Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[F:14][CH:15]([F:40])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]2[CH:24]=[C:25]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][CH:36]([OH:39])[CH2:37][OH:38])[CH:34]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)[N:17]=1>CN(C=O)C.CCOC(C)=O>[Si:10]([O:38][CH2:37][CH:36]([OH:39])[CH2:35][N:33]1[CH:34]=[C:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([CH:15]([F:14])[F:40])[CH:21]=[CH:20][N:19]=3)[CH:24]=2)[CH:31]=[N:32]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO)c2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Imidazole (0.28 g, 4.16 mmol) and tert-butylchlorodimethylsilane (0.574 g, 3.81 mmol) were added to a solution of 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propane-1,2-diol (1.3 g, 3.46 mmol) in DMF (12 mL) at 0° C. The mixture was stirred at 0° C. for 90 minutes. The mixture was allowed to warm to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/Hexane) to afford 1-((tert-butyldimethylsilyl)oxy)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-ol. MS ESI calc'd. for C24H34F2N5O2Si [M+H]+ 490. found 490.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[N:19]=2)O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C1CCCCC1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([Cl:4])[C:18]2[N:19]=[C:20]([O:25][CH3:26])[C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1nc(C(O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: COc1nc(C(Cl)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reaction time: 17 h
Yield: 96 %

Procedure:
Sulfuryl chloride (0.37 mL) was added to a solution of (4-tert-butylphenyl)(5-chloro-6-methoxypyridin-2-yl)methanol obtained in Example 7-4(1) (200 mg) and triethylamine (0.27 mL) in cyclohexane (4 mL) at room temperature, and then the mixture was stirred at the same temperature for 17 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 6-[(4-tert-butylphenyl)(chloro)methyl]-3-chloro-2-methoxypyridine as a colorless oil (203 mg, 96%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.Br[C:30]1[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:37])=[C:33]([CH3:35])[N:34]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:30]2[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:9]1=[NH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccc(F)cc1
Yield: 7 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 7% yield: mp 142-144° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.35 (br s, 1H), 8.16 (t, J=5.9 Hz, 1H), 7.36-7.23 (m, 7H), 7.13-7.07 (m, 2H), 4.45 (s, 2H), 4.29 (d, J=5.9 Hz, 2H), 3.56-3.50 (m, 2H), 3.32-3.26 (m, 2H), 2.41 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 162.4, 159.9, 159.0, 152.8, 137.4, 136.5, 129.6, 129.0, 128.1, 127.7, 115.5, 115.2, 47.6, 45.2, 42.3, 40.9, 17.8; MS (ES+) m/z 424.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH:24]([C:28](=O)[CH3:29])[CH2:25][C:26]#[N:27]>C(#N)C>[CH2:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:24]([CH2:25][C:26]#[N:27])=[C:28]([CH3:29])[N:1]=2)[CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(NCc2ccccc2)cn1
Reactant: CC(=O)C(Cl)CC#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2ccc(NCc3ccccc3)cn2c1CC#N

Procedure:
A mixture of 2-amino-5-benzylamino pyridine (4.0 g), triethylamine (2.1 g),3-chloro-4-oxopentanenitrile (2.7 g) and acetonitrile (50 ml) is stirred and heated under reflux for 18 hr. The solvent is removed in vacuo, and the residue is dissolved in chloroform (200 ml). The solution is washed with water (4×100 ml), dried over anhydrous potassium carbonate and the chloroform is removed in vacuo. The residue is chromatographed on silica gel (200 g) using chloroform as the eluant. The product is obtainedand crystallized from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4([C:23]#N)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:6]=2[CH:25]=1.C[Mg]Br.C(OCC)C.[NH4+].[Cl-:39]>O1CCCC1.O>[ClH:39].[Br:1][C:2]1[C:3]([C:26]([F:27])([F:28])[F:29])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4([CH3:23])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:6]=2[CH:25]=1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4cc(C(F)(F)F)c(Br)cc43)CC2)CCOCC1
Reactant: [Cl-]
Agent: C[Mg]Br
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(N2CCC(n3c(=O)[nH]c4cc(C(F)(F)F)c(Br)cc43)CC2)CCOCC1
Product: Cl
Temperature: 0 °C

