Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[CH:27](N(CC)C(C)C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(N)=O.S(C1C=CC(C)=CC=1)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(N)c3O2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.2 g (5.8 mmole) of toluene-4-sulfonic acid (2R)-8-amino-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in 100 mL of methylene chloride was added 1.3 g (10 mmole) of N,N-diisopropylethylamine, followed by 2.1 g (10 mmole) of trifluoroacetic anhydride. The mixture was stirred at room temperature for 2 hours, then washed with 100 mL portions of 2 N HCl (aq) and water, dried over sodium sulfate, filtered through silica gel, using additional methylene chloride to fully elute the product, and concentrated in vacuum to 2.6 g (5.4 mmole) of the trifluoroacetamide. This was dissolved in 50 mL of N,N-dimethylformamide and 1.2 g (6.5 mmole) of methyl tosylate and 3.0 g (22 mmole) of potassium carbonate added. The mixture was heated at 50-60° C. under nitrogen for 15 hours. After the mixture had cooled, it was diluted to 300 mL with ethyl acetate and washed with 300 mL of water. The aqueous phase was back-extracted with 200 mL of ethyl acetate and the combined organics were washed with 250 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was dissolved in 300 mL of methanol and 5.0 g (36 mmole) of potassium carbonate added. This mixture was stirred at room temperature for 24 hours, then filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 0.80 g of the (R)-enantiomer of the title compound as a yellow solid, m.p. 149-151° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([OH:14])[CH:6]=1.[CH:15]1[N:19]=[CH:18][NH:17][C:16]=1/[CH:20]=[CH:21]/[C:22](O)=[O:23].[Cl-].[Cl-].[Ca+2]>>[NH:19]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22]([O:14][C:7]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[CH:5][CH:6]=2)=[O:23])[N:17]=[CH:18]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(/C=C/c1c[nH]cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 ml (27.5 mmol) of freshly distilled thionyl chloride are added to a finely ground mixture of 1.51 g (10.8 mmol) of p-nitrophenol and 1.5 g (10.8 mmol) of trans-urocanic acid in a round-bottomed flask equipped with a drying tube containing CaCl2. The mixture is progressively brought to 140° C. After 4 h, the mixture is slowly cooled to room temperature. A brown powder is extracted with CHCl3/MeOH (150 ml, 2:1) while heating. The undissolved material is separated by filtration and the filtrate is treated with active charcoal. Concentration is carried out under vacuum and diethyl ether is added so as to induce precipitation of a solid (1.96 g; overall crude yield: 61%). The latter is recrystallized from MeOH and the product is washed with diethyl ether in order to remove any trace of p-nitrophenol, giving a crystalline white solid, M.p. 220°-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[C:20]([CH3:22])=[CH2:21].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:20]([CH3:22])[CH3:21])=[O:4]
Reactant: C=C(C)OC
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccc(F)cc2)cc1NC(C)C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of 3-amino-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester (0.502 g, 2.0 mmol) in 1,2-dichloroethane (6.0 mL) was added sequentially 2-methoxypropene (0.38 mL, 4.0 mmol), AcOH (0.114 mL, 2.0 mmol) and NaBH(OAc)3 (0.84 g, 4.0 mmol) and stirred for 2 hrs. It was then diluted with EtOAc and H2O. The aqueous solution was adjusted to pH=7 by adding NaHCO3. The aqueous phase was extracted with EtOAc, the combined extract was washed with brine and dried on MgSO4 and filtered. Purification on bond elute with hexane to 10% EtOAc-hexane furnished 5-(4-fluoro-phenyl)-3-isopropylamino thiophene-2-carboxylic acid methyl ester (0.538 g, 92% yield).
Reaction SMILES: [C:1]1([C:7](=[CH2:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[C:1]1([C:7](=[CH2:10])[CH2:8][O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a well stirred solution of 2-phenyl-prop-2-en-1-ol (700 mg, 5.22 mmol) in dichlorometane (10 mL) at 0° C. is added triethylamine (0.945 mL, 6.78 mmol) and methylsulfonyl chloride (0.424 mL, 5.48 mmol). The reaction is allowed to stir for 10 min, warmed to room temperature and is stirred for 30 min. The reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted several times with ethyl acetate. The organic layers are combined, washed with 1 N hydrochloric acid, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (10% ethyl acetate in hexanes) to yield the title compound (1.07 g, 4.95 mmol).
