Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[OH:19]>>[CH3:1][O:24][C:23]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([OH:12])[CH:14]=2)[CH2:22][CH2:21]1)=[O:25]
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 775.8 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at 50° C. overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). 1H NMR (DMSO 300 MHz) δ 8.81 (brs, 2H), 6.66 (d, J=2.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.53 (dd, J=2.1, 8.1 Hz, 1H), 3.51 (s, 3H), 1.38-1.35 (m, 2H), 1.07-1.03 (m, 2H).
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6].C(=O)C1OC=CC=1>>[CH2:4]([OH:3])[C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccco1
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 0.08 h

Procedure:
The fermentation medium is napiergrass hydrolysate obtained by a pretreatment process of acid-catalyzed steam explosion. Pretreatment conditions: the concentration of the dilute acid is 2%, the operation temperature is 180° C., the reaction time at this high temperature is 5 min, after which the reactor is immediately depressurized. The reaction mix is then separated by a solid-liquid separation equipment to get the liquid fraction as hydrolysate. In this case, NaOH is added into the napiergrass hydrolysate to adjust to pH 6.0, the fermentation temperature is controlled at 30° C., the agitation of the incubator is maintained at 100 rpm, the ratio of the inocula size of the culture and the volume of the fermentation medium is 1:6 (v/v). The content of xylose in the napiergrass hydrolysate is 15.55 g/L, the content of the inhibitor furfural is 1.19 g/L, and after 40 hr of fermentation, the amount of xylitol produced is 5.11 g/L, and the overall utilization of xylose is up to 95.2%, as shown in Table 5.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124°-128° C. at 2 mm Hg and has a melting temperature range of about 50.2°-50.6° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])=[O:2].C(C=C)=O.COC(=O)C(Br)C(OC)=O.CO>C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:6]([O:8][CH3:9])=[O:7])[C:11]([O:13][CH3:14])=[O:12])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1C=O
Agent: C=CC=O
Agent: COC(=O)C(Br)C(=O)OC
Solvent: CCO
Solvent: CO
Product: COC(=O)C1(C(=O)OC)CC1C=O

Procedure:
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using equivalent amounts of dimethylbromomalonate and methanol instead of diethylbromomalonate and ethanol, respectively, the title compound, nmr (CDCl3) δ 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d, J = 4 cps, 1H), is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].O1CCOCC1.Cl[CH:21]([F:23])[F:22]>O>[Br:1][C:2]1[C:3]([O:11][CH:21]([F:23])[F:22])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 11 h
Yield: 33.4 %

Procedure:
Into a 200-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 4.36 g (0.02 mol) of 2-bromo-6-nitrophenol, 16.7 g (0.1 mol) of 24% sodium hydroxide, 20 ml of 1,4-dioxane and 7 ml of water. The mixture was heated to 80° C. The mixture was stirred at that temperature for 11 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. The reaction mixture was cooled and then subjected to extraction two times each using 20 ml of ether. The ether layer was washed with 20 ml of 12% sodium hydroxide and then with the same volume of water. Then, the ether layer was dried over anhydrous sodium sulfate and then subjected to distillation to obtain 1.79 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 33.4%, purity: 98.8%). To the sodium hydroxide washing was added hydrochloric acid to make the washing acidic, and the resulting precipitate was subjected to extraction with ether, to recover 2.2 g of unreacted 2-bromo-6-nitrophenol (recovery ratio: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Mg]Br)CC.C1COCC1.[N+:19]([C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH:24]=[O:25])([O-:21])=[O:20]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:22]([N+:19]([O-:21])=[O:20])=[C:23]([CH:24]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[OH:25])[CH:26]=1
Reactant: Clc1ccc(I)cn1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CCC[Mg]Br
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Temperature: -45 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.) in 10 mL anhyd. THF was stirred at −40° C. to −50° C. After five minutes, 2.2 mL of 2.1 M PrMgBr/THF (4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the reaction mixture is maintained at −40 to −50° C. for 30 minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was then added and the reaction was maintained at −50° C. After 1 hour, the reaction was allowed to warm to −10° C., and quenched with 50 mL saturated brine after a further fifteen minutes. The crude product was extracted with EtOAc, dried on Na2SO4 and concentrated by rotary evaporation to yield desired product. MS: (M+H)/z=298.9
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li:14])CCC>CCCCC.CCCCCC>[Li:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCC
Product: [Li]c1ccccc1OC
Reaction time: 9 h