Procedure:
A stirred suspension of 4-{4-[6-bromo-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinyl}tetrahydro-2H-pyran-4-carbonitrile (D70, 1100 mg, 0.21 mmol) in tetrahydrofuran (8 ml) at room temperature under argon was treated with 3M methylmagnesium bromide solution in diethyl ether (0.15 ml, 0.46 mmol) and the insoluble material rapidly dissolved. Further methylmagnesium bromide solution was added after a total of 50 minutes (0.15 ml) and a total of 70 minutes (0.20 ml). After another 15 minutes the reaction mixture was cooled to 0° C. and treated dropwise with 1M aq. NH4Cl solution (3 ml), then diluted with water (15 ml) and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and concentrated under vacuum to afford the title compound as a white solid. This was converted to its HCl salt as a white solid (95 mg, 90%).
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:47]([OH:55])(=[O:54])[CH:48]([CH2:50][C:51]([OH:53])=[O:52])[OH:49].[H][H]>O1CCCC1.[Pd].CCOCC>[C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:54][C:47](=[O:55])[CH:48]([CH2:50][C:51]([OH:53])=[O:52])[OH:49])=[O:17])=[CH:14][CH:13]=1)([O:38][CH3:39])=[O:37]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC(=O)C(O)CC(=O)O)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(15-carbomethoxypentadecylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is added 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a tan, crystalline mass.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C:47]([NH2:50])([CH3:49])[CH3:48]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([NH:50][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH:10]=[CH:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:22])[CH3:48]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1C=CCCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At 0° C. to a solution of 165 mg of a mixture of the (E)- and (Z)-isomers of 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid in 2 ml abs. DMF under inert atmosphere 95 mg 1-hydroxybenzotriazole, 110 μl N,N′-diiospropylcarbodiimide and 98 μl N,N-diisopropylethylamine were added. After 15 min at 0° C. 86 mg amino-isobutyric acid methyl ester hydrochloride and 98 μl N,N-diisopropylethylamine were added and the reaction was stirred for 0.5 h at 0° C. and for 4 h at room temperature. Then, the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sat. sodium hydrogen carbonate solution and brine. The organic layer was dried over sodium sulphate, concentrated and purified by chromatography on silica (ethyl acetate/heptane) to yield 85 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: OCC([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6])=O.O=[CH:14][C@@H:15]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH:11]([C:9]1[CH:15]=[CH:14][O:8][C:7]=1[CH:5]=[O:6])=[O:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=Cc1ccoc1C=O

Procedure:
Remarkably, catalyst activity was found to be closely related to the stereo property of the NHC ligands. 1-CrCl2 catalyzed the dehydration fructose and glucose with HMF yields of 65% and 66%, respectively (Table 1). Catalyst with the isopropyl-substituted NHC ligand, 2-CrCl2, showed similar efficiency as 1-CrCl2. In contrast, the HMF yields from sugars were significantly increased using chromium catalysts with the more bulky NHC ligands, such as 3-7. 6-CrCl2 system provided a HMF yield as high as 96% from fructose. It also gave a HMF yield of 81% from glucose, which was a record high efficiency for glucose feedstock. There was no difference in yield for the metal catalysts with saturated vs. unsaturated NHC ligands. The catalysts with the most bulky NHC ligand, 1,3-bis(2,6-diisopropylphenyl)imidazolylidene 6 and 1,3-bis(2,6-diisopropyl)phenylimidazolinylidene 7 provided the highest yields. To better understand the details of this reaction, bidentate ligand 8 was examined. Interestingly, catalyst 8-(Cr)2 gave a good HMF yield (81%) from glucose, while 8-(Cr)1 showed a poor HMF yield (14%). These results suggested that an over-crowded complex would have a lower activity in binding with substrates and initiating the reaction. Control reaction without catalyst showed a very low HMF yield (less than 40% and 1% from fructose and glucose, respectively). The reaction temperature was investigated between 80° C. and 100° C. for both fructose and glucose. Lower temperature led to a lower HMF yield: higher temperature gave rise to byproducts, mainly diformylfuran (DFF) (see FIG. 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[CH2:30]([Mg]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+].C(OCC)(=[O:43])C>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:30][C:31]2([OH:43])[CH:36]=[CH:35][CH:34]=[CH:33][CH2:32]2)=[C:4]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2C=O)cc1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2CCC2(O)C=CC=CC2)cc1
Reaction time: 0.5 h

