Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C([O-])([O-])=O.[K+].[K+].[Br:32][C:33]1[CH:34]=[C:35]([F:42])[C:36]([CH2:40]Br)=[C:37]([F:39])[CH:38]=1>CC(C)=O>[Br:32][C:33]1[CH:34]=[C:35]([F:42])[C:36]([CH2:40][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:37]([F:39])[CH:38]=1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(Br)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (1.00 g, 2.65 mmol) and K2CO3(0.51 g, 3.70 mmol) in acetone (13 mL) was added 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (0.91 g, 3.18 mmol). The reaction mixture was stirred 1 h and then filtered. The filtrate was concentrated under reduced pressure and purified by chromatography (10% MeOH/DCM) to yield 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a tan solid (1.34 g, 87%). MS (EI) m/z 581 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][C:3]=1[F:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[C:3]([F:24])[CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2F)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.4 %

Procedure:
To a solution of N-[6-(4-amino-3-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) in N,N-dimethylacetamide (3.0 mL) were added 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (170 mg, 0.689 mmol), HATU (262 mg, 0.689 mmol) and N,N-diisopropylethylamine (120 μL, 0.689 mmol), and the mixture was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (208 mg, 81%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([OH:21])[CH:15]=1.O>CN(C)C=O.C(OC(=O)C)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([O:21][CH:8]([CH3:10])[CH3:9])[CH:15]=1
Reactant: COC(=O)c1cc(O)cc(I)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cc(OC(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
After adding 298 mg (2.16 mmol) of potassium carbonate and 0.12 ml (1.29 mmol) of 2-bromopropane to a solution of 120 mg (0.43 mol) of 3-hydroxy-5-iodobenzoic acid methyl ester in N,N-dimethylformamide (4.0 ml), the reaction mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 133 mg of 5-iodo-3-isopropoxybenzoic acid methyl ester (yield: 96%) as a colorless oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])=[CH2:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)C1CCC(C)=C1CCC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC1=C(C)CCC1C(C)C
Yield: 99 %

Procedure:
4 g of 3-isopropenyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene were hydrogenated in 50 ml of ethyl acetate in the presence of 400 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and distilled under a high vacuum. There were obtained 4 g of 3-isopropyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene; boiling point 0.005 about 70° C; nD20 = 1.4709; IRfilm : νmax = 1.725, 1390/70 and 1170 cm-1. The compound has a woody, floral note.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[N:2]1.C[C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.N1C=CC=CC=1>CC#N>[C:22]([N:18]1[CH2:19][CH2:20][N:21]([C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:14])[CH2:16][CH2:17]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C(Cl)C(=O)c1n[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
The crude residue containing (1H-Indazol-3-yl)-2-oxo-acetyl chloride (50 mg) was dissolved in dry CH3CN (7 mL), and to the resulting solution was added 3-(R)-methyl-1-benzoyl piperazine (50 mg) and pyridine (1 mL). The reaction mixture was stirred for 1 hour at room temperature then was concentrated in vacuo. The resulting residue was purified using Shimadzu automated preparative HPLC System to give 1-(benzoyl)-4-[(1H-indazol-3-yl)-2-oxoacetyl]piperazine (2.5 mg). 1H NMR (500 MHz, MeOD) δ 8.42 (m, 2H), 7.90 (m, 1H), 7.69 (m, 1H), 7.46 (m, 5H), 5.00-3.00 (m, 8H), 1.30 (m, 3H). MS m/z: (M+H)+ calcd for C21H21N4O3:377.16; found 377.28. HPLC retention time: 1.49 minutes (column A).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:16]([O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(Cc1ccc(OCCOCc2ccccc2)cc1)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(Cc2ccc(OCCOCc3ccccc3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the crude 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-propionic acid methyl ester from step d dissolved in 20 mL of THF/MeOH/H2O (3:1:1) was added lithium hydroxide (270 mg, 6.5 mmol) After stirring for 5 hrs at rt, the organic solvents were removed under vacuum and the reaction residue diluted further with water (25 mL). The aqueous mixture was extracted with diethyl ether, made acidic with 1 N HCl and extracted again with ethyl acetate. The ethyl acetate portion was then dried over Na2SO4 and concentrated under vacuum to afford 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-propionic acid as a semi-solid mass. (456 mg, 81% over 2 steps)
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:34][CH3:35])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][N:14](CC(C)CC)[CH2:13][C@H:12]2[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)[CH3:3].Cl.CN(C)C1C=CC([C@@H]2CCNC[C@H]2COC2C=CC(C(F)(F)F)=CC=2)=CC=1>>[ClH:1].[CH2:34]([N:4]([CH2:2][CH3:3])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1)[CH3:35]
Reactant: CCC(C)CN1CC[C@@H](c2ccc(N(CC)CC)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Agent: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Product: CCN(CC)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Yield: 23 %

