Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]1([CH2:57][NH:58][CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH2:56][CH2:55]1>CN(C=O)C.O>[CH:54]1([CH2:57][N:58]([CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:56][CH2:55]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a solution of [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (0.071 g, 0.26 mmol, 1 eq.) and DIEA (0.089 mL, 0.51 mmol, 2 eq.) in 2 mL of DMF was added HATU (0.107 g, 0.281 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.26 mmol, 1 eq.) in 1 mL of DMF was added and the mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (3×50 mL). The combined organics were concentrated and purified by preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.03 g, 24%). 1H NMR (400 MHz, MeOD) δ ppm 7.94-8.07 (m, 2H), 6.98-7.10 (m, 2H), 4.64-4.70 (m, 1H), 4.54-4.60 (m, 1H), 4.44-4.52 (m, 2H), 4.28-4.37 (m, 1H), 3.94-3.99 (m, 1H), 3.91-3.95 (m, 2H), 3.88 (s, 3H), 3.67-3.80 (m, 2H), 3.40-3.61 (m, 1H), 3.33-3.40 (m, 2H), 3.09-3.27 (m, 2H), 2.50-2.72 (m, 2H), 1.92-2.26 (m, 4H), 0.83-1.15 (m, 1H), 0.12-0.67 (m, 4H). HRMS calculated for C27H35N4O5 495.2607. found (ESI, [M+H]+) 495.2606. MS (ESI) m/z 495.3 (M+H)+. Retention time: 2.89 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I.[Cl-].[NH4+]>CN(C)C=O.CO>[C:1]([O:5][C:6]([N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1)[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl trans-4-(t-butoxycarbonylamino)-cyclohexanecarboxylate (30.00 g) is dissolved in N,N-dimethylformamide (150 ml) and thereto is added 60% sodium hydride in oil (5.60 g) under ice-cooling. After stirring for 0.5 hours under cooling, to the reaction solution are added methyl iodide (14.5 ml) and methanol (0.15 ml) successively, and the reaction solution is warmed to room temperature and stirred for 4 hours. Under ice-cooling, to the reaction solution are poured saturated ammonium chloride and ice-water, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1, followed by 7/1) to give methyl trans-4-(N-t-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate (26.33 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[S:14][C:2]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: COc1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(OC)cc2s1

Procedure:
Using 2.5 g (16.2 mmol) of 2-fluoro-4-methoxybenzaldehyde, 0.97 g (24.3 mmol) of sodium hydride (60% pure) and 1.89 g (17.8 mmol) of methyl mercaptoacetate, 3.05 g (84.7% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].NC1C=CC=C(Cl)C=1O>>[NH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: Nc1cccc(Cl)c1O
Product: Nc1cc(Cl)cc(Cl)c1O

Procedure:
2-Amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044 g, 10%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5]([CH3:33])[CH:4]=1
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1C
Yield: 91 %