Reaction SMILES: C1(C(C2C=CC=CC=2)=N/N=C(/[C:12]2[S:13][CH:14]=[CH:15][C:16]=2[NH:17][N:18]=[C:19]([C:26]2C=CC=CC=2)C2C=CC=CC=2)\C)C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>CCO>[CH3:26][C:19]1[C:12]2[S:13][CH:14]=[CH:15][C:16]=2[NH:17][N:18]=1
Reactant: C/C(=N\N=C(c1ccccc1)c1ccccc1)c1sccc1NN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1n[nH]c2ccsc12
Temperature: 80 °C
Yield: 75 %

Procedure:
To a mixture of (E)-1-(diphenylmethylene)-2-(1-(3-(2-(diphenylmethylene)hydrazinyl)thiophen-2-yl)ethylidene)hydrazine (12.5 g, 25.07 mmol) in EtOH (75 mL) was added concentrated HCl (40 mL). The reaction mixture was heated at 80° C. for 2 hours, then basified with saturated aqueous NaHCO3 (50 mL) and solid NaHCO3 to pH 8-9. The reaction mixture was extracted with EtOAc (2×250 mL). The organic layers were combined, dried over sodium sulfate, and evaporated. The resulting mixture was purified by silica gel column chromatography, eluting with a gradient of 0-20% dichloromethane and methanol. The pure product fractions were combined and evaporated to give the title compound as a tan solid (2.6 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 2.42-2.57 (m, 3H), 6.97 (d, J=5.05 Hz, 1H), 7.40 (d, J=5.31 Hz, 1H), 9.04 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C6H6N2S, 139. found, 139.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1.[CH:21](=O)[C:22]1[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[O:26])[CH:23]=1.C(OC(=O)C)(=O)C>CCCCCC>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH:20]=[CH:21][C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH:25]=[O:26])=[N:17]2)=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
To 15 liters of xylene preheated to 100° were added sequentially 7-chloroquinaldine (3 kg, 16.9 moles; see C. M. Leir, J. Org. Chem., 42, 911-913 (1977)), isophthalaldehyde (3.4 kg, 25.3 moles), and acetic anhydride (4.69 liters, 5.07 kg, 49.7 moles). The mixture was heated at reflux for about 8 to 9 hours and then cooled to room temperature. Hexane (16 liters) was added and the resultant precipitate was collected by filtration. Recrystallization from ethyl acetate yielded pure title compound (67%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[C:19]2[C:28](=[C:29]([Cl:31])[CH:30]=1)[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[NH:21][C:20]2=[O:32]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:28](=[C:29]([Cl:31])[CH:30]=1)[C:22]1([CH2:27][CH2:26][N:25]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:24][CH2:23]1)[NH:21][C:20]2=[O:32]
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cc(Cl)cc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 3 tR=1.312, min, m/z=471; 1H NMR (d6-DMSO) 1.38 (d, 2H), 2.37 (m, 1H), 2.60-2.80 (m, 2H), 2.83-3.02 (m, 3H), 3.35 (m, 2H), 3.94 (d, 1H), 4.51 (d, 1H), 7.38 (t, 1H), 7.55 (m, 2H), 7.64 (m, 2H), 7.80 (s, 1H), 9.88 (s, 1H)
Reaction SMILES: O[Li].O.[CH3:4][C:5]1[C:6]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29]C)=[O:28])=[N:7][C:8]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:9][CH:10]=1>O.C1COCC1>[CH3:4][C:5]1[C:6]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([OH:29])=[O:28])=[N:7][C:8]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:9][CH:10]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1CC(=O)O
Temperature: 40 °C

Procedure:
LiOH.H2O (0.534 g, 12.7 mmol) was added to a solution of methyl 2-(2-(2-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetate (A116) (0.093 g, 0.25 mmol) in H2O (1 mL) and THF (10 mL) and the resulting mixture heated at 40° C. for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (100 mL), washed with aqueous 2 M HCl (50 mL), water (100 mL), brine (50 mL) and dried over MgSO4. The combined aqueous layers were additionally extracted with chloroform/isopropanol (4:1, 2×50 mL). The organic extracts were then combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A117 as a yellow solid (0.067 g, 75%); LCMS-A: rt 4.718 min; m/z 352 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]=[O:7])[CH2:2][C:3]([OH:5])=[O:4].CC([C@@H](O)C(NCCC(NCCS)=O)=O)(COP(OP(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(O)=O)(O)=O)C.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)CC[C:59]([OH:61])=[O:60]>>[CH2:1]([CH:6]=[O:7])[CH2:2][C:3]([OH:5])=[O:4].[O:7]=[C:6]([CH2:1][CH2:2][C:3]([O-:5])=[O:4])[C:59]([O-:61])=[O:60]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCC(=O)O
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: O=CCCC(=O)O
Product: O=C([O-])CCC(=O)C(=O)[O-]

Procedure:
The routes detailed in FIG. 12 are able to achieve the maximum theoretical 6-ACA yield of 0.8 moles 6-ACA per mole glucose utilized. The energetic yield is also favorable, with a maximum of 1.6 moles ATP per mole glucose utilized at the maximum product yield. The following assumptions were used to calculate yield: 1) phosphoenolpyruvate (PEP) carboxykinase is able to operate in the ATP-generating direction, 2) NH4 and 6-ACA are transported into the cell by proton antiport, and 3) succinic semialdehyde is formed from alpha-ketoglutarate and/or succinyl-CoA. Succinic semialdehyde dehydrogenase is a NAD(P)H and CoA-dependent aldehyde dehydrogenase that converts succinyl-CoA to succinic semialdehyde. Succinic semialdehyde is formed from alpha-ketoglutarate by two enzymes: alpha-ketoglutarate decarboxylase and 4-aminobutyrate transaminase.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Br[C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH2:12][CH3:13]>CO>[CH2:12]([C:7]1[N:8]=[C:9]([NH2:11])[S:10][C:6]=1[O:2][CH3:1])[CH3:13]
Reactant: CCc1nc(N)sc1Br
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCc1nc(N)sc1OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Sodium methoxide was freshly prepared by dissolving 0.186 g (8.1 mmol) of sodium metal in 12 mL of abs. MeOH. After cooling to 0° C., 5-bromo-4-ethyl-thiazol-2-ylamine (0.519 g, 2.51 mmol) was added and the cooling bath removed. After 45 min, TLC indicated the absence of starting material. The reaction mixture was poured onto crashed ice, twofold extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated to dryness. Thereby, 0.298 g of the title compound was obtained as brown, rather unstable oil, sufficiently pure to be used for the next step; it should be stored at −28° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[OH:1]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1O

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (10 g) in anh. MeOH (80 mL) was added dropwise H2SO4 (10.8 mL). The mixture was refluxed for 24 h and partitioned between DCM and water. The org. phase was separated, dried (Na2SO4) and evaporated off. The crude was purified by solid phase extraction to give the title product as a yellowish liquid (9.8 g).
