Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21].CC1(C)N([O])C(C)(C)CCC1.F[B-](F)(F)F.CC#N.[OH2:44]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:44])[CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21]
Reactant: O
Reactant: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reaction time: 2 h

Procedure:
A solution of the ester (0.21 g, 0.63 mmol, prepared as described in Step A), in 10 ml of CH3CN--H2O (9:1, v/v) was added dropwise to a stirred solution of TEMPO-BF4 in 10 ml CH3CN--H2O (9:1, v/v). Stirring was continued for 2 h and the reaction mixture was concentrated in vacuo. The residue was partitioned between Et2O and H2O. The organic phase was washed with brine and dried (Na2 SO4). Removal of solvent provides a yellow oil which was purified by flash chromatography (silica gel, hexane- EtOAc 2:1) to give 0.18 g of product as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N+:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: CC(NC(=O)c1coc(Oc2cccc([N+](=O)[O-])c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 49.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-nitrophenol (36 mg, 0.26 mmol) to give the title compound (31 mg, 49%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][Si:16]([CH3:25])([CH3:24])[CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C1COCC1>[CH3:15][Si:16]([CH3:25])([CH3:24])[C@@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1
Reactant: C[Si](C)(C)C1CCC(=O)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of L-selectride (165 mL, 0.165 mol, 1.5 eq) in anhydrous THF (200 mL) at −78° C. was added dropwise a solution of 4-(trimethylsilyl)cyclohexanone (20 g, 0.11 mol, 1.0 eq) in anhydrous THF (100 mL). The temperature was maintained for 3 h, and then the reaction mixture was stirred at room temperature for 16 h. Then the mixture was cooled to 0° C. before being quenched with water. The resulting mixture was warmed up to room temperature, and then sodium hydroxide aqueous solution (80 mL, 3 M) was added, followed by hydrogen peroxide (80 mL, 30%). After being stirred for 3 h, the mixture was extracted with EtOAc (300 mL×3), and the combined organic layers were washed with H2O and brine, dried over Na2SO4, concentrated to give a residue which was purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to obtain the product cis-4-(trimethylsilyl)cyclohexanol as a white solid (10.0 g, 51% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=O)[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.[O:24]([CH2:31][CH2:32][NH2:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>ClCCl>[O:24]([CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C([O-])Cc1cccc(O)c1
Reactant: NCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccc(O)c1)NCCOc1ccccc1

Procedure:
3-Hydroxyphenylacetate (1.5 g, 9.88 mmol) was dissolved in dichloromethane. WSC.HCl (2.82 g, 14.76 mmol) and 2-phenoxyethylamine (1.5 g, 10.95 mmol) were added thereto, and then the resultant mixture was stirred for 4 hours at room temperature. After completion of reaction, water was added to the reaction mixture. The resultant mixture was extracted with chloroform, followed by washing with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by chromatography, whereby 2.85 g, a stoichiometric amount, of the target compound was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17]>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 39.1 %

Procedure:
To a diethyl ether (500 mL) solution of 2,5-dibromopyridine (25 g, 110 mmol) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 45 mL, 120 mmol) at −76° C., which was stirred for 25 minutes. To this solution was added dropwise N,N-dimethylformamide (9.0 mL, 120 mmol) at −76° C. Upon completion of this addition, the reaction solution was gradually cooled to room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain the title compound (8.0 g, 41%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:14]([CH3:13])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CNCCN(C)C
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(C)CCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N′,N′-trimethylethylenediamine as starting materials to give the aimed compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][CH:43]=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2].[CH3:47][O:48][C@H:49]([CH2:55][CH2:56][CH:57]=[CH2:58])[C@@H:50](C)[C:51](O)=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(#N)C>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][C:43](=[O:44])[C@H:50]([CH3:51])[C@H:49]([O:48][CH3:47])[CH2:55][CH2:56][CH:57]=[CH2:58])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC=O)C(C)C)N2)c1
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cc(C=C)ccn2)N1)C(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of crude (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-2-formylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (0.52 mmol) and (2R,3R)-3-methoxy-2-methylhept-6-enoic acid 10d (90 mg, 0.52 mmol) in acetonitrile (10 mL) was stirred at room temperature. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (containing 20% water, 85 mg, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to neat ethyl acetate to afford the title compound (271 mg, 67%) as a gum. 1H NMR (300 MHz, CDCl3) δ 0.17 (s, 6H), 0.86-0.98 (m, 15H), 1.17 (d, J=7.1 Hz, 3H), 1.5-2.2 (m, 11H), 2.45-3.00 (m, 5H), 3.33-3.44 (m, 1H), 3.40 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 4.27-4.33 (m, 2H), 4.97 (dd, J=10.2, 1.7 Hz, 1H), 5.05 (dd, J=17.2, 1.7 Hz, 1H), 5.28 (d, J=7.3 Hz, 1H), 5.56 (d, J=10.7 Hz, 1H), 5.73-5.87 (m, 2H), 6.03 (d, J=17.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 2H), 6.66-6.82 (m, 4H), 7.04-7.10 (m, 1H), 7.31 (s, 1H), 8.56 (d, J=5.1 Hz, 1H). LCMS (m/z) 778 [M+H], Tr=5.78 min.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[CH:25][C:24]=3[O:36][CH3:37])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Reactant: O=Cc1c[nH]c2cc(C(=O)NCC3CCCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 71.9 %