Procedure:
2-Amino-4-chloro-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde (0.20 g; 0.48 mmol) was stirred in dry THF (5 ml) at 0 DC. Benzyl magnesium chloride (1.0 M; 3 eq; 1.45 mmol; 1.45 ml) was added dropwise. The mixture was stirred for, 30 mins before addition of saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The aqueous layer was further extracted with ethyl acetate and the organic layers combined, washed with water, dried and evaporated. The product was purified by column chromatography eluting with 40% EtOAc/petrol (40:60) giving a yellow oil (0.151 g; 0.30 mmol; 62.4%).
Reaction SMILES: [Se](=O)=O.[CH2:4]([NH:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[C:10]=1[O:20][CH:21]([CH3:23])[CH3:22])=[O:8])[CH3:5].OO.C([O-])(O)=[O:27].[Na+]>CO.CCOC(C)=O>[CH2:4]([NH:6][C:7]([C:9]1[S:13](=[O:27])[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[C:10]=1[O:20][CH:21]([CH3:22])[CH3:23])=[O:8])[CH3:5]
Reactant: O=C([O-])O
Reactant: CCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Agent: O=[Se]=O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNC(=O)C1=C(OC(C)C)c2cc(OC)ccc2S1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Selenium dioxide is added to a room temperature solution of N-ethyl-5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (195 mg, 0.66 mmol) in 8 mL of MeOH containing 530 μL of hydrogen peroxide (30% aqueous). The reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into EtOAc and saturated NaHCO3. The organic phase is washed with saturated NaHCO3, 1N HCl, then brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid is chromatographed, eluting with a gradient of 1:9 EtOAc:CH2Cl2 to 1:1 EtOAc:CH2Cl2, to provide 96 mg (47%) of N-ethyl-5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide -1-oxide; mp 88°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[C:10](OC)=[N:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-:26].[NH4+:27]>CO>[ClH:26].[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[C:10]([NH2:27])=[N:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCOC(=O)N1CCN=C(OC)C(N2C(=O)c3ccccc3C2=O)C1
Solvent: CO
Product: CCOC(=O)N1CCN=C(N)C(N2C(=O)c3ccccc3C2=O)C1
Product: Cl
Yield: 79.7 %

Procedure:
To a solution of 39.00 g (112.93 mmol) of (+/−)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-methoxy-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester dissolved in 350 mL of methanol was added 6.34 g (118.57 mmol) of ammonium chloride at room temperature. The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The residue was triturated with diethyl ether and filtered to afford 33.00 g (80%) of (+/−)-5-Amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride (1:1) as a white powder. The compound was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15].OO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the 2-chloro-5-trifluoromethylpyridine (1.8 g, 0.01 mol) in methylene chloride (20 ml) was mixed with trifluoroacetic anhydride (15 g, 0.071 mol). The stirred solution was subjected to the dropwise addition of 30% aqueous hydrogen peroxide (1.4 g, 0.012 mol) over the course of 15 minutes. A mild exotherm ensued and the mixture was allowed to stir at ambient temperature for 1 hour. The solution was poured onto ice and extracted with 3×50 ml of ethyl acetate; the combined organic layers then were passed through a 1 inch pad of silica gel in a sintered glass funnel under suction. The eluate was evaporated and the residue was chromatographed on silica gel, eluting first with methylene chloride to remove unreacted pyridine and then with ethyl acetate to remove the product N-oxide weighing 1.8 g (90%) as an orange oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.S(Cl)(Cl)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:39])[N:24]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:25]2=[O:30].C(N(CC)CC)C>C1COCC1>[O:38]=[C:32]1[CH:31]([N:24]2[C:23](=[O:39])[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20][NH:19][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:25]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5cn4)c3C2=O)C(=O)N1
Yield: 76 %

