Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[O:5]([CH2:12][C:13]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[CH:19]([C:24]([OH:26])=[O:25])[C:20]([CH3:23])([CH3:22])[S:21][C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].Cl>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[O:5]([CH2:12][C:13]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[CH:19]([C:24]([OH:26])=[O:25])[C:20]([CH3:23])([CH3:22])[S:21](=[O:3])[C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1(C)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Reaction time: 2 h

Procedure:
Acetic acid (10 cc) was added to 6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid (1.75 g.), and sodium percarbonate (1.89 g.) was added thereto at 10°-15° C. To the mixture were added water (2 cc) and sodium tungstate dihydrate (120 mg.), and the mixture was stirred for 2 hours. The mixture was acidified to a pH 3 with water (50 cc) and 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to yield crude crystals (1.31 g.) of 6-(2-phenoxyacetamido)-2,2-dimethylpenam-3-carboxylic acid-1-oxide, m.p. 160°-161° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].NN>C(O)C.[Pd]>[CH2:1]([NH:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CCNc1ncccc1N
Reaction time: 8 h
Yield: 74.8 %

Procedure:
N-ethyl-3-nitropyridin-2-amine (19.50 g, 117 mmol) was dissolved in 200 mL of ethanol at room temperature with suspended palladium on carbon 10% (1 g, 9.40 mmol). A solution of hydrazine (14.95 g, 467 mmol) in 50 mL of ethanol was added dropwise at room temperature, and reaction was stirred overnight. Filtering through Celite® pad and evaporation provided N2-ethylpyridine-2,3-diamine as a dark red solid (12 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16]([O:18]CC)=O)=[O:5].[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16](=[O:18])[N:27]([CH3:28])[CH3:26])=[O:5]
Reactant: CNC
Reactant: CCOC(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: CN(C)C(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
The original compound (II) can be prepared by ammonolysis, aminolysis, or by ester exchange from, for example, 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-ethoxycarbonylmethylene)hydrazine (IIa) [Japanese Patent Kokai 101396/1974]. For example, IIa is reacted with dimethylamine to give 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-dimethylcarbamoylmethylene)hydrazine (IIb): ##STR20## Still, another original compound (II), in particular 1-(2-benzoyl-4-chlorophenyl)-2-(1-amino-1-dimethylcarbamoyllmethylene)hydrazine (IIc) is prepared as follows: ##STR21## Thus, the compound (IIc) is prepared by reacting a diazonium salt of 2-amino-5-chlorobenzophenone with the compound (XIV), brominating the resulting compound (XI) and treating with aqueous ammonia; or reacting a diazonium salt of 2-amino-5-chlorobenzophenone with the compound (XV) and treating the resulting product (XIII) with aqueous ammonia.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:13].C(Cl)Cl.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[OH:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1SCCC2O
Temperature: 0 °C
Yield: 99.8 %

Procedure:
A 100 ml three-necked flask was charged with 5.9 g (0.022 mol) of 6-bromo-5,8-dimethylthiochroman-4-one, and then, 30 ml of methylene chloride and 10 ml of methanol were added and dissolved. The entire reaction system was cooled to 0° C. in an ice salt bath, and 0.42 g.(0.011 mol) of sodium borohydride was added by small portions. Thereafter, the mixture was allowed to react for 2 hours while it was cooled as above. The reaction mixture was poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 6.0 g of 6-bromo-5,8-dimethyl-4-hydroxythiochroman as a solid. Then, 6.0 g of this 6-bromo-5,8-dimethyl-4-hydroxythiochroman was charged into a 100 ml eggplant-shaped flask, and 20 ml of ethanol was added to form a solution. Then, 10 drops of concentrated sulfuric acid was added, and the mixture was refluxed under heat for 1 hour. The reaction mixture was allowed to cool and poured into 100 ml of water, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to give 5.8 g of 6-bromo-5,8-dimethyl-4-ethoxythiochroman as an oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].C(O)(=O)C.O.[NH2:19][NH2:20]>CO>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:19][NH:20][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)Cc1c(C)n[nH]c1C
Yield: 89 %

