Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.COOB([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)O.C1C[O:34][CH2:33]C1.C(#N)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:34][CH3:33])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: COOB(O)c1ccccc1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Solvent: CC#N
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (8.0 g, 17.6 mmol), methoxyphenyl boronic acid (2.9 g, 19.4 mmol), dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (646 mg, 0.9 mmol) in THF/Acetonitrile/saturated NaHCO3 (50 ml/50 ml/50 ml) was stirred at 50° C. overnight under nitrogen. The mixture was allowed to cool to room temperature and was extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 29% yield). NMR (500 MHz, DMSO-d6) δ 0.11 (s, 9H), 1.05 (m, 2H), 3.76 (m, 2H), 3.01 (s, 3H), 5.87 (s, 2H), 7.26 (m, 1H), 7.35 (m, 1H), 7.54 (m, 1H), 7.72 (m, 1H), 8.17 (s, 1H), 8.38 (m, 1H), 8.59 (m, 1H). MS: m/z 434.1 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)[CH2:6][NH2:7].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].O>ClCCl>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:2][CH3:1])[CH2:6][NH:7][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:23])([F:34])[F:35])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCON=C(CN)c1ncc(Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 56.1 %

Procedure:
To a solution of 200 mg of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-β-ethyloxime and 90 mg of triethylamine in 3 ml of dichloromethane, 169 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 30 minutes. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 190 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]#N)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-:16].[Na+].Cl.C[OH:20].O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:20])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: [OH-]
Reactant: CO
Reactant: COc1cc(CC#N)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(CC(=O)O)cc(OC)c1OC

