Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][CH2:29][C:30]3=[O:32])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(S(=O)(=O)N3CCCC3=O)cc2)CC1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
8.2 g of product obtained in Stage A, 8.2 g of sodium acetate and 123 cm3 of acetic anhydride are heated to reflux for 30 minutes. The mixture is cooled to ambient temperature, evaporated to dryness, the residue is taken up with 100 cm3 of water, filtered and dried. 5.6 g of 1-[4-(4-benzyloxycarbonylpiperazin-1-yl)phenylsulphonyl]-2-pyrrolidinone is obtained. m.p.=153°-155° C. After recrystallization from an ethanol-acetone mixture (10-1), 3.7 g of product is obtained, melting at 158°-160° C. 7 g of product prepared as above and 1 g of palladium are put in suspension in 105 cm3 of dimethylacetamide, a few drops of triethylamine are added, then the whole is hydrogenated under ambient pressure (with 280 cm3 of hydrogen). The catalyst is filtered off, evaporated to dryness and 2 g of product is obtained which is dissolved in acetic acid and evaporated to dryness. The residue is taken up in isopropyl alcohol and 1.5 g of crystallized product is obtained.
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]>O1CCOCC1.[H][H].[C].[Pd]>[C:5]([CH:4]([CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)C(CCC(C)CCCC(C)CCCC(C)C)C(C)=O

Procedure:
10 Grams of 3-acetyl-6,10,14-trimethyl-5,9,13-pentadecatriene-2-on (Compound No. 2 in the Table) were dissolved in 10 g of dioxane, and one gram of 5% palladium-carbon was added to the solution. The mixture was catalytically reduced in hydrogen flow at an ordinary temperature under atmospheric pressure. After the reaction was completed, the palladium-carbon was filtered off, and the filtrate was subjected to distillation under the reduced pressure, to obtain 10 g of oily product. The product was purified by the column chromatography method as described in Example 1.
Reaction SMILES: N1C=CC=N1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N+:16]([C:14]1[S:13][C:11]2[N:12]=[CH:7][N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Agent: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)ncnc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-pyrazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine. 57-
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1ccc2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc2ccc(OC[C@H]3CO3)cc2c1
Temperature: 5 °C
Reaction time: 13 h
Yield: 67.7 %

Procedure:
Sodium hydride (60 weight %; 0.36 g; 9.0 mmol) is washed with hexanes (3×5 mL) under an argon blanket. DMF (3 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 6-hydroxyquinoline (1.00 g; 6.9 mmol) in DMF (13 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 30 minutes affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (2.04 g; 9.0 mmol) in DMF (10 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 13 hours, quenched by the addition of saturated aqueous ammonium chloride (5 mL), poured onto water (150 mL), and extracted with ether (3×75 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×75 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (40%→70% ethyl acetate in hexanes) affording the desired product (0.94 g) as an oil. CIMS: MH+ 202.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(N(CC)CC)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1OCc1ccccc1
Yield: 93 %

Procedure:
To a mixture of 1.50 g (0.0055 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, 0.56 g (0.0055 mol) of triethylamine and 30 ml of benzene was added 1.03 g (0.0061 mol) of benzyl bromide and the resulting mixture was heated under reflux for 2 hours with stirring. After cooling, precipitated triethyl amine hydrobromide was filtered off. The filtrate was concentrated under reduced pressure and was subjected to column chromatography (silica gel, using ethyl acetate/benzene 1:3 as an eluent) to give 1.79 g of the title compound 4-(2,4-dichlorobenzoyl)-1-methyl-5-benzyloxypyrazole (yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:13]([C:14]([O:16]C)=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Yield: 98 %