Procedure:
Preparation by dealkylation of (44) as described for compound (41). Yield 23%. M.p. 220.5°-227.6° C.
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:21][O:20][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[O:6][C:7]=2[C:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3CCOCC3)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2oc(N)nc12
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a stirred solution of 130 g (4.24 mmol) [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-carbamic acid methyl ester in 90 ml dioxane and 30 ml ethylene glycol was added 90 ml of a 5 N aq. sodium hydroxide solution, and the mixture was heated at 100° C. for 16 h. After cooling to room temperature, the mixture was poured onto water and extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (dichloromethane then 5/95 methanol/dichloromethane) afforded 0.78 g (74%) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-ylamine as a brown solid. ES-MS m/e (%): 249 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(O)(=O)C>[CH3:16][O:15][CH2:14][C:13]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=1
Reactant: COCC(=O)Nc1cccc(C(=O)OC)c1N
Solvent: CC(=O)O
Product: COCc1nc2c(C(=O)OC)cccc2[nH]1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
Methyl 2-amino-3-[(methoxyacetyl)amino]benzoate (280 mg) was dissolved in acetic acid (6 mL), and the solution was heated at 100° C. for 0.5 hour with stirring. After cooling the reaction mixture to room temperature, acetic acid was removed. To the residue was added saturated aqueous sodium bicarbonate under ice-cooling, and it was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the titled compound (241 mg) as pale yellow powder.
Reaction SMILES: C1(C)C=CC(S([CH2:10][C:11]2[N:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[N:12]=2)(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:10][C:11]1[N:12]=[C:13]([CH2:19][OH:20])[N:14]=[C:15]([CH2:17][OH:18])[N:16]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(CO)nc(CO)n2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(CO)nc(CO)n1
Temperature: 50 °C

Procedure:
4-(p-Toluenesulfonylmethyl)-2,6-dihydroxymethyl-s-triazine is dissolved in DMF and sodium azide (1.1 eq.) is added. The reaction mixture is heated to 50° C. for 4 hours. The DMF is removed under reduced pressure and the residue is partitioned between CH2Cl2 and water. The CH2Cl2 layer is separated and the water layer is extracted several times with CH2Cl2. The CH2Cl2layers are combined, dried (MgSO4), and concentrated. The resultant residue is purified by silica gel flash column chromatography to give 4-(azidomethyl)-2,6-dihydroxymethyl-s-triazine.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH3:35]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH3:35]
Reactant: CCCI
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, propyl iodide 0.59 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 40 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.61 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6](Cl)[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O.CCOC(C)=O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:7]=1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(N)c(C(N)=O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Yield: 83.1 %

Procedure:
A mixture of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (500 mg), (4-methoxyphenyl)boronic acid (740 mg), and Pd(PPh3)4 (56.3 mg) in 2M aq. Na2CO3 (3.25 ml) and dioxane (20 ml) was refluxed for 3 hours. Water (40 ml) and of EtOAc (30 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHCl3:MeOH (25:1). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxamide (512 mg) as a yellow powder.
Reaction SMILES: COC1C=CC(COC([NH:11][CH:12]2[CH2:17][CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]2)=O)=CC=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C1(OC)C=CC=CC=1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:11][CH:12]1[CH2:17][CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]1
Reactant: COC(=O)C1=CC(NC(=O)OCc2ccc(OC)cc2)CC=C1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)C1=CC(N)CC=C1
Temperature: 0 °C

