Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:16][CH:17]([CH2:21][CH2:22]Br)[C:18](Cl)=[O:19].[OH-].[Na+]>C(#N)C>[Br:16][CH:17]1[CH2:21][CH2:22][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:18]1=[O:19]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C(Br)CCBr
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=C1C(Br)CCN1c1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of phenylamine L (465 mg, 5.0 mmol) and potassium phosphate (530 mg, 2.5 mmol) in acetonitrile (20 mL) was added 2,4-dibromo-butyryl chloride III (1.32 g, 5.0 mmol) at 0° C. The mixture was brought to rt and stirred for 1 hr. Then NaOH (1 mL, 50% aqueous solution) was added, and the mixture was stirred overnight. After the mixture was filtered, the solid was washed with acetonitrile (10 mL), and the combined filtrate was concentrated. The residue was purified by column chromatography (eluate: EtOAc/petroleum ether from 1/5 to 1/3) to afford 3-bromo-1-phenyl-pyrrolidin-2-one LI as white solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]([NH2:20])[NH:17][N:16]=1)(=[O:14])=[O:13].[C:21](OC)(=[O:27])[CH2:22][C:23](OC)=[O:24]>C(O)C>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]2[N:20]=[C:21]([OH:27])[CH:22]=[C:23]([OH:24])[N:17]2[N:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(O)cc(O)n3n2)c1Cl
Reaction time: 72 h

Procedure:
Sodium (3.11 g, 135 mmol) was added to 250 ml of absolute ethanol in a 500 ml round bottom flask and allowed to react under nitrogen. N-(2,6-dichloro-3-methylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide (14.5 g, 45 mmol) and then dimethyl malonate (11.9 g, 90 mmol) were added and the mixture heated at reflux with stirring for about three days. The mixture was then cooled with an ice bath and filtered to collect the solids. These were washed with hexane and dissolved in about 75 ml of cold water and the resulting solution was acidified to about pH 2 with conc. hydrochloric acid. The precipitate that formed was collected by filtration and dried to obtain 13.55 g (77.1 percent of theory) of the title compound as a white powder, which decomposes above 200° C. This was shown to be the title compound by NMR.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)c1cccc(OCCF)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OCc1cccc(OCCF)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Thirty grams of ethyl 3-hydroxybenzoate, 14.9 g of 1-fluoro-2-chloroethane and 37.4 g of anhydrous potassium carbonate were added to 130 ml of dimethylformamide. With stirring, the reaction was carried out at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.6 g of crude ethyl 3-(2-fluoroethoxy)benzoate. The resulting crude ethyl 3-(2-fluoroethoxy)benzoate (32.6 g) was added at 40° to 45° C. to a solution of 6.0 g of lithium aluminum hydride in 200 ml of dry tetrahydrofuran, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature. Ethanol and water in this order were added to the mixture to decompose the unreacted lithium aluminum hydride. Water was then added, and the mixture was extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was removed to give 26.0 g of crude 3-(2-fluoroethoxy)benzyl alcohol This compound was chlorinated to give 30.0 g of 3-(2-fluoroethoxy)benzyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:15][C:14]1[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:3]=2)=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Product: O=S(=O)(Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl)c1ccc(Cl)cc1
Yield: 30.6 %

Procedure:
In a similar way to Example 37, reaction of 2.5 g of 2-(3-amino-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine and 1.9 g of 4-chlorobenzenesulfonyl chloride, and purification of the crude product by recrystallization from ether, resulted in 1.2 g of colorless crystals. Yield: 31%; melting point: 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Br.C(OC(=O)C)C.CCCCCC>ClCCl>[CH3:30][O:31][C:32](=[O:35])[CH2:33][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:3]2[CH:4]=[C:5]([C:6](=[O:7])[NH:8][CH:9]3[C:14]([CH3:15])([CH3:16])[CH:13]4[CH2:17][C:10]3([CH3:18])[CH2:11][CH2:12]4)[CH:19]=[CH:20][C:2]=2[CH3:1])(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCNCC1
Reactant: COC(=O)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CN1CCN(S(=O)(=O)c2cc(C(=O)NC3C4(C)CCC(C4)C3(C)C)ccc2C)CC1

