while cooling in an ice bath for 30 minutes then filter and rinse the solids with MeOH. Air dry the solids and vacuum oven dry at 40° C. to afford 4.59 g (83%). Additional product can be obtained from the filtrate. MS (ES), m/z 322 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[C:5]([F:29])=[CH:4][CH:3]=1.[Cl:30][C:31]1[C:32]([C:39]([NH2:41])=[O:40])=[N:33][N:34]([CH:36]([F:38])[F:37])[CH:35]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:15])([F:17])[F:16])[CH2:13][C@:8]([C:6]2[N:7]=[C:2]([NH:41][C:39]([C:32]3[C:31]([Cl:30])=[CH:35][N:34]([CH:36]([F:37])[F:38])[N:33]=3)=[O:40])[CH:3]=[CH:4][C:5]=2[F:29])([CH2:27][F:28])[N:9]=1
Reactant: O=C(NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: NC(=O)c1nn(C(F)F)cc1Cl
Product: NC1=N[C@](CF)(c2nc(NC(=O)c3nn(C(F)F)cc3Cl)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method R, Example 134 above, except N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (11i) underwent the conditions described in step 10 with 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide (intermediate 32) followed by the conditions described in step 9. MS m/z=488.9 [M+H]+. Calculated for C16H12ClF7N6O2: 488.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[O:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH2:27])[CH2:22]1>CC(N(C)C)=O>[O:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cccc(NC3CCCOC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and tetrahydro-pyran-3-ylamine hydrochloride (CBI, 257 mg; 1.87 mmol; 5 eq.) in DMA (1 mL) as a white powder (32 mg, 26%). 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.00 (d, J=6.8 Hz, 2H), 7.48-7.63 (m, 4H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=9.0 Hz, 1H), 6.36 (d, J=7.9 Hz, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.50 (m, 2H), 2.06 (m, 1H), 1.22-1.97 (m, 3H). HPLC, Rt: 2.27 min. (purity 99.6%). LC/MS, M+(ESI): 338.1, M−(ESI): 336.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=2)[CH:63]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:57][C:58]2[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]3[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=3)[CH:63]=2)=[O:8])=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
3-Furoic acid (557 mg, 4.97 mmol), HATU (1.89 g, 4.97 mmol), HBTU (560 mg, 4.14 mmol), methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.0 g, 4.14 mmol) and DIPEA (2.17 ml, 12.43 mmol) were mixed in DMF (5 ml) and the reaction stirred at room temperature for 18 h. The DMF was evaporated under vacuum, the residue partitioned between DCM (50 ml) and aqueous sodium carbonate (1M, 50 ml) and the aqueous extracted with DCM (2×30 ml). The combined organics were washed with brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified on a silica flash column eluting with DCM/ethanol/ammonia (500:8:1), which after evaporation of the solvents under vacuum gave methyl 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylate (800 mg, 58%). LCMS: retention time 3.41 min, MH+336.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=2)[CH:12]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
Potassium carbonate (2.49 g, 18.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 5-fluoro-2-nitrobenzotrifluoride (3.14 g, 15.0 mmol) in DMF (20 ml), and the mixture was stirred under heating at 70° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (40 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish solid of 5-methyl-3-(4-nitro-3-trifluoromethylphenyloxy)pyrazole (2.74 g, yield: 63.6%). mp: 96-98° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.34 (s, 3H), 5.77 (s, 1H), 7.40 (dd, J=2.6 and 8.9 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H), 9.20-10.15 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](N(OC)C)=[O:17])[N:6]=1)([CH3:4])[CH3:3].[CH2:22]([Mg]Br)[CH3:23]>O1CCCC1.C(OCC)C>[CH3:13][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([C:16](=[O:17])[CH2:22][CH3:23])[N:8]=1)([CH3:14])[CH3:15]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h

