Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>[OH-].[Na+]>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: On1nnc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Yield: 91.4 %

Procedure:
In 1 N aqueous sodium hydroxide (300 ml) is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (38 g) and thereto is added ether (100 ml). To the solution is added dropwise p-chlorobenzenesulfonyl chloride (57 g) with stirring under ice-cooling during 15 minutes, and the mixture is stirred at the same temperature for 70 minutes. The reaction mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off, and the resulting crystals are recrystallized from benzene-petroleum ether to give 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (70.5 g), melting point: 125°-127° C. Infrared spectrum (Nujor): 1190, 1085 cm-1.
Reaction SMILES: CC(CCC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H:13]3[C@H:24]([CH2:25]C2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H](C[CH2:21]2)O)=[CH:15][CH2:14]3)CC1)C)C.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH:24]12[CH2:25][CH:15]([CH2:14][CH2:13]1)[C:16](=[CH2:17])[C:22]2([CH3:21])[CH3:23]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: C=C1C2CCC(C2)C1(C)C
Reaction time: 0.17 h

Procedure:
Total cholesterol, triglyceride and glucose levels in the serum were measured twice for each using a commercially available kit (Bio Clinical system), and insulin level was measured by ELISA using a mouse insulin kit (Shibayaki, Japan). Lipids were extracted from the liver tissue according to Folch et al.'s method. After adding 1 mL of distilled water to 0.25 g of liver tissue, the liver tissue was homogenized using a Polytron homogenizer (IKA-Werke GmbH & Co., Ultra-Turrax, Staufen, Germany). After adding 5 mL of chloroform:methanol solution (2:1, v/v) to the homogenate and mixing well, the mixture was centrifuged at 1000×g for 10 minutes. After adding 2 mL of chloroform:methanol solution (2:1, v/v) again to the supernatant, the same procedure was repeated to completely separate the lipid components of the liver. After adding 3 mL of chloroform:methanol:0.05% CaCl2 (3:48:47, v/v/v) solution to the remaining pellets and mixing well for 1 minute, followed by centrifugation at 1000×g for 10 minutes, the resulting pellets were completely dried with nitrogen gas. The dried lipids were dissolved in 1 mL of methanol and then analyzed. The same kit (Bio Clinical system) as the one used for the serum analysis was used to measure the triglyceride level of the liver tissue.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([CH3:24])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(O)=O>[CH:1]([NH:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([CH3:24])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(C)cc(C(=O)O)c(N)c1C
Solvent: O=CO
Product: CCOC(=O)c1c(C)cc(C(=O)O)c(NC=O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To 14.5 ml of 90% formic acid was added 30 ml of acetic anhydride. The mixture was warmed, and then heated to 50°-60° C. for two hours. To the mixture cooled to room temperature was added portionwise with stirring 15.0 g of 2-amino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid. The mixture was further stirred at room temperature for 3 hours and poured into ice water. The resulting precipitate was filtered and recrystallized from ethyl acetate/n-hexane to yield 11.8 g (70.5% of theory) of 2-formylamino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid melting at 144.5°-146° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:9](=[O:27])[N:10]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]([CH3:20])=[CH:12][C:13]=1[S:14]([CH2:17][CH2:18]Cl)(=[O:16])=[O:15]>CC(N(C)C)=O>[CH2:25]([O:24][C:22]([CH2:21][N:10]1[C:11]([CH3:20])=[CH:12][C:13]2[S:14](=[O:16])(=[O:15])[CH2:17][CH2:18][NH:7][C:8]=2[C:9]1=[O:27])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cn1c(C)cc(S(=O)(=O)CCCl)c(N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cn1c(C)cc2c(c1=O)NCCS2(=O)=O
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of potassium carbonate (45 mg) and 3-amino-4-(2-chloroethylsulfonyl)-1-ethyloxycarbonylmethyl-6-methyl-2-pyridinone (120 mg, 0.33 mmol) in dimethyl acetamide (1.0 mL) was stirred at 160° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl acetate and dilute HCl. The organic layer was washed with brine, dried (Na2SO4) and evaporated to a semi-solid. The crude product was purified by flash column chromatography on silica gel (70-100% ethyl acetate/hexanes gradient) to give the title compound as a colorless crystalline solid:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH3:13])=[CH:4][CH:3]=1.B([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C.CN(C=O)C.CO>[CH3:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(Br)cc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
In a microwave reaction vial was added (R)-1-(4-bromophenethyl)-2-methylpyrrolidine (200 mg, 0.746 mmol), 3-(4-boronophenyl)propanoic acid (289 mg, 1.491 mmol), Na2CO3 (395 mg, 3.73 mmol), dihydrogen dichlorobis(di-tert-butylphosphinito-kP)palladate (POPd) (11.23 mg, 0.022 mmol) and a mixture of H2O (0.4 mL), MeOH (0.6 mL), and DMF (2.0 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 15 min. To the mixture was added acetonitrile (20 mL) and filtered. The filtrate was concentrated and the residue was purified by HPLC to give the title compound. LCMS m/z=338.2 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.24 (d, J=14.9 Hz, 0.5H), 1.46 (d, J=6.3 Hz, 2.5H), 1.72-1.84 (m, 1H), 2.01-2.15 (m, 2H), 2.20-2.32 (m, 1H), 2.66 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 3.02-3.20 (m, 4H), 3.33-3.46 (m, 1H), 3.48-3.62 (m, 1H), 3.75-3.86 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>COCCOC.O.CO>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([N:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=4)[CH:2]=[N:3]3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(cnn2-c2ccc3c(c2)OCCO3)c1
Temperature: 45 °C
Yield: 72.1 %