Procedure:
3,4,5-trimethoxyphenyl acetonitrile 5.5 g was dissolved into 50 ml of methanol/water (9:1). To this 1 .5 g of sodium hydroxide was added and they were then stirred and refluxed for 5.5 hours. The temperature of the reactive liquid was lowered down to room temperature and neutralized with 2N hydrochloric acid, and the methanol was distilled off under reduced pressure. Extraction was performed thrice by means of 100 ml of chloroform. After distilling off the solvent under reduced pressure, 5.8 g of captioned compound was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1Br
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-3-nitro-phenol synthesized above (11.5 mmol, 1.0 eq.) in DMF at room temperature was added cesium carbonate (13.8 mmol, 1.2 eq.), followed by iodomethane (33.7 mmol, 2.9 eq.), and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, stirred for 2 hours, filtered, the cake washed with two portions of water, and the resultant solid dried to afford 2-bromo-3-nitro-anisole (I-9, X═Br, R1═CH3) as a pale orange solid. Yield: 97%; 1H NMR (400 MHz; CDCl3): 3.97 (s, 3H), 7.07 (dd, J=8.4, 1.2 Hz, 1H), 7.32 (dd, J=8.0, 1.6 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12]O)=[CH:8][CH:7]=1.P(Br)(Br)[Br:21]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][Br:21])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: CCCCCC
Product: Fc1cc(F)cc(Oc2ccc(OCCBr)cc2)c1
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
To a mixture of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol 1.00 g, 3.76 mmol) and n-hexane (50 ml), phosphorus tribromide (0.71 g, 2.63 mmol) was gradually added with stirring under ice-cooling. After completion of the addition, the temperature was elevated to room temperature and stirring was continued at the same temperature for 30 minutes, followed by stirring under reflux for 1 hour. After allowed to cool, the upper n-hexane layer was collected by decantation, and the n-hexane layer was washed with water two times, an aqueous sodium carbonate solution three times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl bromide (915 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]Cl>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CN(C)CCCCl
Product: Cc1ccccc1C1=CN(CCCN(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=568.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[CH:6](NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1.BrCC(C)=C>C1COCC1.O>[CH3:6][C:32]1[CH:31]=[CH:30][C:29]([CH:33]([CH2:4][CH:3]=[CH2:2])[C:34]([OH:36])=[O:35])=[CH:28][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1cccc(-c2ccccn2)c1
Reactant: [Li]CCCC
Agent: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C(=O)O)c1ccc(C)c(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
nBuLi (21 ml, 2.5 M in hexanes, 52.16 mmol) was added dropwise to a solution of diisopropyl amine (5.3 ml, 52.5 mmol) in THF (60 ml) at 0 degrees C. The reaction was stirred 20 minutes, then cooled to −78 degrees C. The LDA solution was then added dropwise into a cooled solution of 3-(2-pyridyl)phenyl acetic acid (5.0 g, 23.5 mmol) in THF (20 ml) at −78 degrees C. After addition, the reaction mixture was warmed to 0 degrees C., then cooled again to −78 degrees C. 3-Bromo-2-methylpropene (3.55 ml, 35.2 mmol) was then added rapidly. The reaction mixture was stirred for 1 h. then quenced with water (20 ml). The THF from the reaction mixture was then removed in vacuo, then the pH of the solution was adjusted to 7 by adding con HCl and pH 7 buffer (1 M). The aqueous reaction mixture was then extracted twice with CHCl3. The combined organic extracts were dried with magnesium sulfate, concentrated in vacuo, and chromatographed (silica gel, 3% MeOH-CH2Cl2) to yield a white solid (4.8 g, 77%): MS ES(+) 268.3 (M+H+).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[F:27])[CH3:18].[CH2:28](OC(OCC)OCC)C>C(O)(C)C>[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][CH:28]=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=2[Cl:16])=[O:5])=[CH:22][C:21]=1[F:27])[CH3:18]
Reactant: CCOc1ccc(N)cc1F
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Solvent: CC(C)O
Product: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1F
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (5.9 g, 22.7 mmol) in 400 mL of isopropanol was added 4-ethoxy-3-fluoroaniline (3.7 g, 23.8 mmol). This mixture was heated to reflux to give a clear solution. To this solution, triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 18 hours. Additional triethylorthoformate (11.6 mL, 69.6 mmol) was added dropwise and the reaction mixture was heated at reflux for 42 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40° C. to give 6.4 g (67%) of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a grey solid, mp 245-247° C.; MS 424.1, 426.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1)=[O:5])[CH3:2].Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Li+].[Li+].C(#N)C.CN(C=O)C>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9](=[O:11])[N:8]([C:12]([CH3:14])([CH3:13])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C(C)(C)C)c(=O)[nH]1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1nn(C(C)(C)C)c(=O)n1CC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
A solution of 3.0 g of the product of Step B, 7.41 g of 1-bromo-3,3-dimethyl-2-butanone, and 4.15 g of lithium carbonate in a 2:1 mixture of acetonitrile/DMF (90 mL) was heated at 100° C. for four h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with sat. ammonium chloride solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with sat. lithium chloride solution, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography afforded 1-tert-butyl-4-(3,3-dimethyl-2-oxo-butyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester as a yellow oil. MS (M+H+)=312.3.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:27]=[CH:26][C:15]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]3)[O:18][C:14]=2[CH:13]=1.CCN(CC)CC.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl>[CH:14]([OH:18])=[O:41].[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:27]=[CH:26][C:15]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:24][CH2:23][CH:22]([NH:25][C:40]([NH2:39])=[O:41])[CH2:21]3)[O:18][C:14]=2[CH:13]=1
Reactant: NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.3 %