Procedure:
Compound 30 was prepared from 117 mg 29 by stirring in 5 mL dry dichloromethane adding 100 μl N,N-diisopropylethylamine and 25 μl bromoacetic acid methylester overnight at room temperature. After aqueous work-up the product 30 was isolated by SiO2 chromatography (5-20% ethylacetate/hexane) and 23 mg of an off white solid was obtained (21% yield). MS (M+1)=492.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([OH:9])[C:7]=1[OH:8].[N+]([O-])(O)=O>>[C:4]1([Cl:11])[C:3]([Cl:12])=[C:2]([Cl:1])[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[Cl:10]
Reactant: Oc1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: O=[N+]([O-])O
Product: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl

Procedure:
The continuous oxidation involves a system of two container vessels for the reactants, a flow reactor, a quench reactor, and a scrubber. The FIGURE shows a laboratory arrangement as used for the Example below. Flask 1 is the storage for the tetrachlorocatechol slurry; flask 2 is the storage for concentrated nitric acid. Both flasks are cooled to between 0° C. and 5° C., e.g., by an icebath. Each flask is connected individually to the flow reactor 3 with pumps moving the reactants along at the desired rates. In reactor 3 (at between -2° and 6° C., with +2° to 5° C. preferred) the actual oxidation takes place giving o-chloranil.
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[N:13]([C:21](C)(CC)[C:22]#N)=NC(C)(CC)C#N>C[Si](N[Si](C)(C)C)(C)C>[CH:21]([N:13]1[CH2:8][CH2:10][CH2:6][C:5]1=[O:4])=[CH2:22].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: CCOC(C)=O
Reactant: CCC(C)(C#N)N=NC(C)(C#N)CC
Agent: C=C(C)C(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C=CN1CCCC1=O
Reaction time: 0.05 h

Procedure:
A 25 ml reaction vessel was charged with 12 g ethyl acetate, 3.54 g (0.008 mol) TRIS, 0.26 g (0.002 mol) NVP, 0.21 g (0.002 mol) methacrylic acid (MA) and 0.08 g. 2,2′-azobis(2-methylbutanenitrile). After nitrogen flushing for 3 minutes, the vessel was closed and placed in an oil bath. The polymerization was run for 16 hours at 63-82° C. The polymer was precipitated into water, filtered, dissolved in acetone, precipitated in water and dried at 50° C. resulting in a 58% yield. The polymer was partially soluble in HMDS at 10 wt % polymer in the liquid. When cast on glass the dried film had a moderate number of domains between 0.01 mm and 0.05 mm (test defined, Examples 28-30). A 10 mil thick film of the dried polymer had a moisture vapor transmission rate of 199 g/m2/24 hr. The dried film had an elongation of 87% (test defined, Examples 15-24). When applied to human forearm the dried polymer film adhered for 3 days.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:34])=[O:33]>>[O:33]=[S:24]1(=[O:34])[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)ccc3ccccc32)CC1

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone was prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.08 (d, J=6.73 Hz, 1H), 7.90 (m, 3H), 7.7 (d, J=9.5 Hz, 1H), 7.6 (d, J=9.2 Hz, 1H), 7.56 (d, J=7.62 Hz, 1H), 7.26 (m, 2H), 6.71 (d, J=9.47 Hz, 1H), 3.85 (br m, 3H), 3.45 (br m, 1H), 3.25 (br m, 3H), 3.14 (br m, 6H), 1.95 (br s, 4H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[F:41][C:42]([F:54])([F:53])[C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[CH:50][CH2:51][NH2:52])=[CH:45][CH:44]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O.CN(C=O)C.C(Cl)Cl>[F:41][C:42]([F:53])([F:54])[C:43]1[CH:44]=[CH:45][C:46]([CH:49]=[CH:50][CH2:51][NH:52][C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)=[O:22])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: NCC=Cc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)NCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 393 (926 mg, 2.52 mmol), trifluoroacetic acid (10 ml) and methylene chloride (3 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (3 ml) and neutralized with triethylamine (2 ml, 14.35 mmol). To the solution, a mixture of 3-(4-trifluoromethylphenyl)-2-propenylamine (761 mg, 3.78 mmol), 1,1′-carbonyldiimidazole (613 mg, 3.78 mmol) and DMF (3 ml) stirred at room temperature overnight was added followed by stirring at room temperature overnight. To the reaction mixture, water was added followed by extraction with ethyl acetate. The extract was washed with water three times and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid[3-(4-trifluoromethylphenyl)-2-propenyl]amide (1.2 g, yield 96%) as a light yellow powder.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:12][NH:13][NH2:14]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[C:3]1[CH2:4][C:5](=[O:6])[N:13]([CH3:12])[N:14]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: Cc1ccccc1
Product: CN1N=C(C(F)F)CC1=O
Temperature: 100 °C