Procedure:
A solution of Intermediate 4 (23 mg) in DMF (1.0 ml) was added with methyl boronic acid (18 mg, Ald), sodium carbonate (30 mg), and PdCl2dppf.CH2Cl2 (8.0 mg, Ald), and stirred at 120° C. for 8 hours. The reaction mixture was added with water (30 ml), and ethyl acetate (30 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:7][C:6]2[C:8]([C:13]=1[OH:12])=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 4-methoxyaniline (40 g, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
D-tagatose is typically produced in a two-step process wherein lactose is enzymatically hydrolyzed to d-Galactose and d-glucose using immobilized lactase. The d-galactose is typically separated using a cation exchange resin. The separated d-galactose is then isomerized to produce d-tagatose under alkaline conditions (typically at a pH of 12) using calcium hydroxide to form a precipitate. The precipitate is subsequently treated with sulfuric acid to free the d-tagatose, and the filtrate is demineralized in a cation and anion exchanger. Typically, the resulting solution is concentrated and purified by chromatic fractionation using a cation exchanger. The d-tagatose is recovered by crystallization.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1.[CH3:23]I>C1COCC1>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CI
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of LiN(TMS)2 (Aldrich, 1.0 M solution in THF, 30 mL, 30 mmol) in THF (30 mL) was added ethyl 4-pyridylacetate (Aldrich, 4.7 mL, 30 mmol)) at 0° C. Methyl iodide (Aldrich, 2.4 mL, 38 mmol) was added 30 min later. After 1 h, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography. Mass Spec. m/z+ion 180 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.COC(C)(C)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: CCOc1cc(Cl)ncc1Br
Reactant: COc1ccc(CO)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (75 g, 317.1 mmol) in toluene (500 mL) was added (4-methoxyphenyl)methanol (52.6 g, 380.6 mmol), KOH (35.6 g, 634.3 mmol) and 18-crown-6 (8.4 g, 31.2 mmol) at rt. The reaction mixture was stirred at 120° C. for 2 h. The mixture was portioned between 2-methoxy-2-methylpropane (500 mL) and brine (800 mL). The organic layer was concentrated. The residue was purified by column (PE/EA=10:1, Rf=0.5) to give 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (72.2 g, 221 mmol, 70% yield): 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.90-6.84 (m, 2H), 6.38 (s, 1H), 5.20 (s, 2H), 4.16-4.05 (m, 2H), 3.77 (s, 3H), 1.43 (q, J=6.8 Hz, 3H); ES-LCMS m/z 338 (M+2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromophenol (10 g, 58 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (9.6 g, 69 mmol) and potassium carbonate (13.6 g, 98 mmol). The mixture was stirred at room temperature for 12 h. LCMS showed the reaction was almost complete. The mixture was partitioned between water and ethyl acetate (20 mL×3), The combined organics were dried and concentrated to give the title compound that was used in the next step without further purification (14.7 g, quant). 1H NMR (400 MHz, CD3OD) δ 7.36 (d, 2 H), 6.84 (d, 2 H), 4.05 (t, 2 H), 3.72 (t, 2 H), 1.96 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1>C(OCC)(=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:10]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Product: COc1cccc(C=NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
To a solution of t-butyl carbazate (5.59 g, 42.3 mmol) in ethyl acetate (15 mL) was added with stirring m-anisaldehyde (5.17 mL, 5.76 g, 42.3 mmol). Hexanes (70 mL) was added slowly and crystallization occurred. The resulting slurry was stirred at rt for 45 min and then cooled to 0° C. The slurry was stirred at 0° C. for 60 min, then filtered and rinsed with cold hexanes (20 mL), and dried in vacuo at 40° C. to afford the title compound as a solid (9.68 g, 91.4%): mp 135.6-137.4° C.; 1H NMR (DMSO-d6) δ 10.93 (s, 1H), 7.29 (t, 1H, J=8 Hz), 7.14 (d, 2H, J=7 Hz), 6.92 (q, 1H, J=7 Hz), 3.75 (s, 3H), 1.45 (s, 9H); 13C NMR (DMSO-d6) δ 160.2, 153.1, 143.7, 136.8, 130.5, 120.0, 116.2, 111.3, 80.1, 55.7, 28.7; IR (KBr mull): 3360, 3010, 2982, 2838, 1510, 1487 cm−1; A portion was recrystallized from ethyl acetate and submitted for elemental analysis. Anal. Calcd. for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.34.; H, 7.46; N, 11.19.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>CCCCCC.O1CCCC1>[C:1]1([S:7][CH2:8][Li:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]CSc1ccccc1

Procedure:
To a solution of 1.17 ml. of thioanisole in 20 ml. of dry tetrahydrofuran were added 8.4 ml. of a 1.2M solution of n-butyllithium in n-hexane at -20° C. and the mixture was stirred at the same temperature of 1.5 hours to give a 0.28M solution of phenylthiomethyllithium in tetrahydrofuran.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:10])/[C:6](=[CH:8]/[CH3:9])/[CH3:7].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:15]=1[CH:8]([CH3:9])[CH:6]([CH3:7])[C:5]2=[O:10]
Reactant: COc1ccc(OC)cc1
Reactant: C/C=C(\C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c2c1C(=O)C(C)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
AlCl3 (64 g, 0.48 mol) and CH2Cl2 (250 ml) (dried with magnesium sulfate) were placed under an argon atmosphere in a 500 ml three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and 1,4-dimethoxybenzene (48.4 g, 0.35 mol, dissolved in CH2Cl2 (75 ml)) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −2° C. to −5° C. the mixture was allowed to come to ambient temperature and was stirred overnight. The dark red mixture was then refluxed for 2 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the resulting yellow mixture was transferred to a separation funnel, the lower CH2Cl2 layer was isolated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure to give a dark brown liquid. This residue was distilled using a 15 cm Vigreux column to obtain an orange-yellow light viscous liquid (110-115° C., 0.8 mbar). The liquid was purified via column chromatography [(SiO2, 25×9 cm) eluent: cyclohexane:ethylacetate (1:1)] to afford 2,3-dimethyl-4,7-dimethoxy-1-indanone (36) (9.53 g, 12%), Rf 0.35 (cyclohexane:ethylacetate (5:1)) as an orange liquid. The liquid was found to be a mixture of the two isomers of 4,7-dimethoxy-2,3-dimethyl-1-indanone (36a to 36b approximately 4:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 16 h