Procedure:
To a suspension of 1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-ylmethyl]-pyrrolidin-3-ylamine hydrochloride (70 mg, 0.174 mmol) in DCM (3 mL), was added Et3N (0.12 mL, 0.869 mmol), followed by trimethylsilyl isocyanate (0.19 mL, 1.39 mmol) and the resulting solution was stirred (rt, 14 h). The reaction mixture was concentrated and the resulting residue was purified by reverse phase HPLC to afford the title compound as a white solid (33 mg, 42%). MS (ESI): mass calcd. for C20H19N5O3S, 409.1; m/z found, 410.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.49 (bs, 1H), 8.31 (dd, J=8.0, 1.4, 1H), 7.74 (d, J=8.5, 1H), 7.70 (d, J=1.8, 1H), 7.38-7.32 (m, 2H), 7.10 (s, 1H), 4.36-4.29 (m, 2H), 4.33 (s, 1H), 3.52-3.38 (m, 2H), 3.25-3.14 (m, 2H), 2.45-2.34 (m, 1H), 1.99-1.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([NH2:22])[CH:18]=[CH:17][C:16]=1[OH:23]>O.CC(C)=O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([OH:23])=[C:15]([CH3:14])[C:20]=2[CH3:21])[C:4](=[O:10])[CH:3]=1
Reactant: Cc1c(N)ccc(O)c1C
Reactant: COc1ccc(O)cc1N
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(O)ccc(NC2=CC(=O)C(N)=CC2=O)c1C
Reaction time: 3 h

Procedure:
0.01 mole (1.39 g) of 3-amino-4-methoxy phenol is dissolved in 100 cc of water to which have been added 50 cc of acetone and 10 cc of ammonia (22° Be'). To this solution there are added 100 cc of H2O2 (20 volumes) and immediately thereafter, with good agitation, 0.01 mole (1.37 g) of 2,3-dimethyl-4-amino phenol in suspension in 100 cc of water. The resulting reaction mixture is agitated for three hours at which time it is filtered to recover the 2-amino-5-(4'-hydroxy-2',3'-dimethyl anilino)-1,4-benzoquinone which is first washed with water and then with acetone. It is dried for 8 hours under a vacuum with a boiling water bath and is chromatographically pure, melting at 320° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][C:9]1[CH:42]=[CH:41][C:12]2[O:13][CH2:14][C:15]3[N:40]=[CH:39][CH:38]=[CH:37][C:16]=3[C:17](=[CH:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([OH:27])[C:23]([CH3:36])([CH3:35])[CH2:22]3)[C:11]=2[CH:10]=1)([CH3:7])[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH:18]=[C:17]3[C:16]4[CH:37]=[CH:38][CH:39]=[N:40][C:15]=4[CH2:14][O:13][C:12]4[CH:41]=[CH:42][C:9]([O:8][C:5]([CH3:6])([CH3:7])[CH2:4][OH:3])=[CH:10][C:11]3=4)[CH2:22][C:23]2([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a cooled (0° C.) solution of 2-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid ethyl ester (117 mg, 0.193 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 0.39 mL, 0.39 mmol). The reaction was allowed to stir at 0° C. for 2 h. Excess hydride was quenched by the addition of a saturated aqueous potassium/sodium tartrate solution. The mixture was stirred at rt until two clear phases formed. The mixture was diluted with ethyl acetate and shaken. The extracts were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride—90:10 methylene chloride/methanol gradient) to afford the titled compound (102 mg, 94%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([OH:27])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (730 mg, 1.76 mmol) (obtained as described in Reference Example 37(4)) in methylene chloride (37 ml) were added methanesulfonyl chloride (409 μl, 5.29 mmol) and triethylamine (741 μl, 5.29 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (846 mg, yield 98%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[N:12]=[CH:11][C:10]([C:13](=[C:19]([CH3:21])[CH3:20])[C:14]([O:16]CC)=[O:15])=[CH:9][N:8]=1)([CH3:6])[CH3:5]>C(O)(C)C.O>[CH3:6][C:4]([C:7]1[N:8]=[CH:9][C:10]([C:13](=[C:19]([CH3:21])[CH3:20])[C:14]([OH:16])=[O:15])=[CH:11][N:12]=1)([CH3:3])[CH3:5]
Reactant: CCOC(=O)C(=C(C)C)c1cnc(C(C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)=C(C(=O)O)c1cnc(C(C)(C)C)nc1
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide 0.24 g) and ethyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.4 g) in isopropanol (10 cm3) and water (2 cm3) was heated to the reflux temperature for a period of 3 hours. After cooling to the ambient temperature the crude reaction mixture was concentrated by evaporation of the solvent under reduced pressure, and the residue was dissolved in water, and extracted with ethyl acetate. The aqueous portion was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to give 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoic acid, containing a small amount of 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-3-enoic acid. The crude produce was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:2]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH2:24]>C1COCC1.CCN(CC)CC>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH:24][C:10]([C:9]1[C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Oc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Oc1cccnc1
Yield: 55 %

