Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[OH:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(O)c1ccc(SC)c(Cl)c1
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (3.93 g, 15.19 mmol) in methanol (30 mL) was cooled to 0° C. and then treated with sodium borohydride (530.9 mg, 14.03 mmol). The reaction mixture changed from yellow to colorless. The mixture was stirred for 15 min and then quenched with a 1N aqueous hydrochloric acid solution (10 mL). The resulting reaction mixture was then extracted with methylene chloride (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 then 4/1 hexanes/ethyl acetate) afforded (3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester (1.43 g, 38%) as a white solid: mp 56-57° C.; EI-HRMS m/e calcd for C11H13ClO3S (M+) 260.0273, found 260.0276.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[C:13]([Cl:14])[C:8]=2[O:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:14][C:13]1[C:8]2[O:7][CH:6]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]
Reactant: COC(=O)Cc1coc2c(Cl)c(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1coc2c(Cl)c(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a mixture of methyl(7-chloro-6-((2,4-dichlorobenzyl)oxy)-1-benzofuran-3-yl)acetate (218.9 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (1.643 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The residue was concentrated. The residue was neutralized with 1N HCl, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The precipitate was collected by filtration, and crystallized from EtOH-hexane to give the title compound (184 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:13][CH:14]([C:20]1([CH3:25])OCC[O:21]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH2:13][CH:14]([C:20](=[O:21])[CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2=[O:26]
Reactant: CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (95 mg, 19%) in the same manner as described in the above example 6 (20) from ethyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.58 g, 1.57 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[C:22]([Cl:23])=[N:21][C:19](Cl)=[N:18][C:16]=1[Cl:17]>C1C=CC=CC=1>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][C:10]([C:19]2[N:21]=[C:22]([Cl:23])[N:15]=[C:16]([Cl:17])[N:18]=2)=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccc(-c2ccccc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: c1ccccc1
Product: Clc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
A mixture of 4-phenyl-phenyl magnesium bromide (prepared from 4-bromobiphenyl (7.75 g, 33 mmol) and magnesium turnings (0.83 g, 35 mmol) in 40 mL ether) and cyanuric chloride (4.00 g, 21.7 mmol) in benzene (90 mL) was stirred at 0° C. for 90 minutes. The reaction was evaporated to dryness, and the residue was flash chromatographed on silica gel with 50% hexanes/methylene chloride to provide the desired compound (2.80 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10]C(OC(C)(C)C)=O)[C@@H:7]([OH:18])[CH2:6]1)=[O:4].[ClH:19]>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([OH:18])[C@@H:8]([NH2:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1

Procedure:
A solution of (1S,2S,4R)—N—Boc-1-amino-2-hydroxycyclopentane-4-carboxylic acid methyl ester (0.2 g) in 4M HCl in dioxane (4 ml) was stirred under an argon atmosphere at r.t. for 2 hrs. The reaction mixture was concentrated to give (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester hydrochloride (165 mg, contains some dioxane) as light brown gum. MS: 160.4 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 60.1 %

Procedure:
32.3 g (0.21 mol) of 2-nitrobenzaldehyde and 35.0 g (0.21 mol) of diethyl malonate were added to 100 mL of acetic anhydride at room temperature. 27.0 g (0.32 mol) of sodium hydrogen carbonate was added to this mixture, and the resulting mixture was allowed to react overnight at 100° C. The reaction mixture was concentrated under reduced pressure to approximately a half of the original volume, and ice water was added to this reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium hydrogen carbonate and water in this order, and was dried and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), and thus 37.0 g (yield: 59%) of the title compound was obtained as light yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)[C:8]([Cl:9])=[CH:7][N:6]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1cc(CBr)c(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cc2cc(Cl)ncc2Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of 4-bromomethyl-2,5-dichloro-pyridine (500 mg, 2.08 mmol) in toluene (10 mL) was added with stirring the [1,1-bis(diphenylphos-phino)ferrocene]dichloropalladium DCM complex (74 mg, 0.101 mmol), B-(3-fluorophenyl)-boronic acid (290 mg, 2.08 mmol) and sodium carbonate (440 mg, 4.15 mmol) in water (2 mL). The resulting mixture was stirred at 80° C. for 3 h, cooled, poured onto water (20 