Procedure:
2-Bromoanisole (97.0 g, 0.52 mol, 1.0 eq) was dissolved in 150 ml pentane. A 1.6M solution of n-butyllithium (0.52 mol, 1.0 eq) in 325 ml hexane was slowly added drop wise with vigorous stirring and cooling with an ice bath. A white suspension formed which was stirred for a further 3 hours at 0° C., then for 9 hours at room temperature. The white solid was filtered off and washed with pentane (4×30 ml). After drying under vacuum, 2-lithioanisole was isolated as a fine white powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([O-:15])=[O:14])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C([O-])C1=Cc2ccccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
Into a solution of methyl 7-[3,4-dipropoxy]benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) in THF-methanol (5-2.5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.0 ml), and the resulting mixture was stirred at 65° C. for 24 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(3,4-dipropoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (306 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5][N:6]=[N+:7]=[N-:8].[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23]>>[CH:18]1[C:13]([C:12]([C:11]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:5][N:6]3[N:7]=[N:8][C:24]([C:25]([NH2:27])=[O:26])=[C:22]3[NH2:23])=[CH:9][C:10]=2[Cl:21])=[O:20])=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=1
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N

Procedure:
After protection of the alcohol group in 3,5-dichlorobenzyl alcohol, as the TBDMS ether step (step 1), the ether is reacted with 4 chlorobenzoyl chloride to form the substituted benzophene (step 2). The benzophene is treated with thionyl chloride (step 3) and then with sodium azide (step 4) to form 3,5-dichloro-4-(4-chlorobenzoyl)benzyl azide. Reaction of this azide with cyanoacetamide produces L651582 (step 5). Reaction of L651582 with orotic acid forms the L651582 orotate (2:1) (step 6).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C[Si]([C:14]([F:17])([F:16])[F:15])(C)C>O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:14]([F:17])([F:16])[F:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Product: OC(c1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
The title compound was prepared by an adaptation of the method described in Xue, Y. et al. (Bioorg. Med. Chem. 2007, 15, 2156-2166). Tetrabutylammonium fluoride hydrate (0.05 eq., 131 mg, 0.050 mmol) was placed in a 40 mL vial equipped with a magnetic stir bar, and the vial was evacuated and backflushed with Ar. Dry THF (25 mL) was added via syringe, and 2-bromobenzaldehyde (1.16 mL, 10.0 mmol) and trimethylsilyltrifluoromethane (1.3 eq., 1.90 mL, 13.0 mmol) were sequentially added via syringe. The reaction was stirred at RT for 16 h, and additional CF3 TMS (1 mL) was added. After stirring for 2 h, the reaction was poured into 3 M aq HCl (30 mL) and stirred at RT for 2 h. The reaction mixture was extracted three times with DCM (30 mL), and the combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure, yielding 1.83 g (72%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J=7.8 Hz, 1H), 7.60 (dd, J=8.1, 1.3 Hz, 1H), 7.40 (td, J=7.6, 1.1 Hz, 1H), 7.27 (td, J=7.7, 1.8 Hz, 1H), 5.56-5.68 (m, 1H), 2.77 (d, J=4.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-fluoro-pyridine (9.4 g, 83.1 mmol, 1 eq.) in MeCN (470 mL) under argon at 0° C. was added NBS (7.4 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then cooled to 0° C. before introducing additional NBS (7.39 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then diluted in EtOAc. The organic layer was washed with a saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was diluted in DCM, washed with a 1 N NaOH solution. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford Intermediate Gen-1-a (2-amino-5-bromo-3-fluoropyridine).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7]C1C=CC=C2C=1/C(=C/C1NC=CC=1OC)/C(=O)N2.[F:27][C:28]1[C:29](I)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:38]\[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7][C:29]1[C:28]([F:27])=[CH:36][CH:35]=[C:34]2[C:30]=1/[C:31](=[CH:38]/[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44])/[C:32](=[O:37])[NH:33]2
Reactant: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) (Aldrich) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 15 mg, 21%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.OP(O)(O)=O>O.C1(C)C=CC=CC=1>[OH2:2].[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCC1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 107.5 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a N2 purged pressure reactor is charged resorcinol (44.0 g, 0.40 mol), cyclopentanol (44 mL, 0.49 mol) and 85% aqueous H3PO4 (55 mL, 0.80 mol). The slurry is heated to 95-120° C. for 6-18 hours. The pink reaction mixture is cooled to ˜70° C. and diluted with water (50 mL) and toluene (200 mL). The layers are allowed to separate at 60±5° C. The bottom orange aqueous layer is cut away. The remaining pink organic layer is extracted with 2×50 mL water at 60±5° C. and then stirred with carbon (5 g) at 60±5° C. for 1-2 hours. The slurry is filtered hot through Supercel, rinsing the cake with hot toluene (50 mL). The orange filtrate is diluted with 5 mL water and allowed to cool to ˜30° C. at which time the product crystallizes. The slurry is cooled to 0-5° C. and the product collected, washed with cold toluene (40 mL) and pulled dry on the funnel to afford 41 g of 4-cyclopentyl resorcinol monohydrate as a white to pale pink solid (≧98% area by HPLC). The material can be recrystallized if desired from hot toluene (5 mL/g) and carbon (10% by weight) filtering through Supercel and/or silica gel to the Form I polymorph of 4-cyclopentyl resorcinol afford as a white solid (≧99.7% by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
A mixture of (4-amino-phenyl)-acetic acid (25 g) in acetic acid (200 mL) was treated with acetic anhydride (31.3 mL). The mixture was heated on a steam bath for 4 hours, then cooled, then treated with water (20 mL) and then evaporated. The residue was dried under vacuum to give the title compound (30.4 g) as a beige coloured solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:12]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]([F:9])([F:10])[F:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 15 °C