Procedure:
The title compound was prepared as described in Example 405 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.354 g, 1.15 mmol), in ethylene glycol dimethyl ether (20 mL), 2H,3H-benzo[e]1,4-dioxin-6-boronic acid (0.250 g, 1.39 mmol), [1,1′-bis(diphenyl phosphino-ferrocene] complex with dichloromethane (1:1) (0.094 g, 0.11 mmol) and potassium phosphate (2.40 g, 11.5 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (silica gel, 20% ethyl acetate/hexanes) gave a solid. Methanol (30 mL) and aqueous 6 N hydrochloric acid (30 mL) were added to the solid and the mixture was heated at 45° C. for 5 h. Water (30 mL) was added and the solid was filtered and dried in a vacuum oven to afford the title compound (0.230 g, 71% yield over 2 steps): ES-MS (m/z) 278 [M+1]+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:11]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1O>>[CH2:24]([C:21]1[CH:22]=[N:23][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:10]3[CH:11]=[C:7]([CH2:6][O:5][C:32]4[CH:33]=[CH:34][C:35]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:36][C:31]=4[F:30])[C:8]([C:26]([F:27])([F:28])[F:29])=[N:9]3)[CH2:17][CH2:16]2)=[N:19][CH:20]=1)[CH3:25]
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1
Product: CCc1cnc(N2CCC(n3cc(COc4ccc(S(C)(=O)=O)cc4F)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl methanesulfonate and 2-fluoro-4-(methylsulfonyl)phenol in a manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.25 (2H, s), 8.17 (1H, s), 7.71 (2H, m), 7.52 (1H, m), 5.30 (2H, s), 4.90 (2H, m), 4.65 (1H, m), 3.13 (3H, s), 3.05 (2H, m), 2.47 (2H, q), 2.20 (2H, m), 1.98 (2H, m), 1.18 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:21]([OH:23])=[O:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OCc4ccccc4)cc3c2c1CC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1CC
Yield: 78.8 %

Procedure:
At room temperature and under normal pressure, 970 mg of 6-benzyloxycarbonyl-4-ethyl-β-carboline-3-carboxylic acid ethyl ester is hydrogenated for one hour in 50 ml of methanol with 3 ml of 1N hydrochloric acid and 1.50 g of 10% palladium/carbon. After the catalyst has been removed by filtration, the mixture is evaporated, thus obtaining 593 mg of 3-ethoxycarbonyl-4-ethyl-β-carboline-6-carboxylic acid as the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Br)cc1OC
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#CCCO)cc1OC
Yield: 31.6 %