mL), and partitioned between water and ethyl acetate. The organic portions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (241 mg, 32%) as white solid. LC-MS (UV peak area, m/z) 70%, 255.0, 257.0 (M+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)Cc1ccc(SC)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC(=O)C(=Cc1ccccc1)c1ccc(SC)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-(4-methylthiophenyl)-2-butanone from Step 2 (9.74 g, 50 mmol), benzaldehyde (5.85 g, 55 mmol) and piperidine (0.5 mL) in toluene (200 mL) was heated at reflux with a Dean-Stark trap for 16 hours. The mixture was cooled and solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed successively with saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude pentenone was recrystallized from ethyl acetate and hexane to give 8.64 g of 2-(4-methylthiophenyl)-1-phenyl-1-pentene-3-one (60%) as light yellow crystals: mp 98°-99° C. Anal. Calc'd. for C18H18OS: C, 76.56; H, 6.42; N, 11.35. Found: C, 76.58; H, 6.17; N, 11.35.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12](N(CC)CC)C.CI>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CI
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5 g) and triethylamine (6.5 ml) in tetrahydrofuran (1000 ml) at 0° C. was added methyliodide (1.94 ml) dropwise over a period of 1 hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and solvent removed by evaporation to give the title compound (3.7 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](O)=[O:38]>>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:38]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2ccccc2c1Br
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5c4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-bromonaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[NH:5][C:4]2[C:12](=[O:20])[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:3]1=2>Cl>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:5][C:4]2[C:12](=[O:20])[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:3]1=2
Reactant: COC(=O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Agent: Cl
Product: O=C(O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A suspension of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-3-carboxylic acid, methyl ester (10.0 g, 0.037 mole) in 5N hydrochloric acid (170 ml) is stirred at 100 for 16 hours under nitrogen. The reaction mixture is cooled. The product is filtered off, washed with water, with acetone and sucked dry. Recrystallization from dimethyl formamide-methanol gives white crystals (6.2 g, 65%), mp 265-268 (dec).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].F[C:22](F)(F)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.O>CN1C(=O)CCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)(C)C)ccc42)CN(C)CC3)cn1
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
To a solution of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.82 mmol) in NMP (3.0 ml), powdered KOH (462 mg, 8.23 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (286 mg, 1.65 mmol) was added slowly to the above solution and stirred for 14 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethylacetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×5 0 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 30 mg of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole as TFA salt
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH:13]=[O:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: OCc1conc1-c1ccc(F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1conc1-c1ccc(F)cn1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-methanol (2.1 g, 10.8 mmol) in DCM (45 mL) was added a suspension of DMP (5.5 g, 13.0 mmol) in DCM (35 mL) portionwise and under Argon at room temperature and then the mixture was cooled to 0° C. and the resulting mixture warmed up to room temperature overnight. The mixture was then poured carefully into stirred saturated sodium hydrogen carbonate solution and the aqueous layer extracted with DCM. The combined organic layers were then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) gave the title compound (1.85 g, 89%) as a white solid. MS: m/e=193.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([OH:26])[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[Cl:29][C:30]1[C:31](Cl)=[N:32][CH:33]=[C:34]([CH:40]=1)[C:35]([O:37][CH2:38]C)=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:29][C:30]1[CH:40]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=[N:32][C:31]=1[O:26][C:24]1[CH:23]=[C:13]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])[CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:28])[CH3:27])[CH:25]=1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)c(Cl)c1