Procedure:
18.6 grams 3,3-diacetyl-propionic acid-ethyl ester, 9.0 grams glacial acetic acid and 150 milliliters methanol were mixed, and 5.3 grams hydrazine hydrate were added dropwise to this mixture within 30 minutes. The reaction mixture was then heated to the boiling temperature under reflux for 3 hours. The reaction mixture was then evaporated and distilled in vacuo. The fraction obtained at 142°-150° C./0.05 Torr consisted of an oil which later crystallized. 16.2 grams 3,5-dimethyl-1H-pyrazol-4-acetic acid-ethyl ester were obtained, representing a yield of 80%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O.C(OCC)(=O)C.S(=O)(=O)(O)O>O1CCCC1.CCCCCCC.O>[C:17]1([CH:14]2[CH2:15][CH2:16][CH:11]([CH2:9][OH:8])[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CCC(c2ccccc2)CC1
Temperature: 55 °C
Yield: 92.2 %

Procedure:
Dry tetrahydrofuran (THF) (420 ml) was added to lithiumaluminum hydride (11.1 g, 0.293 mol) and the mixture was vigorously agitated, followed by dropwise adding to the mixture, a solution obtained by dissolving trans-4-phenylcyclohexanecarboxylic acid methyl ester (II) (64.0 g, 0.293 mol) in THF (70 ml), while keeping the reaction temperature at 20° C. or lower. After completion of the dropwise addition, the reaction mixture was warmed up to 55° C., reacted for 2 hours and cooled, followed by adding ethyl acetate (12 ml) and water (100 ml), and then adding 18% sulfuric acid (350 ml) to form two separated layers of a tetrahydrofuran layer and an aqueous layer. n-Heptane (200 ml) was added to the former layer and the mixture was transferred into a separating funnel, followed by washing with water (500 ml), washing with 2% aqueous solution of sodium carbonate (500 ml), further washing with water till the aqueous layer became neutral, distilling off n-heptane and THF, recrystallizing solid as still residue from n-heptane (20 ml), filtering off the resulting crystals and drying to obtain 4-phenylcyclohexylmethanol (III) (51.4 g). M.P. 47.3°~48.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
42 g of sodium hydride (60%) is introduced at room temperature in portions into 900 ml of absolute DMF. 88.6 ml of 1,4-butanediol in 450 ml of absolute DMF is added in drops to the suspension that is cooled to −20° C. in such a way that the internal temperature does not exceed −15° C. After the addition has been completed, a solution of 121 ml of benzyl bromide in 870 ml of absolute DMF is quickly added in drops, and then the reaction mixture is stirred for 30 minutes at room temperature. The reaction is completed by careful addition of 315 ml of water. For working-up, the reaction mixture is stirred into 1.5 l of water and extracted 3 times with 1 l of ether in each case. The ethereal phases are combined, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography on silica gel with a hexane-ethyl acetate gradient yields 105 g of 4-benzyloxy-butan-1-ol as an oil.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[N:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:7][CH2:6][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1)[C:2]#[CH:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Propargyl bromide (356.9 mg, 3 mmol) was slowly added to a mixture of tert-butyl 1-piperazinecarboxylate obtained in step 2(i) above (558.8 mg, 3 mmole) and diisopropylethylamine (407.1 mg, 3.15 mmol) in CHCl3 (25 ml) at 0° C. The mixture was stirred for 24 h at room temperature. 50 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to give tert-butyl 4-propargylpiperazine-1-carboxylate (D6) (crude 337 mg, 86%). H1 NMR (250 MHz, CDCl3): 1.42 (s, 9H), 2.22(s, 1H), 2.46 (s, 4H), 3,26 (s, 2H), 3.41 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][C:12](=O)[CH3:13]>C(COC)OC.C(O)C>[CH3:13][C:12]1[N:1]=[C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]2[CH:11]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: Cc1cn2cccc(C=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-aminonicotinaldehyde (92.8 g, 0.76 mol) and bromoacetone (114.5 g, 0.84 mol) in dimethoxyethane (980 ml) is stirred for 2 hours at room temperature and then heated at 65° with stirring for 14 hours.The solid which separates is isolated by filtration, dissolved in 800 ml absolute ethanol and heated under a reflux for 6 hours. The ethanol solvent is removed under reduced pressure and the residue treated with 138ml 6 N hydrochloric acid in 750 ml water for 0.5 hour. The acidic aqueous layer is washed with ether (2×300 ml) and basified with cooling (78 ml) 50% sodium hydroxide and 25 g sodium bicarbonate). The aqueous layer is extracted with dichloromethane. The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the solvent is removed under reduced pressure to afford 2-methyl-8-formyl-imidazo[1,2-a]pyridine, mp 136°-139.5° C.
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][NH:12][C:11]2=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O.CCN(C(C)C)C(C)C.C(#N)C>C(OCC)(=O)C.O>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[Cl:21])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2nc[nH]c(=O)c12
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Temperature: 87.5 °C
Yield: 77.8 %