Procedure:
A mixture of 6-(N-cyclopentylmethylcarbamoyl)-3-formylindole (0.92 g), t-butyl 4-bromomethyl-3-methoxybenzoate (1.2 g), and potassium carbonate (0.7 g) in N,N-dimethylformamide (17 ml) was stirred for 48 hours under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and dried to yield t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]-3-methoxybenzoate (1.2 g, 71%) as an ivory powder; mp 134°-135°.
Reaction SMILES: [CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][OH:4].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][O:4][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CO)[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(COCc1ccccc1)[N+](=O)[O-]
Reaction time: 48 h
Yield: 15.2 %

Procedure:
To a suspension of 2-methyl-2-nitro-1-propanol (2.3975 g, 20.13 mmol) and Ag2O (4.6385 g, 20.02 mmol) in DMF (25 ml) was added benzyl bromide (2.65ml, 22.28 mmol) and stirred for 48 hours. The mixture was filtered and the filtrate was added to 5% KHSO4 aqueous solution, extracted three times with ethyl acetate/hexane=1/1 and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (toluene) to give the title compound (639.4 mg; 15%).
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[I:11][C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][NH:16][CH:17]=1>C(Cl)Cl>[Cl:8][C:15]1[C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]([I:11])=[CH:17][N:16]=1
Reactant: COC(=O)C1=CC(I)=CNC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cnc1Cl
Temperature: 25 °C
Reaction time: 28 h
Yield: 43 %

Procedure:
To a solution containing 0.12 ml of dry dimethylformamide and 0.14 ml of distilled phosphorus oxychloride in 20 ml of anhydrous methylene chloride are added 0.28 g of methyl 5-iodo-1,2-dihydro-3-pyridinecarboxylate in one portion. The mixture is stirred at room temperature under a nitrogen atmosphere for 28 hours. Workup as described in Procedure 1 yields 0.13 g (43%) of recrystallized methyl 2-chloro-5-iodo-3-pyridinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].O1CCCC1CCO.Cl>O>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1C
Agent: Cl
Agent: OCCC1CCCO1
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2ccncc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 4-methyl-2-(4-pyridyl)thiazole-5-carboxylate (744 mg), 1 N NaOH (4 ml) and tetrahydrofuran-ethanol (1:1, 6 ml) was stirred at room temperature for 1 hour and diluted with water, to which was added 1 N hydrochloric acid (4 ml) to give the title compound as crystals (595 mg, 90.2%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(C)(=O)=O)c3)n2)n1
Yield: 18.9 %

Procedure:
To a stirred and cooled solution of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.400 g, 0.986 mmol) in EtOAc (4 mL) and sat. NaHCO3-sol. (2 mL) was added methanesulfonyl chloride (1.08 mL, 14.7 mmol) and the mixture was stirred at 23° C. for 2 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (0.090 g, 19%). MS (ISP) 484.4 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)(=[O:3])N.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)([OH:12])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: COc1nscc1C(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nscc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 7.9 g. (0.05 mole) of 4-carbamoyl-3-methoxyisothiazole prepared as in Example 19 in 90 ml. of 80% sulfuric acid at 10°-15° C. was added slowly beneath the surface of the liquid a solution of 9.5 g. (0.137 mole) of sodium nitrite in 13 ml. of H2O. When addition was complete the solution was allowed to come to 25° C., and then was heated to 60° C., for several minutes. After cooling to 25° C. the reaction solution was poured onto ice to precipitate 3.64 g. (46%) of 4-carboxy-3-methoxyisothiazole as a white solid, m.p. 182°-185° C.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)O)cc1
Product: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-propoxyphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:18][N:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p.107) (2.0 g) was dissolved in DMF (15 ml) prior to the addition of K2CO3 (2.07 g) and MeI (0.71 ml). After 2 h, the solution was concentrated and 1N HCl solution (aq) was added. The solution was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Filtration through a plug of silica of the resulting residue gave N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide. This material (2 g) was dissolved in EtOH prior to the addition of a solution of NaOH (2 g) in H2O (2 ml). The mixture was heated to reflux for 2 h, cooled to rt, and neutralized with 1N HCl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (2.07 g). This solution was placed on a Parr apparatus under H2 (50 psi) for 2 h. The Pd/C was filtered off and the solution was concentrated. The resulting residue was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 45 min. After cooling to rt, flash chromatography of the crude reaction gave (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.05 g). A portion (200 mg) of this material was dissolved in THF (17 ml) prior to the addition of a solution of LiOH (31 mg) in H2O (6 ml). MeOH (6 ml) was added. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (189 mg). MS found: (M+H)+=259.2 (4b) A portion (13 mg) of the above derivative (4a) was dissolved in DMF (2 ml) prior to the addition of diisopropylethylamine (0.05 ml) and example (3i)(30 mg). After cooling to 0° C., BOP (23 mg) was added. The resulting mixture was warmed to rt and stirred overnight. The reaction was concentrated. Water was added and the solution was extracted with EtOAc. The EtOAc layer was washed with NaHCO3 solution (aq), dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (14 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[Cl:20][C:21]1[C:22](B(O)O)=[CH:23][C:24]([F:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC>[Cl:20][C:21]1[C:22]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[N:4][C:3]=2[C:16]([F:19])([F:18])[F:17])=[CH:23][C:24]([F:27])=[N:25][CH:26]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: FC(F)(F)c1ncc(NCC2CCOCC2)nc1Cl
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: COCCOC
Product: Fc1cc(-c2nc(NCC3CCOCC3)cnc2C(F)(F)F)c(Cl)cn1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 67 %