Yield: 77.4 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.0 g, 2.47 mmol), ethyl 5,6-dichloronicotinate (0.57 g, 2.59 mmol), and potassium carbonate (0.855 g, 6.14 mmol) in acetonitrile (15 mL) was heated at 160° C. for 4 hours using microwave heating. The acetonitrile was removed in vaccuo and the residual oil partitioned between water (50 mL) and ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in hexane to give the desired compound (1.1 g). The analytical data indicated that transesterification had occurred at some stage in the procedure to furnish the methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[CH:12]2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN(C=O)C>[CH2:21]([O:17][CH2:16][C:14]1[N:13]=[CH:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=2)[CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2cnc(COCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.3 %

Procedure:
To a solution of 4-(4-hydroxymethylimidazol-1-yl-methyl)benzoic acid methyl ester of Example A1 (0.4 g, 1.6 mmol) in THF/DMF (6/4) was added portionwise NaH 60% (162 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then benzyl bromide (328 mg, 1.92 mmol) was added and the reaction was stirred overnight. The solvent was removed under reduced pressure, then water (10 ml) was added and the mixture was extracted with CH2Cl2. The aqueous phase was acidified with HCl 1 N to pH=4 and extracted with CH2Cl2. The latest organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 95/05) to give a white solid (17 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[C:15]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)cc2)CC1
Reactant: C=CC(=O)OC(C)(C)C
Product: COC(=O)C1(c2ccc(OCCC(=O)OC(C)(C)C)cc2)CC1
Temperature: 110 °C
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (7.0 g, 3.6 mmol) in acrylic tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. The mixture was heated at 110° C. for 1 h. After cooling to room temperature, the resulting mixture was quenched with water and extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material (3.0 g). 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 3.62 (s, 3H), 2.69 (t, J=6.6 Hz, 2H), 1.59-1.56 (m, 2H), 1.47 (s, 9H), 1.17-1.42 (m, 2H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15].[C:21](Cl)(Cl)=[S:22]>O.C(Cl)(Cl)Cl>[CH:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:8][C:7]=1[N:6]=[C:21]=[S:22])([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1N=C=S
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium bicarbonate (16.8 g, 199.5 mmol) in water (400 mL) was added to 3-amino-4-isopropoxy-benzenesulfonamide (15.3 g, 66.5 mmol, example 2, step d) in a mixture of chloroform (200 mL) and water (200 mL). Thiophosgene (6.37 mL, 83.1 mmol) was then added. The biphasic solution was stirred at room temperature for 1.5 h. The phases were separated and the aqueous phase was extracted with CH2Cl2. The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated, yielding the crude title compound as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5]2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1n[nH]c(C)n1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc(C)n(Cc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (50 mg, 0.28 mmol) and 2-chloro-4-(chloromethyl)pyridine (50 mg, 0.31 mmol) in DMF (2 mL), K2CO3 (116 mg, 0.84 mmol) was added. The mixture was stirred at RT overnight, and was then diluted with H2O (20 mL), extracted with EtOAc (3×20 mL), 4:1 CHCl3:iPrOH (3×20 mL), dried with MgSO4 and concentrated under reduced pressure. The crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford ethyl 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (29 mg, 40%) as a white solid. MS (ES+) C12H13ClN4O2 requires: 280 found: 281[M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][NH:30][C:31]([N:13]2[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:11]3[CH2:12]2)=[O:32])=[CH:33][CH:34]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCCN12
Reactant: O=C=NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To hexahydro-1,1-diphenyl-1H-oxazolo[3,4-a][1,4]diazepin-3-one (60 mg, 0.2 mmol) were added tetrahydrofuran (5 mL) and 4-fluorobenzyl isocyanate (59 mg, 0.39 mmol), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=6:1 to hexane:ethyl acetate=1:4) and powder was formed from diethyl ether to obtain the title compound (73 mg, yield 82%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C@@H:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[C@@H:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(O[C@H]2CN3CCC2CC3)cc1
Product: CN(C)c1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 9B (282 mg, 1 mmol) was treated with N,N-dimethyl-4-amino-phenyl boronic acid (230 mg, 1.4 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.2) as a solid (118 mg, yield, 37%). 1H NMR (MeOH-d4, 300 MHz) δ 1.41-1.56 (m, 1H), 1.61-1.88 (m, 2H), 1.98-2.12 (m, 1H), 2.14-2.22 (m, 1H), 2.72-3.01 (m, 11H), 3.22-3.34 (m, 1H), 4.48-4.57 (m, 1H), 6.83 (dt, J=8.8, 3.0 Hz, 2H), 6.92 (dt, J=8.8, 2.1 Hz, 2H), 7.39-7.49 (m, 4H) ppm. MS (DCl/NH3) m/z 323 (M+H)+.