Procedure:
To a mixture of 5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (300 mg, 1.20 mmol), phosphorus oxychloride (368 mg mL, 2.4 mmol) and DIEA (0.5 mL, 2.80 mmol) was added acetonitrile (10 mL). The reaction was heated at 85-90° C. for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated and dried with sodium sulfate, concentrated in vacuo and purified by silica gel flash chromatography (eluted with 1-25% EtOAc/CH2Cl2) to give the title compound (250 mg, 78%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[C:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([C:17]([F:19])([F:20])[F:18])=[N:8]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH ˜1 with 1N aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C11H7F3N2O2 (m/e) 256, obsd 255 (M−H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[C:10]1(=[O:11])[N:6]([CH2:5][CH2:4][O:3][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 2 g) was added portionwise to a solution of N-(2-hydroxyethyl)phthalimide (9.6 g) in dry dimethylformamide (70 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour prior to the addition of 4-fluorobenzaldehyde (6.2 g, 5.3 ml), and the mixture then heated at 80° C. for 15 hours. The solvent was evaporated and the residue dissolved in water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with water (2×100 ml), brine (100 ml), dried (MgSO4) and evaporated to yield an oil. The oil was triturated with hexane, and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane to afford the title compound mp 138° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>C1(C)C=CC=CC=1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 74, Step 1) (2.0 g, 5.2 mmol), tetrakis(triphenylphosphine)palladium (0) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) was heated to 110° C. for 3 days. The reaction mixture was allowed to cool to room temperature and filtered through a plug of silica gel eluting with 25% ethyl acetate in hexanes. The filtrate was concentrated in vacuo and then purified by flash chromatography (silica gel, ethyl acetate-hexanes, 1:9). The fractions containing desired, product were combined and concentrated in vacuo. To remove the remaining tin impurities the mixture was taken up in THF (10 mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford the ester as an oil (1.30 g, 65%). 1H NMR (CDCl3/300 MHz) 7.67 (s, 1H), 7.47–7.36 (m, 5H), 7.31 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J=7.1 Hz). 19FNMR (CDCl3/282 MHz) d −78.27 (d, J=7.2 Hz). FABLRMS m/z 383 (M+H). ESHRMS m/z 400.0937 (M+NH4, Calc'd 400.0927)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8]([CH2:11][C@H:12]([NH:16][C@@H:17]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([F:21])([F:20])[F:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])[CH:2]=1.[CH:29]1([NH:32][C:33](=[O:41])[CH:34]([OH:40])[C@@H:35]([NH2:39])[CH2:36][CH2:37][CH3:38])[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH4+].[Cl-]>C(OCC)(=O)C>[CH:29]1([NH:32][C:33](=[O:41])[CH:34]([OH:40])[C@@H:35]([NH:39][C:13](=[O:15])[C@@H:12]([NH:16][C@@H:17]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:18]([F:21])([F:20])[F:19])[CH2:11][S:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:10])[CH2:36][CH2:37][CH3:38])[CH2:31][CH2:30]1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCC[C@H](NC(=O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1