Procedure:
6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine (0.020 g, 0.068 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.036 g, 0.203 mmol), and sodium carbonate (0.088 ml, 0.176 mmol, 2 M in H2O) were dissolved in DME (0.70 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.011 g, 0.014 mmol). The reaction mixture was then heated in a microwave at 110° C. for 25 min. Boronic acid (˜0.036 g, 0.203 mmol) and PdCl2(dppf)CH2Cl2 adduct (˜0.011 g, 0.014 mmol) were added. Heating in the microwave was continued at 110° C. for 25 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 0.0759 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc/75 heptane to 100 EtOAc gave 0.0178 g (67%) of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine. LCMS (m/z): 391.1 (MH+), retention time=0.96 min.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]([NH2:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:12]I>CO>[CH2:1]([N:7]([CH2:8][C:9]([NH2:11])=[O:10])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNCC(N)=O
Reactant: CI
Solvent: CO
Product: CCCCCCN(C)CC(N)=O

Procedure:
In a flask of 100 ml, 7.9 gr (0.05 mol) of 2-(n-hexylamino)acetamide and 7.8 gr (0.055 mol) of methyl iodide were mixed in 50 ml of methanol. This solution was left for 1 month at room temperature, then evaporated. The residue was dissolved in a 1N NaOH solution until basic pH and extracted with ether. The ether phase was dried on MgSO4 and evaporated. The solid as obtained was chromatographed on a column of SiO2 by eluting with a benzene-methanol mixture (7:3). The desired product was thus obtained.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH3:27])(=O)C>O1CCOCC1.COC1C(N)=CC=CC=1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:11][C:10]1[CH:9]=[CH:1][CH:2]=[CH:27][C:26]=1[O:25][CH3:22])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Solvent: COc1ccccc1N
Solvent: C1COCCO1
Product: COc1ccccc1Nc1c(C(=O)c2ccccc2)cnc2c(OC)cccc12
Yield: 61 %

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (2.8 g, 0.0094 mol) was heated under reflux in a mixture of 1,4-dioxan (50 ml) and o-anisidine (7 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, and washed with dilute hydrochloric acid sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to give an oil which afforded yellow crystals of 3-benzoyl-4-(2-methoxyphenylamino)-8-methoxyquinoline (2.2 g, 61%) from ethyl acetate, m.p. 200°-202°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:14][NH:15][C:16](=[O:17])[NH:18][N:19]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=O)NN
Product: O=C(NN=Cc1c(O)ccc2ccccc12)NN=Cc1c(O)ccc2ccccc12
Yield: 97 %

Procedure:
Following the general procedure of Example 1, condensation of 2-hydroxy-1-naphthaldehyde and carbohydrazide gave a white solid (97%): mp>285° C. (dec); 1H NMR d 11.90 (br s, 2 H); 11.05 (s, 2 H), 9.23 (s, 2 H), 8.33 (d, 2 H, J=8.4 Hz), 7.88 (d, 2 H, J=9.0 Hz), 7.87 (d, 2 H, J=7.8 Hz), 7.59 (t, 2 H, J=7.6 Hz), 7.38 (t, 2 H, J=7.5 Hz), 7.22 (d, 2 H, J=9.0 Hz); 13C NMR d 156.71, 151.56, 143.24, 131.88, 131.50, 128.72, 127.87, 127.56, 123.35, 121.58, 118.61, 109.40; MS (CI) m/e 399.0 (M +H)+; Anal. (C23H18N4O3 0.3 H2O) C, H, N.