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:46]1[C:51]([Cl:52])=[CH:50][C:49](O)=[C:48]([O:54][C:55]2[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=2[Cl:61])[CH:47]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:49]1[CH:50]=[C:51]([Cl:52])[CH:46]=[CH:47][C:48]=1[O:54][C:55]1[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=1[Cl:61])(=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h

Procedure:
2-Octanoyloxy-1-(octanoyloxymethyl)ethyl hydrogen glutarate (4.22 g.) was dissolved in dry toluene (40 ml.) and stirred with trifluoroacetic anhydride (5.2 ml.) for 2.5 hours. Triclosan (2.67 g.) was added and the mixture stirred for a further 20 hours. The solution obtained was washed successively with water (2×40 ml.), saturated sodium bicarbonate solution (2×40 ml.) and saturated brine (40 ml.). The organic phase was dried (MgSO4) and evaporated. The oil obtained was chromatographed on silica gel using methylene chloride as eluant to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-octanoyloxy-1-(octanoyloxymethyl)ethyl glutarate as an oil, having the same NMR and mass spectra as described for the ester in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C1C=CC=CC=1>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:18])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(F)cc2)cc1
Solvent: c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [(4-dimethylaminophenyl)methyl](4-fluorophenyl)amine (0.52 g) in benzene (5 mL) was added 2,6-diisopropylphenyl isocyanate (0.46 mL) and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The obtained crystals were subjected to recrystallization from a mixed solvent of diisopropyl ether and hexane to give N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-fluorophenyl)urea (0.38 g). melting point: 124–125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][CH:46]=[CH:45][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]([CH:28]=[N:29][NH:30][C:31](=O)[CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)=[O:5].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:48]=[CH:47][CH:46]=[CH:45][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH:28]=[N:29][N:30]=[C:31]1[CH2:32][N:33]1[C:34](=[O:43])[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:40]2[C:41]1=[O:42]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1C(=O)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 7, 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-fluorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide is heated to 100°-110°C with trifluoroacetic acid to give 2'-chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C1COCC1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[CH3:27][S:28]([O:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1cccc(CCCO)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCOc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(3-propoxyphenyl)-1-propanol (731 mg) and THF (20 ml) were added at 0° C. triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(3-propoxyphenyl)propyl methanesulfonate (1.10 g) as a colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH:15]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[C:24]([O:32][CH3:33])[CH:23]=3)C(OCC)=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>CS(C)=O.O>[CH:1]1[C:14]2[CH:13]([CH2:15][C:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:34])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C(=O)OC)c(OC)c1)C1c2ccccc2Oc2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=O)CC2c3ccccc3Oc3ccccc32)cc1OC

Procedure:
To a solution of ethyl 2-(9H-xanthen-9-yl)-2-(3-methoxy-4-methoxycarbonylbenzoyl)acetate (7.0 g, 14.6 mmol) in dimethylsulphoxide (40 ml) was added water (0.53 ml, 29.3 mmol). The solution was stirred under an atmosphere of nitrogen at reflux for 1.5 h before cooling and diluting with water. The mixture was extracted with dichloromethane (3×) and the combined extracts washed with water (5×) and a saturated solution of sodium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to a yellow oil. Purification on flash silica eluting with dichloromethane-hexane (3:2 then 4:1) gave a solid which was crystallised from methanol to give methyl 4-[2-(9H-xanthen-9-yl)acetyl]-2-methoxybenzoate as a yellow solid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH3:11])[C:5]=1[CH3:12])([O-])=O.[Na+].[Cl-:14].Cl.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.CC#N>[Cl:14][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH3:11])[C:5]=1[CH3:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: [Cl-]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Cl)cc[n+]([O-])c1C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
83.0 g (0.49 mol) of 4-nitro-2,3-dimethylpyridine N-oxide and 90 g (1.54 mol) of NaCl were admixed with 1350 ml of CH3CN, 180 ml of aq. HCl (36%) and 16.6 g of benzyltributylammonium chloride, and the resulting suspension was boiled under reflux with stirring for 12 h. The resulting reaction mixture was adjusted to pH=9 using 350 ml of 20% NaOH, wherefor the existing precipitate largely dissolved. The organic phase was separated off, water was added to the aqueous phase until the precipitate had completely dissolved, and it was subsequently extracted using dichloromethane. The organic phases were combined and the solvent was removed under reduced pressure. 76.6 g (98.5%) of 4-chloro-2,3-dimethylpyridine N-oxide were obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Solvent: c1ccncc1
Product: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Methyl 3-O-benzyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside (13.3 g; 26.05 mmoles) was dissolved in dry pyridine (41 ml) and cooled in an ice bath under nitrogen. p-Toluenesulfonyl chloride (9.93 g, 52.09 mmoles) was added all at once and the reaction was stirred at room temperature under nitrogen overnight. The reaction was partitioned between ether and water. The ether layer was extracted four times with water, dried (K2CO3, anhyd), and the solvent evaporated in vacuo to leave 19.1 g of crude product which was chromatographed on silica gel (1 kg) eluting with methylene chloride until excess p-toluenesulfonyl chloride had been eluted. Elution was continued with 2% (by volume) acetone in methylene chloride. Fractions containing the product were collected and evaporated to dryness to leave 15.5 g of methyl 3-O-benzyl-4-O-tosyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside as a glassy gum, [α]D25 =66.24 (C, 1.0, CHCL3)