Procedure:
A mixture of 3-(pyridin-3-ylmethanesulfonyl)-2-(R)[2,2,2-trifluoro-1(s)-(4-fluorophenyl)ethylamino]propionic acid (420 mg, 1 mmol), 3(S)-amino-2-hydroxyhexanoic acid cyclopropylamide (186 mg, 1 mmol) prepared as described in PCT application publication No. WO-02/18369 as compound xiii, HBTU (455 mg, 1.2 mmol), and NMM (0.44 mL, 4 mmol) in acctonitrile was stirred at room temperature overnight. Sat. NH4Cl (10 mL) and ethyl acetate (10 mL) were added and after 20 min the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with MgSO4, filtered and the filtrated was concentrated under the reduced pressure to give 2-hydroxy-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionylamino}-hexanoic acid cyclopropylamide which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:9](O)([CH3:12])([CH3:11])[CH3:10].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5-hexenoic acid q-1 (6.00 g, 52.6 mmol), t-butyl alcohol (72.2 mL, 735.84 mmol) and DMAP (1.28 g, 10.51 mmol) in DCM (150 mL) at −10° C. was added DCC (16.26 g, 78.84 mmol). After stirring at room temperature overnight, solid was filtered off. The filtrate was evaporated under reduced pressure to give a crude oil, which was purified by chromatography (Biotage; 65i). Elution with a gradient of EtOAc/Hexane from 5/95 to 10/90 yielded 4.16 g (46.53%) of t-butyl ester q-2, which displayed a 1H NMR spectrum that matched literature (Johnson, P. Y.; Berchtold, G. A. J. Org. Chem. 1970, 35, 584-592) and was used without further purification).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6](O)[CH2:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCCCC

Procedure:
The following tests were carried out on the residue stream drawn from the base of a continuously-operating still-reactor column within which n-butanol and acrylic acid were being reacted in the presence of para-toluenesulfonic acid catalyst to form butyl acrylate. Acrylic acid and n-butanol were continuously introduced into the base section of the column, where they were mixed into a continuously-circulating stream drawn from the base of the column which then passed through a reboiler and was reintroduced into the column below the first tray. The esterification reaction took place in the base of the column, from which there was a small continuous drawoff of refractory tars.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.CO>C(O)(=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(N2Cc3c(NCc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (1.04 g, 4 mmol) was dissolved in acetic acid (7 ml) with heat. The mixture was cooled slightly and methylene chloride (50 ml) was added slowly followed by 3-chlorobenzaldehyde (0.91 ml, 8 mmol) and sodium triacetoxyborohydride (2.54 g, 12 mmol). The reaction mixture was stirred at room temperature under a nitrogen atomosphere for 2 h, diluted with methylene chloride (100 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a white solid. The solid was recystallized from methylene chloride/methanol to give 0.48 g (31%) of product as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.45 (s, 1H), 7.37-7.19 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.45 (t, J=5.9 Hz, 1H), 5.14 (dd, J=5.1 and 13.1 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.34 (d, J=17.3 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H) 3.01-2.87 (m, 1H), 2.66-2.60 (m, 1H), 2.42-2.25 (m, 1H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.90, 171.24, 168.74, 143.03, 142.59, 133.08, 132.16, 130.19, 129.12, 126.80, 126.70, 125.73, 112.27, 110.55, 51.54, 45.73, 45.47, 31.25, 22.79; Anal. Calcd. For C20H18ClN3O3: C, 62.58, H, 4.73; N, 10.95. Found: C, 62.32; H, 4.61; N, 10.80.