Procedure:
Ethyl 4,4-difluoroacetoacetate (30.12 g, 0.172 mol) was stirred in toluene (600 mL) over ice water. Solution of N-methylhydrazine (7.6 mL, 0.14 mol) in toluene (200 mL) was added slowly, dropwise over 20 min. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture evaporated to dryness. The resulting material was triturated with methyl t-butylether/heptane to give 3-(difluoromethyl)-1-methyl-1H-pyrazol-5(4H)-one in three batches (total 10.7 g, 51%) as orange powder. This material was used without further purification for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)[N:12]([C:22]3C=CC=CC=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(OC(C1C(O)=C2C(Br)=C(Br)N(CC3C=CC=CC=3)C2=CN=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:14]=[CH:22][N:12]([CH2:13][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Agent: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1O

Procedure:
Prepared in analogy to that of 2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 1-benzyl-2,3-dibromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 297 (M+H+).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:26])(=O)=O>CN(C=O)C.CCOCC>[CH2:1]([Cl:26])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOCC
Product: ClC/C=C\c1ccccc1
Reaction time: 12 h

Procedure:
A solution of the cinnamyl alcohol (1-1) (17.8 g, 133 mmol; Fukuda, et al., Tetrahedron 55, 1999, pp 649-664) in DMF (75 mL) was treated with collidine (35.1 mL, 32.2 g, 266 mmol), lithium chloride (11.2 g, 266 mmol), and methanesulfonyl chloride (20.7 mL, 30.6 g, 173 mmol) at room temperature. After stirring for 12 h, the reaction was diluted with Et2O (300 mL) and washed with water, satd aq NH4Cl, and brine. The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 5% EtOAc/hexanes) to give allyl chloride (1-2) as a colorless oil. 1NMR (500 MHz, CDCl3) δ 7.40 (m, 2H), 7.32 (m, 3H), 6.68 (d, J=11 hz, 1H), 5.94 (m, 1H), 4.30 (m, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[H][H]>O1CCOCC1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(CO)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(CO)cc(C(=O)O)c1
Yield: 121.4 %

