Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][NH2:19].CO>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-Dichloro-3-nitropyridine (2.0 g, 10 mmol) and sodium carbonate (2.8 g, 25.9 mmol) were added to a round bottom flask under nitrogen, and suspended in ethanol (100 mL). Methylamine in methanol (7.8 mL, 16 mmol, 2M) was then added and stirred at room temperature for 3 hours. The yellow solution was concentrated, and then re-dissolved in ethyl acetate followed by washing with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The yellow solid was then re-dissolved in ethanol and recrystallized to give 6-chloro-N-methyl-3-nitropyridin-2-amine (28-1) as a yellow solid. HRMS (M+H)+: observed=188.0216, calculated=188.0221.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
2-tert-Butyl-phenol (5 g, 0.033 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (16.05 g, 0.033 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a clear oil (6.8 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-leucine and 3.7 g of triethylamine were dissolved in 150 ml of chloroform, to which was added dropwise 3.9 g of ethyl chlorocarbonate under sodium chloride-ice cooling conditions. The solution was stirred for 2 hours, to which was then added 3.7 g of 2-amino-1,3,4-thiadiazole, followed by stirring for further 24 hours. The reaction solution was washed with water, and after drying, the solvent was removed by distillation to obtain 9.0 g (yield: 71%) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 118°-120° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][O:10][CH3:9]
Reactant: Oc1ccccc1I
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccccc1I
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 2-iodo phenol (1 eq.) and 2-bromoethyl methyl ether (1.1 eq) in DMF (0.21M) at 0° C. was added Cs2CO3 (1.5 eq). The mixture was stirred at 50° C. for 6 h, cooled to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 10%, afforded the desired compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1)([O-])=O.C(O)CC.Cl.[Sn]>O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Agent: Cl
Agent: [Sn]
Solvent: CCCO
Solvent: O
Product: Nc1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 93 %

Procedure:
A 3 L round-bottom-flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 3-nitro-dibenzothiophene-5,5-dioxide (26 g, 0.1 mol), n-propanol (280 mL), water (840 mL), concentrated hydrochloric acid (325 mL), and tin powder, 20 mesh (65 g, 0.55 mol) then purged with nitrogen. The slurry was heated to a reflux overnight, which led to the consumption of the yellow crystals. The hot solution was filtered to remove the remaining tin powder then cooled to room temperature and chilled in an ice bath to crystallize the product. The yellow crystals were collected by vacuum filtration without washing with water then air dried. The crystals were added to a 10% solution of sodium hydroxide (200 mL) to liberate the free amine from the hydrochloride salt. The yellow powder was collected by vacuum filtration, washed well with water, then dried under vacuum to give 21.5 g of 3-amino-dibenzothiophene-5,5-dioxide (93% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O.[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
The first step was to protect 6-aminocaproic acid using benzyl chloroformate to give N-benzyloxycarbonyl-6-aminocaproic acid. This first step was carried out as follows. A solution of 6-aminocaproic acid (32.8 g, 0.25M) in 75 mL of H2O and 42 mL of 6N NaOH was cooled in a salt-ice bath to below 10° C. With stirring, benzyl chloroformate, 46.9 g, 0.275M) and 2N NaOH (138 mL) were alternatively added in small portions over 90 min. After the addition was complete, the solution was brought to room temperature, and stirring was continued for an additional 1 hr. The product was precipitated by lowering the pH to 2 with concentrated HCL, and H2O was added as required to keep the suspension stirring. The white precipitate was filtered, then resuspended and triturated with 1 liter of water. The solid was filtered, washed with water, compressed and then washed with hexane. The solid was then thoroughly dried in a vacuum desiccator to yield 55 grams (83% yield) of N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1cn[nH]c1
Product: COc1ccc(-n2cccn2)cc1
Yield: 40 %