Procedure:
A mixture of 10 g (46 mmol) of 1-bromo-3,4-dimethoxybenzene, 3.4 g (48 mmol) of 3-butyn-1-ol and 8 mL (58 mmol) of triethylamine in 20 mL of methylene chloride was stirred and flushed with argon. To the mixture there was added 0.12 g (0.06 mmol) of cuprous iodide and 0.30 g (0.43 mmol) of bis(triphenylphosphine)palladium dichloride. The reaction mixture was stirred at room temperature for 4 hours and at reflux for 16 hours. After filtration, the filtrate was washed with water, dried and concentrated. The crude product was purified by HPLC using 30% ethyl acetate-toluene to give 3.0 g (32% yield) of 4-(3,4-dimethoxyphenyl)-3-butyn-1-ol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[NH2:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[SH:18]>>[Cl:17][C:16]1[C:11]2[NH:10][C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]=3[S:18][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1c(S)cccc1Cl
Reactant: Cn1c(=O)cc[nH]c1=O
Product: Cn1c(=O)[nH]c2c(c1=O)Nc1c(Cl)cccc1S2

Procedure:
Employing the procedure of Example 1, parts A and B with 3-methylpyrimidine-2,4(1H,3H)-dione and 2-amino-3-chlorobenzenethiol yielded the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>>[CH3:8][N:9]([C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][OH:12]
Reactant: Clc1ncccn1
Reactant: CNCCO
Product: CN(CCO)c1ncccn1
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of 2-chloropyrimidine (20.8 g) and 2-(methylamino)ethanol (180 ml) was heated at 120° C. for 15 hours and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure to obtain 2-(methyl-2-pyrimidylamino)ethanol (24.6 g, yield 88%) as a colorless oil. b.p. 130-132° C./1-1.5 mmHg
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH:10]([CH2:18][OH:19])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[CH2:18][OH:19])[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(CO)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@H]1CNCC[C@H]1N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (373 mg, 1.25 mmol) in anhydrous DCM (10 mL) was slowly added a solution of diisobutylaluminum hydride in hexanes (1M, 3.8 mL, 3.8 mmol) at −70° C. The reaction mixture was allowed to warm to −10° C. over 90 min, then stirred at RT for 15 min. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (188 mg, 88%).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:30])[C@H:15]([CH2:28][CH3:29])[CH2:16]/[CH:17]=[CH:18]/[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.OO.O.[OH-].[Li+].S([O-])([O-])(=[O:38])=S.[Na+].[Na+]>O.O1CCCC1>[CH2:21]([O:20][CH2:19]/[CH:18]=[CH:17]/[CH2:16][C@@H:15]([CH2:28][CH3:29])[C:14]([OH:30])=[O:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C/C=C/COCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 23.4 g of (S)-4-benzyl-3-[(2R,4E)-6-benzyloxy-2-ethylhex-4-enoyl]oxazolidin-2-one (57.5 mmol) obtained in Example (106a) in a mixed solvent of tetrahydrofuran (800 ml) and water (260 ml) was cooled in an ice bath, and then 35.0 ml of a 30% hydrogen peroxide aqueous solution and 4.83 g of lithium hydroxide monohydrate (115 mmol) were added thereto. The mixture was stirred at the same temperature for one hour, and then raised to room temperature and further stirred for 12 hours. After cooling in an ice bath, 250 ml of a 1.5 M sodium thiosulfate aqueous solution was added to the reaction mixture. The mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, diluted with 500 ml of water and washed with ethyl acetate. Then, the aqueous layer was made acidic with 30 g of sodium dihydrogenphosphate, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 14.3 g of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl([O-])=[O:34].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([C:23]([OH:34])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Yield: 99.3 %