Procedure:
To 2.75 g of mono-methyl 5-nitroisophthalate (5-(methoxycarbonyl)-3-nitrobenzoic acid), compound 67, dissolved in 30 mL of THF was added 100 mg of 10% palladium on carbon. The reaction was placed in a Parr hydrogenator under a H2 atmosphere of 45 psi and shaken for 16 hr. The solid palladium catalyst was removed by vacuum filtration through celite and 5 mL of 1N HCl in diethyl ether was added to the filtrate. After sitting for 12 hr, the solid was collected by vacuum filtration and was washed with ethyl acetate. This provided 1.82 g of the desired product. The product was identified by 1H NMR and mass spectroscopy and purity was assessed by RP-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[CH:7]=[N:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(C=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ncc(C=O)cc1Br
Temperature: 90 °C
Reaction time: 5 h

Procedure:
(see Eur. J. Med. Chem.-Chim. Ther. 1977, 12, 531) 54.8 g (400 mMol) 6-methoxy-3-pyridinecarbaldehyde (Aldrich) are dissolved in 180 ml of acetic acid. 63.8 g (778 mMol) sodium acetate are added portionwise (slightly exothermic). Then a solution of 30 ml (582 mMol) of bromine in 120 ml of acetic acid is added dropwise during 30 min. The mixture is stirred for 5 h at 90° C., then cooled to RT and concentrated partially in vacuo. The residue is diluted with icewater, neutralized to pH 7.5 with 4 N NaOH and extracted with 4 portions of EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2; CH2Cl2) of the resulting oil and crystallization from CH2Cl2/hexane gives the title compound: mp: 94-95° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:48]4[N:53]=[CH:52][CH:51]=[CH:50][N:49]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Product: COc1c(Cc2ccc(-c3ncccn3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxylnaphthalene obtained in Example 265-(3) and 2-tributylstannylpyrimidine were treated in a manner similar to Example 128-(5) and (6) to give 1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienyl-methyl)-4-methoxylnaphthalene. APCI-Mass m/Z 495 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:12]
Reactant: OCCc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCO
Reaction time: 8 h
Yield: 60.5 %

Procedure:
4.4 g of 2-hydroxyphenethyl alcohol was dissolved in 80 ml of N,N-dimethylformamide, and 15.3 g of ethyl iodide and 4.7 g of potassium carbonate were added. After stirring was continued at 70° C. overnight, the solution was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 3.2 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-methyl-2-butenoxy)phenol (1.64 g, 9.2 mmol), ethyl 2-chloroethylcarbamate (1.81 g, 11.9 mmol), and potassium carbonate (2.54 g, 18.4 mmol) in 20 ml of dimethylformamide (DMF)is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral followed with brine and dried over calcium sulfate. The solvent was removed in vacuo and the residue was placed under high vacuum at 80° for ca. 2 hours to remove the excess ethyl 2-chloroethylcarbamate. Purification by preparative thin layer chromatography (prep. TLC) gave ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}carbamate (compound 1, Table A).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C(OCC)(=O)C>[CH3:12][O:11][P:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:15])[O:13][CH3:14]
Reactant: COP(OC)OC
Reactant: Fc1ccc(CBr)cc1
Solvent: CCOC(C)=O
Product: COP(=O)(Cc1ccc(F)cc1)OC
Temperature: 110 °C
Yield: 67.5 %

Procedure:
4-fluorobenzyl bromide (25 mL, 0.20 mol) was added to a stirred solution of trimethyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was heated at 110° C. for six hours, and then at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotatry evaporation. The resulting crude product was purified by flash silica chromatrography using 0-35% acetonitrile in ethyl acetate as eluant to yield (4-fluoro-benzyl)-phosphonic acid dimethyl ester (29.44 g, 135 mmol, 66% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 2H); 7.17-7.12 (dd, 2H); 3.61-3.58 (d, 6H); 3.31-3.24 (d, 2H); ESMS (m/z): (M+1)+ found, 219.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](N)=[O:11])=[N:2]1.[OH-:13].[Na+].Cl>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:11])=[O:13])=[N:2]1
Reactant: NC(=O)c1nsc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1nsc2ccccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxamide (5.0 g, 0.028 mole) and 1N aqueous sodium hydroxide (55 ml) is heated on a steam bath until solution is achieved (approximately 30 minutes), cooled to room temperature, and acidified with 2N hydrochloric acid. The resulting precipitate is filtered and dried in vacuo to afford the title compound (1.85 g, 96%) as a white solid, which is identified by NMR and IR spectral analysis.