Procedure:
A solution of 8.4 g (28 mmol) of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide in 150 mL of tetrahydrofuran was cooled in ice and treated dropwise with 40 mL (120 mmol) of a 3.0M solution of ethylmagnesium bromide in diethyl ether. The mixture was stirred in ice for 2 hours, then at room temperature for an additional 16 hours. The reaction mixture was again cooled in ice, and excess Grignard reagent was destroyed by dropwise addition of 50 mL of saturated aqueous ammonium chloride solution. The reaction mixture was added to 400 mL of ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated. Recrystallization of the residue from hexane yielded 5.0 g (67%) of the ethyl ketone product, mp 123° C.-125° C.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.N([O-])=O.[Na+].[ClH:17]>C(O)(=O)C.O.[Cu]>[Cl:17][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1
Reactant: Cl
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nnc(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 2-amino-5-phenyl-[1,3,4]thiadiazole (6.45 g, 36.4 mmol; Aldrich) and copper (230 mg, 3.6 mmol; Aldrich) in hydrochloric acid (36 mL, 12 M) and glacial acetic acid (180 mL) was chilled to 0° C. and treated with a solution of sodium nitrite (2.64 g, 38.2 mmol; Aldrich) in water (12 mL), added dropwise over 40 minutes. After stirring at room temperature for 4 hours, the mixture was poured into ice water. The aqueous solution was extracted with chloroform (3×), and the combined extracts were washed sequentially with 5% sodium bicarbonate and brine, and dried over sodium sulfate. The crude product was filtered through a short silica gel plug with chloroform to afford the title product: 1H NMR (300 MHz, CDCl3) δ ppm 7.46-7.55 (m, 3H), 7.85-7.93 (m, 2H) MS (DCI/NH3) m/e 197/199 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:17])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:3][CH:4]=1)=[O:18]
Reactant: C1COCCN1
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(=O)c1ccc(N2CCOCC2)cc1)N1CCOCC1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
15.08 g (0.06 mol) of 1-(4-fluorophenyl)-2-methyl-2-morpholinopropan-1-one and 5.23 g (0.06 mol) of morpholine are dissolved in 25 ml of dimethyl sulfoxide, and the solution is heated to 160° C. together with 8.3 g (0.05 mol) of potassium carbonate. After 18 hours of stirring at about 160° C. the suspension is cooled down and is poured onto an ice-water mixture. The crystals are filtered off, are washed with water and are recrystallised from ethanol. Melting point 114°-116° C.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].ClC1C=C[C:23]([NH2:24])=CC=1.C(O)(=O)C.[OH-].[Na+]>CS(C)=O>[OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:23]=[N:24][CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(C(=CO)C(=O)Nc2cccnc2)on1

Procedure:
General method for the synthesis of α-[4-(chlorophenylamino)methylene]-3-methyl-N-pyridyl-5-isoxazoleacetamide: α-Hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide (0.25 g, 1.0 mmol) was stirred with 4-chloroaniline (0.13 g, 1.0 mmol) and acetic acid (200 μL) in DMSO (3 mL) at rt for 24 h. The resulting solution was mixed with 10 mL of an aqueous 0.5 N NaOH solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was then recrystallized from MeOH.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14].O>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:9][CH2:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cccc1OCC1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 103.7 %

Procedure:
Sodium hydride (60%; 349 mg; 8.7 mmol) was suspended in DMF (3 mL) and cooled to 0° C. under inert atmosphere. Cyclopentylmethanol (0.79 mL; 7.3 mmol) was added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 20 minutes. The solution was then added dropwise to a solution of 2,6-difluorobenzonitrile (1.03 g; 7.4 mmol) in DMF (3 mL) cooled to 0° C. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solution was poured over 50 mL of cooled water and extracted with ethyl acetate and solvent removed. Purification by column chromatography (5% ethyl acetate/hexane) yielded 1.66 grams of 2-fluoro-6-(cyclopentylmethoxy)benzonitrile.
Reaction SMILES: [C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:27].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[O:27])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 0.17 h

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to ≈+3° C. m-Chloroperbenzoic acid 69.5% (2.43 g, 9.8 mmol) dissolved in CH2Cl2 (20 ml) was added dropwise under stirring. Stirring was continued for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).