Procedure:
5-Nitro-3-hydroxymethyl benzoic acid (39.6 g, 0.20 mol) was suspended in a mixture of dioxane (25 ml) and water (50 ml). Palladium on carbon (5%) was added and the mixture was hydrogenated in a Parr apparatus until the stoichiometric amount of hydrogen had been consumed. The catalyst was filtered off and the filtrate passed into concentrated hydrochloric acid (12M, 17 ml). The filtrate was evaporated to dryness to give 40.6 g of a crystalline product. Yield is almost quantitative. The product was used without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[C:13]1([NH:19][CH2:20]C(O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([N:19]2[CH2:20][CH2:3][CH:2]3[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)CNc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(c3ccccc3)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate and 7.6 g (50 mmol) of phenylglycine are heated under reflux overnight in 200 ml of toluene. The mixture is decanted from resinous material and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=O)[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:11][N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][CH2:23][OH:24])=[C:2]2[CH3:1])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCO)c(C)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) was immersed in an ice bath to maintain an internal temperature of 10–15° C. To this solution was added BF3-Et2O (30 mL, 230 mmol) over 5 min, resulting in the formation of a precipitate. Sodium borohydride (4.2 g, 110 mmol) was added portionwise over 10 min resulting in vigorous effervescence. After gas evolution subsided the flask was stoppered and allowed to warm to room temperature. After 1 hour the pressure was vented through a needle. The heterogeneous mixture was stirred for 6 hours. The mixture was cooled in an ice bath and was quenched by adding saturated NaHCO3. To break the resultant emulsion the mixture was made acidic with 1N HCl and extracted with a 3:1 mixture of Et2O:Hexane (270 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was taken up in a 3:1 mixture of hot Hex:EtOAc (80 mL). Upon cooling to room temperature, crystals began to form. Crystallization was completed by cooling to −20° C. The solid was removed by filtration, washed with cold 3:1 Hex:EtOAc (2×25), Hexane (1×25) and dried in vacuo. This gave the title compound (4.5 g, 49%) as a white solid. mp 113–115° C. 1H-NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.29 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH+). Anal calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6.30; N, 4.08; Cl, 10.60.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([OH:9])=[O:8].[CH3:11][C:12]1([CH3:26])[CH:14](/[CH:15]=[C:16](\[F:22])/[C:17](=[O:21])[O:18]CC)[CH:13]1[C:23]([O-:25])=[O:24]>>[CH3:1][C:2]1([CH3:10])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([OH:9])=[O:8].[CH3:11][C:12]1([CH3:26])[CH:14](/[CH:15]=[C:16](\[F:22])/[C:17](=[O:18])[OH:21])[CH:13]1[C:23]([O-:25])=[O:24]
Reactant: CCOC(=O)/C(F)=C/C1C(C(=O)[O-])C1(C)C
Agent: CC1(C)C(C=O)C1C(=O)O
Product: CC1(C)C(/C=C(\F)C(=O)O)C1C(=O)[O-]

Procedure:
Using the procedure of Step A of Example 14, (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-hydroxy-propenyl]-cyclopropane-1-carboxylate which was reacted by the process of Step B of Example 14 to obtain (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+15.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 6.3, 35.0 g, 106 mmol) in methanol (200 mL) at 0-5° C. was added aqueous sodium hydroxide (12.7 g, 318 mmol in 100 mL water) drop-wise. The resulting mixture was stirred for 3 h at 60° C., then cooled to ambient temperature and the volatile organics were removed under reduced pressure. The pH of the remaining aqueous material was adjusted to ˜4 with hydrogen chloride (aqueous, 2 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield the title compound as a white solid (31.0 g, 93%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[NH:12]([C:19]1[N:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:21]2[C:26]([C:27](=[O:29])[CH:28]=1)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=[C:23](Cl)[N:22]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[NH:12]([C:19]1[N:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:21]2[C:26]([C:27](=[O:29])[CH:28]=1)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=[C:23]([O:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[N:22]=2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCN1CCO
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CCOc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0° C.) and stirred solution of 1-(2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130° C. for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH+: 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
Reaction SMILES: [F:1][C:2]([F:49])([P:45]([OH:48])([OH:47])=[O:46])[C:3]1[CH:44]=[CH:43][C:6]([CH2:7][C:8]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:42])([F:41])[P:37]([OH:40])([OH:39])=[O:38])=[CH:32][CH:31]=2)([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:5][CH:4]=1>C(O)=O.CO.Cl[Pd]Cl>[F:42][C:36]([F:41])([P:37]([OH:40])([OH:39])=[O:38])[C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:49])[P:45]([OH:48])([OH:47])=[O:46])=[CH:44][CH:43]=2)([C:19]([OH:21])=[O:20])[C:9]([OH:11])=[O:10])=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: O=CO
Product: O=C(O)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)O
Reaction time: 24 h
Yield: 66.6 %

Procedure:
A mixture of the product of Example 2 (0.2 g), PdCl2 and a few drops of HCO2H in 20 mL of MeOH was shaken under 50 psi of H2 for 24 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was lyopholized to give 0.1 g of the title compound.