Procedure:
The product of Step A. above is suspended in 80 ml. of aqueous sodium hydroxide (5%) and refluxed for 30 minutes. The mixture is acidified with aqueous hydrochloric acid and extracted three times with 150 ml. of toluene. The combined toluene extracts are concentrated and the 5-(2,4-difluorophenyl)salicylic acid is crystallized out. Filtration yields 29.4 mmole of final product, a 98% yield.
Reaction SMILES: [OH-].[Li+].I[CH3:4].[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]#[N:12]>O.CO>[CH3:4][C:7]1([C:11]#[N:12])[CH2:8][CH2:9][CH2:10][C:6]1=[O:5]
Reactant: CI
Reactant: N#CC1CCCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C#N)CCCC1=O
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of lithium hydroxide (0.2226 g, 9.30 mmol) in water (5 mL) and iodomethane (0.591 mL, 9.46 mmol) were added to a stirred solution of 2-oxocyclopentanecarbonitrile (0.86 g, 7.88 mmol) in methanol (5 mL) at room temperature. The resulting mixture was heated to 50° C. for 1.5 h. The methanol solvent was removed in vacuo. The aqueous residue was extracted with ether (2×25 mL). The combined ether extracts were dried (Na2SO4), decanted and concentrated to give 1-methyl-2-oxocyclopentanecarbonitrile (0.76 g, 78% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 2.63-2.74 (1 H, m), 2.43 (2 H, t, J=7.21 Hz), 1.59-1.93 (4 H, m), 1.34 (3 H, d, J=6.94 Hz).
Reaction SMILES: C[O-].[Na+].CCO.Cl.[N:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[NH2:13].Br[C:15](=[CH:18]OCCC)[CH:16]=[O:17]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:13]1[C:15]([CH:16]=[O:17])=[CH:18][N:8]2[CH2:12][CH2:11][CH2:10][C:9]=12
Reactant: NC1=NCCC1
Reactant: CCCOC=C(Br)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=Cc1cn2c(n1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
28% Sodium methoxide (5.26 g) was added to the EtOH (250 mL) solution of 4,5-dihydro-3H-pyrrol-2-ylamine hydrochloride (3.27 g) at room temperature. After stirring for 5 min at room temperature, 2-bromo-3-propoxy-propenal (5.79 g) was added to the mixture at room temperature, then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was taken to dryness in vacuo. The residue was dissolved in CHCl3 (300 mL) and triethylamine (3.8 mL) was added. The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, washed with 50% K2CO3, dried over anhydrous K2CO3, filtered, and evaporated under reduced pressure. The residue was applied with silicagel column chromatography, eluted with CHCl3-acetone (2:1), and 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde (41%, 1.51 g) was obtained as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:36]=[C:37](\[C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)/[C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1(/[CH:36]=[C:37](\[C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:48])=[O:49])=[CH:43][CH:42]=2)/[C:38]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A solution of triphenylphosphine (2.09 g, 8 mmol) in methylene chloride (25 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (1.42 g, 8 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (1.345 g, 4 mmol) in methylene chloride (10 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (1.2 g, 12 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclooctyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (1.22 g, 73%) as an amorphous solid: EI-HRMS m/e calcd for C21H26N2O3S2 (M+) 418.1385, found 418.1385.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:21][CH2:22][O:23][CH3:24])[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:21][CH2:22][O:23][CH3:24])[CH2:15][C:16]([F:17])([F:18])[F:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COCCN(CC(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 4-[(2-methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (685 mg) in dry THF (7 mL) was added borane-methyl sulfide complex (405 uL) at 0° C. under inert atmosphere. The reaction mixture was refluxed for 3 h, and then stirred at room temperature overnight, quenched with MeOH, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-[(2-methoxy-ethyl)-(2,2,2-trifluoro-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an oil (635 mg). Treatment of this compound with HCl in DCM/MeOH furnished the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2cc(-c3ccccc3)ccn2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (113 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (100 mg, 0.418 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound as solid product. This was recrystallized from a mixed solvent of hexane and ethyl acetate to give the titled compound 67.2 mg (44.8%) as solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:25])[CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH3:16])=[O:9])=[CH:4][CH:3]=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.[O:40]1CCOC[CH2:41]1>>[N:1]([C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:25])[CH:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]=[C:41]=[O:40])=[CH:22][CH:23]=2)[CH3:16])=[O:9])=[CH:4][CH:3]=1)=[C:29]=[O:31]
Reactant: C1COCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)COc1ccc(N)cc1
Product: CC(Oc1ccc(N=C=O)cc1)C(=O)OCCOC(=O)COc1ccc(N=C=O)cc1
Temperature: 77.5 °C
Yield: 37.2 %