Procedure:
The title compound was prepared from 4-methoxyphenylboronic acid (0.45 g, 2.94 mmol), pyrazole (0.4 g, 1.47 mmol) using the general procedure A with a yield of 40% (0.4 g); MS (APCI) m/z: 203 (M+1, 100).
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[N:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[C:5]([O:7]CC)=[O:6].[Li+].[OH-]>O1CCOCC1.O>[F:21][CH:2]([F:1])[C:3]1[N:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate (200 mg, 0.66 mmol) in 1,4-Dioxane was added a solution of LiOH (70 mg, 1.66 mmol) in H2O (1 mL) and the reaction mixture was stirred at rt for 1 h. Then the reaction mixture was quenched with 1N HCl and the precipitated solid was filtered and dried to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 13.98 (br s, 1H), 8.72 (s, 1H), 8.45 (t, 1H), 8.17 (s, 1H), 7.67-7.32 (t, J=54 Hz, 1H), 4.39-4.37 (d, J=5.7 Hz, 2H), 2.43 (m, 1H), 1.04-1.02 (d, J=6.6 Hz, 6H).
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([Br:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1.[Li+].[OH-].Cl>O1CCCC1.O>[CH2:26]([O:25][C:11]1[CH:12]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([Br:16])=[CH:15][C:10]=1[C:9]([OH:33])=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,4-Bis-benzyloxy-5-bromo-benzoic acid benzyl ester (47.8 g, 95 mmol) was then dissolved in mixture of tetrahydrofuran (150 ml) and water (150 ml). LiOH (7.2 g, 0.3 mol) was added, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete, the reaction was cooled to r.t., acidified with 1M HCl to pH=1. After extraction with Et2O (500 ml×3), the combined organics were washed with water (250 ml) and saturated brine (250 ml) and dried over Na2SO4. After filtration and concentration, 2,4-bis-benzyloxy-5-bromobenzoic acid was obtained as a white solid (37.7 g, 96%). M.p.: 116-119° C.; 400 MHz 1H NMR (CDCl3) δ: 8.36 (s, 1H), 7.45-7.33 (m, 10H), 6.59 (s, 1H); 5.19 (s, 2H), 5.17 (s, 2H); LCMS: 413, 415 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:16]=[CH2:15])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Reaction time: 16 h
Yield: 93 %

Procedure:
4-Allyloxy-3-allylbenzoic acid methyl ester was prepared by reacting 3-allyl-4-hydroxybenzoic acid methyl ester (Example 49, Step 2) with allyl bromide following Method C in 93% yield. The reaction was conducted at room temperature for 16 h and the resulting product was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.CN(C=O)C.S(Cl)([Cl:22])=O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:22])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCBr
Temperature: 39 °C
Yield: 36.9 %

Procedure:
20.0 g of 11-bromoundecanoic acid (0.0754 mol) are placed in 20 ml dichloromethane in the presence of 0.28 g DMF (0.05 eq). The reaction mixture is heated to reflux and 10.68 g of thionyl chloride (0.0905 mol) are added drop wise over a period of 1 h 40 min at 39° C. After 3 h at 39° C. the reaction mixture is cooled down to r.t. and evaporated to dryness, yielding to 7.9 g of the expected compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCBr
Product: O=C(Cl)CCCCCCCCCCBr
Yield: 90 %

Procedure:
55 g (0.20 moles) of recrystallised 11-bromo undecanoic acid were refluxed with 48 g (0.4 moles) of thionyl chloride for 3 hours. Excess thionyl chloride was then removed by vacuum distillation at 10-14 mm Hg pressure. The crude acid chloride remaining was distilled under higher vacuum (0.1 mm Hg) to give 50 g (0.18 moles) of pure 11-bromo undecanoyl chloride.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1ccc(-c2ccccn2)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide. 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg. was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p. 159°-162° . The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH2:9][CH:10]=[C:11]([CH3:14])[CH:12]=O.C(N(CC)CC)C.C([O-])(=O)C.[NH4+]>CCOCC>[CH3:14][C:11]1[CH:10]=[N:9][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: CC(C=O)=CN
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)C(=O)CCC2
Reaction time: 12 h

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the 3-methyl-7,8-dihydro-5(6H)-quinolone as a colorless crystalline solid b.p. 80° (7.5 g. 48%). A mixture of 3-methyl-7,8-dihydro-5(6H)-quinolone (20 g.), hydrazine hydrate (14 ml), diethylene glycol (150 ml.) and sodium hydroxide (14 g) was heated at reflux with stirring for 1 hour. The condenser was replaced by a Dean and Stark Water Separator and the heating continued for a further 3 hours. The cooled reaction mixture was diluted with water (200 ml.) and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled at 15 mm Hg to give the title compound as a colourless oil b.p.116° (17 g, 93%) G.L.C. (3% SE30, T=150°) RF =3.5 min.
Reaction SMILES: [Na].[C:2]([O:13]CC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:11][CH2:10][O:9][C:7]([CH:6]1[C:2](=[O:13])[CH2:3][CH2:4][CH2:5]1)=[O:8]
Reactant: CCOC(=O)CCCCC(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1=O
Yield: 85.3 %