Procedure:
To a suspension of 16.5 g of methyl 3-(p-methoxybenzyloxycarbonylamino)-1,5-cyclohexadienecarboxylate in 40 ml of anisole at about 25° C. is added slowly 30 ml of trifluoroacetic acid. After the addition of the first 5 ml the solid dissolves. The solution is cooled in a ice bath and the addition of trifluoroacetic acid continues. The solution is maintained at 0° C. for one hour, then the solvents are removed in vacuo (1 mm) maintaining the temperature below 40° C. The resulting oily residue is cooled to 0° C. and anhydrous ether added with stirring. The precipitate is filtered off to give 8.1 g of methyl 3-amino-1,5-cyclohexadienecarboxylate trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:27][S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:19][C:15]1[CH:14]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([N:34]3[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH2:33]3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 39, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and 1-methanesulfonyl-piperazine (CAS RN: [55276-43-2]) was prepared the title compound as a yellow solid, MS (ESI+): m/z=493.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)([CH3:9])[CH:7]=[CH2:8])[CH3:2].B(Br)(Br)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([CH3:9])[CH:7]=[CH2:8])[CH3:2]
Reactant: C=CC(C)(CC(=O)OCC)Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: C=CC(C)(CC(=O)OCC)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of the product of STEP 4 (0.79 g) and dichloromethane (15 ml) was cooled to 0° C. A 1 M solution of boron tribromide in dichloromethane (6.00 ml) was added slowly. The solution was stirred at room temperature for 1 hour. Ethanol (5 ml) was added to quench the reaction. Solvent was removed. Residue was extracted with 1% of hydrochloric acid aqueous solution and ethyl acetate. The organic extract was washed with saturated sodium bicarbonate/water, and then dried over MgSO4. Solvent was removed. The crude product was purified on a silica gel column, eluting with 20% ethyl acetate/hexane to afford colorless oil (0.32 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
The de-tosylated nitrile 38 (26.7 mg, 107 μmol) was dissolved in dimethyl sulfoxide (2.49 g). To this was added potassium carbonate (32.7 mg, 237 μmol) and 30% hydrogen peroxide in water (85.5 mg) and the reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was washed with water, acetonitrile and ether to give final product 39 (25.3 mg, 88%). 1H NMR DMSO-d6 11.86 (s, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 8.11 (m, 1H), 7.81 (m, 2H), 7.70 (s, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.16 (m, 1H), 3.91 (s, 3H). LC/MS(M+1)=268
Reaction SMILES: S(=O)(=O)(O)O.C([Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:40])([O:33]C3CCCCO3)[CH3:32])[CH:21]=2)[CH:13]=1)(C)(C)C>C1COCC1.O>[OH:33][C:31]([CH3:40])([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([CH:19]=[CH:18][C:14]2[CH:13]=[C:12]([OH:11])[CH:17]=[CH:16][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C=Cc2cccc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.133 ml of concentrated sulphuric acid with 1.25 g (2.39 mmol) of tert-butyldimethyl-[3-(2-{3-[6-methyl-6-(tetrahydropyran-2-yloxy)heptyl]phenyl}-vinyl)phenoxy]silane in 20 ml of THF and 10 ml of water, after crystallization from a heptane/ethyl acetate mixture, white crystals (m=697 mg; Y=90%) are obtained. m.p.=96-7° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[N+:25]([C:24]1[CH:23]=[CH:22][N+:21]([O-:28])=[CH:20][C:19]=1[O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)([O-:27])=[O:26]
Reactant: Oc1cccc2c1CCCC2
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5,6,7,8-tetrahydro-1-naphthol (6.0 g) in DMF (100 ml) was added Na2CO3 (10 g) portionwise at room temperature. Then a solution of 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 20 ml of DMF was added dropwise and the mixture was stirred at room temperature for four hours. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat NaCl, anhy. MgSO4).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br>C(Cl)(Cl)Cl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Cl)C(=O)CCC2)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Using chloroform as solvent. A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (5.12 g) in chloroform (50 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the organic solvent was removed under reduced pressure and the residue triturated with aqueous ammonia to yield the title compound m.p. 192°-3° C. (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10]([C:15](N)=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH-:20].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10]([C:15]([OH:20])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CSc2cccnc2C(N)=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CSc2cccnc2C(=O)O)cc1

Procedure:
A suspension of 5 g. of 3-(p-methoxybenzylthio)-picolinamide in 50 ml. of 20% aqueous sodium hydroxide is refluxed for about 24 hours, then cooled and acidified with dilute hydrochloric acid. Filtering, washing the precipitate with water, drying and recrystallizing from methanol gives 3-(p-methoxybenzylthio)picolinic acid.