Procedure:
To a stirred solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.432 g, 2.0 mmol) in THF (15 mL) at 0° C. was added oxalylchloride (2 mL, 2M in CH2Cl2, 4.0 mmol) dropwise. The solution was stirred at room temperature for 3 h. The solvent was evaporated in vacuo to yield 2-(pyridin-3-yloxy)-nicotinoyl chloride as a solid. To a solution of 2-(pyridin-3-yloxy)-nicotinoyl chloride in 15 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (0.376 g, 2.0 mmol) in 5 mL THF and 1 mL Et3N at 0° C. The reaction mixture was refluxed for 6 h and the solvent was evaporated. The residue was purified by chromatography with EtOAc:hexanes, 1:2, yielding (0.425 g, 55%) of the title compound. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.90 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.41 (m, 2H), 6.43 (m, 2H).
Reaction SMILES: CS(C)=[O:3].[OH:5][CH2:6][C:7]1([O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])[OH:8].[NH2:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[OH:22]>O.C(=O)([O-])[O-]>[NH2:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][C:21](=[O:22])[OH:23].[OH:5][CH2:6][C:7]1([O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])[OH:8].[OH:3][CH:15]1[O:16][C@H:7]([CH2:6][OH:5])[C@H:9]([OH:10])[C@H:11]([OH:12])[C@H:13]1[OH:14].[OH:22][CH:15]1[O:16][C@H:7]([CH2:6][OH:5])[C@@H:9]([OH:10])[C@H:11]([OH:12])[C@@H:13]1[OH:14]
Reactant: CS(C)=O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 0.5 h

Procedure:
Solutions of Glu (40 mM-4.0 μM), Fru (0.4 mM), Gal (0.4 mM) and Man (0.4 mM) in deionized water were prepared. An aliquot (2.0 mL) of the solution of TPEDB (0.1 mM) in the carbonate buffer containing 4 vol % DMSO was added into a 10 mL volumetric flask, followed by the addition of 1.0 mL of a solution of Fru (0.4 mM) and 1.0 mL of a solution of Glu (40 mM). After shaking for a few seconds, a solution of TPEDB (50 μM) with 10 mM of Glu and 0.1 mM of Fru in the carbonate buffer containing 2% DMSO was obtained. The solution was allowed to stand for 30 min before its FL measurement. The solution of TPEDB and Glu containing another saccharide (Gal or Man) was prepared by similar procedures.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].Cl.[F:26][CH2:27][CH2:28][NH2:29]>N1C=CC=CC=1.C(Cl)Cl>[F:26][CH2:27][CH2:28][NH:29][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: NCCF
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCF)OC3=O)ccc21
Temperature: 90 °C

Procedure:
A solution of butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 985 mg, 2.81 mmol) in pyridine (5.5 mL) in a thick-walled, screw-cap vial is treated with fluoroethylamine hydrochloride (2.20 g, 22.1 mmol), and the stirred reaction mixture is placed in an oil bath maintained at 90° C. for 24 h. The mixture is then cooled to ambient temperature, diluted with CH2Cl2 (50 mL), washed with 0.2 M hydrochloric acid (25 mL portions, until the washings are at pH<2) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with MeOH/CH2Cl2 (1/99-2.5/97.5). Those fractions with an Rf=0.32 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the residue triturated and filtered from MeOH to give the title compound, mp 201-203° C.; MS (ESI−) for C14H14N3O4FS m/z 338 (M−H)−.