Procedure:
2-(4-Aminophenoxy)propionic acid-2-[2-(4-aminophenoxy)acetoxy]ethyl ester 56 (5.2 g, 13.9 mmol) was dissolved in dry dioxane (80 ml) under nitrogen atm. and cooled below 20° C. A solution of triphosgene (7 g, 23.6 mmol) in dry dioxane (20 ml) was added dropwise. The mixture was heated slowly to 75-80° C. and maintained for 3 hrs. The condenser was arranged for distillation and solvent removed by distillation at one atm. until the volume of the reaction mixture was reduced to approx. one third. Fresh dry dioxane (50 ml) was added and solvents distilled off under vacuum. The residue was re-evaporated twice from dry dioxane to give 57 (2.2 g, 37.2%) as a light yellow syrup.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:14][NH:15][C:16]([C:17]([F:20])([F:19])[F:18])=[O:21])[C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C(NCc1c(F)c([N+](=O)[O-])cc(Br)c1Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of the compound (204 mg) obtained in Example 519a, N-hydroxymethyl-2,2,2-trifluoroacetamide (115 mg) and 10% fuming sulfuric acid (1.6 ml) was stirred at 80° C. for 10 h. The reaction mixture was cooled, put into ice water and subjected to extraction with ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cn1
Yield: 93.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylate (0.35 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylic acid as crystals (0.31 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 151-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.I[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH3:22])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: CCI
Reactant: Oc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1
Product: CCOc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Bromo-2-chloro-1-(5-methoxybenzo[b]thiophene-2-ylmethyl)benzene obtained in Reference Example 54 was treated in a manner similar to Reference Example 132-(1) to give 5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)benzene. ESI-Mass m/Z 351/353 (M−H). (2) The above 5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)benzene and iodoethane were treated in a manner similar to Reference Example 132-(2) to give the desired 5-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-benzene. APCI-Mass m/Z 382/380 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[C:3]=1[CH3:25]
Reactant: Cc1c(N)cccc1C(=O)NCC(O)CN1CCc2ccccc2C1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(NC2CCOCC2)cccc1C(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylbenzamide (200 mg, 0.59 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (118 mg, 1.18 mmol). The mixture was stirred at 25° C. for 2 h. NaBH3CN (186 mg, 2.95 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (24 mg, Yield 9.6%). 1H NMR (CD3OD, 400 MHz): δ 8.41 (s, 1H), 7.35-7.23 (m, 3H), 7.20 (d, J=7.0 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H), 4.44 (s, 2H), 4.33 (brs, 1H), 3.99 (d, J=11.5 Hz, 2H), 3.66-3.43 (m, 7H), 3.38-3.16 (m, 4H), 2.15 (s, 3H), 2.01 (d, J=12.8 Hz, 2H), 1.63-1.48 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[O:11][CH2:10]2.C=O.[C:25]([BH3-])#N.[Na+].CC(O)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]([CH3:25])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[O:11][CH2:10]2
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=O)c(OC)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(CN(C)c2ccc3c(c2)COC3=O)c(OC)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
To a stirred suspension of 5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-one (18.0 g, 60 mmol) in acetonitrile (200 ml), was added 37% formaldehyde aqueous solution (44.7 ml, 600 mmol) and sodium cyanoborohydride (8.31 g, 132 mmol). The mixture was cooled to 0° C., followed by addition of 10% AcOH aqueous solution (150 ml). The mixture was stirred from 0° C. to room temperature during 2.5 hour period. The resulting solid was filtered, washed with acetonitrile and dried under vacuum to give 5-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-one as off-white powder (15.3 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH2:74][CH3:75])([CH2:72][CH3:73])[O:70][B:69]([OH:76])[C:68]=2[CH:77]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]5[C:71]([CH2:72][CH3:73])([CH2:74][CH3:75])[O:70][B:69]([OH:76])[C:68]=5[CH:77]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)cc3C)ccc21
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) was stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and prep-HPLC to provide the final title compound (118 mg, yield 79%). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.88 (t, 1H), 7.80 (t, 1H), 7.60 (m, 5H), 7.42 (d, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.47 (d, 2H), 4.36 (d, 2H), 4.27 (d, 2H), 2.35 (s, 3H), 1.78 (m, 4H), 0.52 (t, 6H) ppm; HPLC purity: 92.43% at 220 nm and 93.69% at 254 nm; MS: m/z=620; 661 [M+CH3CN].