Procedure:
The same operation as in Example (33c) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (68b) (about 0.63 mmol), sodium chlorite (113 mg, 1.25 mmol), sodium dihydrogenphosphate (320 mg, 2.05 mmol) and 2-methyl-2-butene (0.33 mL, 3.12 mmol), to obtain 312.7 mg of the title compound as a white solid (99%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[O:3]1.[OH-].[Na+].S(OC)(O[CH3:35])(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:35][N:6]1[CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[O:3][C:2]1=[O:1]
Reactant: COS(=O)(=O)OC
Reactant: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A mixture of 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 0.84 mmol), tetrabutylammonium bromide (0.05 g, 0.16 mmol), aqueous sodium hydroxide (0.10 g, 2.52 mmol) and dimethyl sulfate (0.21 g, 1.68 mmol) in anhydrous tetrahydrofuran (5 mL), was stirred at an ambient temperature for 1 h. The mixture was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate (30%) in hexanes to afford 1′-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.13 g, 40%): mp 98-102° C.; 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.05 (s, 1H), 5.84 (d, J=6.2 Hz, 2H), 4.74 (ABq, 2H), 3.93-3.88 (m, 2H), 3.82-3.74 (m, 1H), 2.92 (d, J=4.0 Hz, 3H), 2.55-2.40 (m, 1H), 2.36-2.26 (m, 1H), 2.20-2.07 (m, 1H), 1.95-1.85 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.2, 178.1, 175.2, 175.1, 156.1, 156.0, 149.1, 142.5, 142.4, 142.2, 142.0, 132.1, 132.0, 129.2, 124.5, 124.4, 123.9, 123.8, 119.0, 118.9, 108.1, 102.8, 102.7, 101.6, 93.8, 93.7, 80.5, 80.4, 58.2, 58.1, 58.0, 57.9, 43.1, 43.0, 29.3, 29.2, 28.8, 28.7, 22.8, 22.7; MS (ES+) m/z 417.3 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12](=[NH:14])[NH2:13])[CH:6]=[CH:7][C:8]=1[F:9].C(=O)([O-])[O-].[K+].[K+].[CH:21]([CH:23]([CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[C:24](OCC)=O)=[O:22]>C1(C)C=CC=CC=1.O>[Br:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][CH2:11][C:12]1[NH:13][CH:24]=[C:23]([CH2:29][C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)[C:21](=[O:22])[N:14]=1
Reactant: CCOC(=O)C(C=O)Cc1cncnc1
Reactant: N=C(N)CCc1ccc(F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1nc(CCc2ccc(F)c(Br)c2)[nH]cc1Cc1cncnc1
Temperature: 115 °C
Reaction time: 2.5 h
Yield: 79.5 %

Procedure:
The mixture of 3-(3-bromo-4-fluorophenyl)propanimidamide hydrochloride (5.0 g, 19.38 mmol), potassium carbonate (9.37 g, 67.8 mmol) and ethyl 2-formyl-3-(5-pyrimidinyl)propanoate (4.03 g, 20.35 mmol) in toluene (100 mL) was stirred at 115° C. for 2.5 h. After cooling, the mixture was diluted with water, then extracted with DCM (50 mL×2). The combined organic phase was concentrated to give the crude title compound as a light yellow solid (6.0 g, 77% yield). The crude was used without further purification. LCMS: rt=1.20 min, [M+H+]=389
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][OH:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][CH2:18][CH:15]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:17]=3[O:16]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 89.2 %

Procedure:
Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-ol (17.95 g, 75.06 mmol) with potassium carbonate (41.38 g, 299.43 mmol) and allyl bromide (10.89 g, 90.08 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol (16.5 g, 59.10 mmol) with 3-chloroperoxybenzoic acid (30.59 g, 177.3 mmol, 77%) followed by potassium carbonate (20.41 g, 14.77 mmol) generally according to the procedure described for Intermediate 9 afforded 11.2 g (64%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (11.2 g, 37.94 mmol) with p-toluenesulfonyl chloride (8.68 g, 45.53 mol) generally according to the procedure described for Intermediate 10 gave 15.2 g (89%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 58.1; H, 4.05.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[Cl:17]N1C(=O)CCC1=O>C1COCC1>[Cl:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1F
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)O)cc1F
Reaction time: 1 h

Procedure:
A solution of 3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (196 mg, 0.89 mmol) and N-chlorosuccinimide (119 mg, 0.89 mmol) in THF (5 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM, the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (192 mg, 85%): LC-MS (ES) m/z=255 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C@H:22]([CH2:23][CH3:24])[C:20]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:8]2[C:7]3[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=3[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CCc1noc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1noc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c12
Reaction time: 2 h

Procedure:
1,1-dimethylethyl {(1R)-1-[({6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 34, 4.4 mg) was dissolved in dichloromethane (1.0 ml) and, at 0° C., TFA (0.100 ml, 1.3 mmol) was added. The reaction mixture was stirred at that temperature for 2 hours. After removal of the volatiles, the residue was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M in MeOH) to afford the title compound.