Procedure:
15.0 g (0.652 mmol) of sodium was placed in 150 mL toluene, heated to reflux, shaken, and made into sodium sand. 81.6 g (0.400 mol) of diethyl adipate was added in drops to the mixture in an outside bath at 105-110° C., and the resultant solution changed into a yellow sticky product. After refluxing for 8 h, the solution was cooled by ice bath, and 400 mL of 10% acetic acid solution was added in drops. The mixture was suction filtered and washed with a small amount of toluene. The filtrate was separated into layers. The upper layer was washed with 7% sodium carbonate (260 mL×2) followed by saturated brine (200 mL×2), and dried overnight with anhydrous magnesium sulfate. The solution was filtered, concentrated and distilled under reduced pressure to collect the fractions of bp: 142-150° C./2660 Pa, yielding 53.3 g of colorless liquid with a yield of 85.6%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>ClCCl.C(N(CC)CC)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
To N—BOC-piperazine (500 mg) in dichloromethane (5 mL) and triethylamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 hour the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([NH:20][C@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:20]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:21]([C:23]([NH:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:25])[CH3:22]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
One equivalent of EDC [1-(3-dimethylaminopropyl)3-ethylcarbodiimide.hydrochloride] (1 g, 5.3 mmol, Aldrich) is added into a cold stirred solution of 1 g (5.3 mmol) Boc Alanine (Sigma), 1.07 g of (5.3 mmol) of Gly-OBzl (Sigma), 0.71 g of HOBT (Aldrich), and 0.5 ml of NMM in 50 ml DCM. The reaction mixture is stirred at 0° C. for 3 h and at ambient temperature for 22 h. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The organic layer is washed with 10% aqueous citric acid, water, saturated NaHCO3, water, and saturated brine. The organic layer is dried over anhydrous Na2SO4 and the solid is decanted from the mixture. The organic solvent is evaporated and the residue is recrystallized using petroleum ether to give a colorless solid of Boc-Ala-Gly-OBzl (11). 1H-NMR (CDCl3): 1.35 (3H,d, J=6 Hz), 1.42 (9H, s), 4.05 (2H, d, J=5 Hz), 4.25 (1H, m), 5.15 (2H, s), 5.28 (1H, d, J=5 Hz), 7.02 (1H, br), 7.33 (5H, s). FABMS: 337 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>CC#N>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Yield: 83.6 %

Procedure:
To a solution of the 2,4-dihydroxybenzaldehyde (100 g, 0.67 mol) in CH3CN (1 L), BnBr (112.4 g, 0.67 mol) and NaHCO3 (90.8 g, 0.67 mol) were added. The reaction mixture was refluxed for 48 h and was monitored by TLC. Upon completion, the white precipitate was filtered and the filtrate was evaporated under vacuum. The residue was dissolved in MeOH (500 mL) and was precipitated at 0° C. The precipitates were further recrystallized from MeOH to obtain 4-Benzyloxy-2-hydroxybenzaldehyde (G3a) (127.5 g, 0.56 mol, 84%) as an off-white solid: mp 80-82C (Lit.10 78-80° C.); 1H NMR (DMSO, 400 MHz) δ 10.99 (1H, s), 9.99 (1H, s), 7.37 (5H, m), 6.61 (1H, m), 6.54 (1H, d), 5.15 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:20]=[C:17]([CH3:18])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
(Step 2) A mixture of 145 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 97.8 g of acetamidine hydrochloride, 191 g of powdered potassium carbonate, and 1.16 L of ethanol was stirred at 60-70° C. for 16 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. To the residue was added water and the resultant was neutralized with acetic acid. The crystals that separated out were collected by filtration, washed with water, and dried to provide 88.7 g of the title compound as white crystals. m.p. 290-292° C. (decomp.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: O=C(O)CC1CCNCC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(CC(=O)O)CC1
Yield: 98.7 %

Procedure:
4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted with acetic anhydride (10.7 grams) (105.0 mmoles) as described in Preparative Example 13A to give the title compound (Yield: 6.4 grams, 99%, MH+ 185).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11].[OH-].[K+].Cl>O.CS(C)=O>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
A mixture of 2,3,5-trichloropyridine (2.5 g, 13.7 mm), hydroquinone (3.02 g, 27.4 mm), KOH (3.07 g, 54.8 mm) and DMSO (10 ml) is heated to 160° for 3 hours. The mixture is poured into water, acidified with dilute HCl and extracted with ether. The ethereal solution is washed, dried and evaporated to dryness. The crude product is chromotographed on silica gel to give crystalline 4-(3,5-dichloropyridyloxy)phenol.