Procedure:
A mixture of isoquinoline 3-carboxylic acid (0.39 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at reflux for 90 minutes. The solvent was evaporated and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.67 g of the product with 96:4 methylene chloride-methanol, in 76% yield: mp 198-200° C.; 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.53-2.66 (m, 2H), 2.85-2.97 (m, 1H), 5.02 (d, J=6.3 Hz, 2H), 5.19 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.71-7.92 (m, 5H), 8.21 (d, J=7.8 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H) 8.59 (s, 1H), 9.43 (s, 1H), 9.65 (t, J=6.3 Hz, 1H), 11.17 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.5, 48.9, 120.0, 121.9, 127.2, 127.8, 128.0, 129.2, 129.3, 131.4, 131.6, 133.0, 134.8, 135.4, 139.2, 143.4, 151.7, 164.7, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H18N4O5.0.5H2O: C, 63.85; H, 4.24; N, 12.41. Found: C, 63.85; H, 3.93; N, 12.31.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=1.[CH:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.O1CCCC1.CCCCC>[Cl:16][C:17]1[N:18]=[C:19]([O:23][CH3:24])[C:20]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:22]=1
Reactant: COc1cccc(Cl)n1
Reactant: O=Cc1ccccc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1C(O)c1ccccc1
Reaction time: 1 h

Procedure:
100 ml of a pentane solution containing 1.56 mol of tert-butyllithium was slowly added dropwise into a solution of 200 ml of tetrahydrofuran containing 11.9 ml of 2-bromomesitylene at −78° C. under cooling. After stirring at the same temperature for one hour, 7.2 ml of 2-chloro-6-methoxypyridine was slowly added dropwise thereinto. After stirring under ice-cooling for one hour and then at room temperature for one hour, 8.5 ml of benzaldehyde was added thereto under ice-cooling, followed by stirring at room temperature for further one hour. Water was added to the reaction solution, followed by extracting with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (7:1), to give 15.0 g of the target compound.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C:10]1([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[C-:22]#[N:23].[K+]>CO.O>[CH2:3]([C:10]1([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][CH2:14][C:13]([NH:23][CH3:22])([C:1]#[N:2])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: [C-]#N
Reactant: CN(C)CC1(Cc2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC1(C#N)CCC(Cc2ccccc2)(CN(C)C)CC1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
40% aqueous methylamine solution (15.3 mL, 121 mmol) and 4-benzyl-4-((dimethylamino)methyl)cyclohexanone (6.20 g, 25.3 mmol) dissolved in methanol (25 mL) were added to a solution of 4N hydrochloric acid (6.6 mL) and methanol (4.00 mL) cooled to 0° C. The reaction mixture was then mixed with potassium cyanide (4.00 g, 60 mmol) and stirred for 5 d at room temperature. For work up the mixture was diluted with water (180 mL) and extracted with ether (3×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated until dry in a vacuum.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[N:11]=1.[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:15][CH3:16])(=[O:14])=[O:13]>C(OCC)(=O)C>[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O-:15])(=[O:14])=[O:13].[CH3:16][N:7]1[CH:8]=[CH:9][C:10]2=[NH+:11][CH:3]([S:2][CH3:1])[S:4][C:5]2=[CH:6]1
Reactant: CSc1nc2ccncc2s1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: CSC1[NH+]=C2C=CN(C)C=C2S1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.127 g of 2-methylthiothiazolo[5,4-c]pyridine (from methylation of thiazolo[5,4-c]pyridine-2(1H)-thione with potassium carbonate and methyl iodide) and 0.143 g methyl tosylate is heated at 120° C. for one hour. Ethyl acetate (8 mL) is added, the mixture is stirred for 30 minutes, and Compound 6 is isolated by suction filtration.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9][OH:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C.[Cl:25]CCl>>[Cl:25][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: OCCc1sccc1CO
Reactant: CS(=O)(=O)Cl
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1sccc1CCl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2.0 g of the compound obtained in Example 2 was dissolved in 35 mL of dichloromethane, and the resulting solution was cooled to below 5° C. To the solution, 3.0 g of methanesulfonyl chloride and 4.1 g of diisopropylethylamine were added, and the resulting mixture was stirred for 30 minutes. 30 mL of dichloromethane was added to the reaction solution, and the resulting mixture was washed twice with 30 mL portions of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.9 g (yield of 91%) of the title compound as an oil.