Procedure:
2 gms of 3-methyl benzotrifluoride is dissolved in 5 mls of methylene chloride and added dropwise with stirring at -20° C. to -25° C. to 6 gms of 98% HNO3 dissolved in 10 ml methylene chloride. After addition, the reaction was allowed to finish by warming the mixture to 15° C. After treatment with ice and water followed by sodium bicarbonate wash, near quantitative yield was recovered. Isomer distribution was as follows:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (500 g, 2.94 mol), ethane-1,2-diol (656 mL, 11.76 mol) and p-toluene sulfonic acid (10.06 g, 0.053 mol) was stirred at room temperature under nitrogen atmosphere for 3 days. After pouring in to diethyl ether (1 L), the mixture was washed with water (500 ml), dilute NaHCO3 solution (300 mL) followed by brine (500 mL). The organic layer was then dried (Na2SO4) filtered and concentrated to afford (590 g, 94% yield) the title compound as a colorless oil. Ref. J. Org. Chem. 1997, 62, 5284-5292.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].CCOCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Yield: 74 %

Procedure:
A solution of ethyl-4-oxocyclohexane carboxylate (28.9 g, 169 mmol), ethylene glycol (36.7 g, 33.0 mL, 592 mmol) and p-toluol sulphonic acid (380 mg, 2.0 mmol) in toluol (90 mL) was stirred overnight at room temperature. The reaction solution was poured into ether (150 mL) and washed with water and 5% sodium hydrogencarbonate solution (150 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. Since the raw product (26.8 g) was obtained in pure form, it could be directly converted further.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 27.6 %

Procedure:
To a solution of 3-{4-[1-hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (150 mg, 0.277 mmol) in dichlorormethane (10 mL) is added TFA (160 mg, 1.4 mmol). 5 min later, triethylsilane (161 mg, 1.4 mmol) is added dropwise. 5 h later, the reaction mixture is diluted with ethyl acetate, washed with 1N NaOH, water, brine, dried over sodium sulfate, concentrated and purified by column chromatography to give the title compound (40 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[Na+]>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: NCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCNC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A stirred solution of β-alanine (50.10 g, 0.562 mol) in 2M NaOH (281 mL) at 0° C. was treated with benzyl chloroformate (88 mL, 1.1 equiv), dropwise over 1 h. Stirring was continued for 1.5 h at 0° C., followed by 1.5 h at rt. The resulting mixture was extracted with ether (4×500 mL). The aqueous phase was acidified with 5M HCl (120 mL). The resulting white precipitate was collected by filtration, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and concentrated in vacuo to give a white solid (114.95 g, 92%). 1H-NMR (CDCl3) 6 2.61 (t, 2H), 3.48 (q, 2H), 5.12 (s, 2H), 5.29 (br, 1H), 7.37 (s, 5H). MS (DCl) 224 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>>[Cl:1][C:2]1[C:3]([O:13][C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)C(Cl)(Cl)Cl)c1Cl

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16].C(O)C>CCOCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia-ethanol solution (30 ml), and the reaction mixture is reacted at room temperature in a sealed tube for three days. The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=(10:1)~ethyl acetate) to give 6-chloro-5-(4-methylphenyl)pyrimidin-4-amine (1.89 g).