Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Cl:4])(C)=O.C([Si](C)(C)[O:10][C@H:11]1[C@H:18]2[C@H:14]([O:15][C:16](C)(C)[O:17]2)[O:13][C@H:12]1[C@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[CH:24]=1)[OH:22])(C)(C)C>CO>[ClH:4].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:21]2[C@H:12]([OH:13])[C@@H:11]([OH:10])[C@H:18]([OH:17])[CH:14]([O:15][CH3:16])[O:22]2)=[CH:24][C:25]=1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=1
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: Cl
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of 0.35 M HCl in MeOH was prepared by adding AcCl (0.25 ml, 3.5 mmol) to MeOH (10 ml) and stirring for 15 minutes The alcohol from step D (0.84 g, 1.5 mmol) was treated with this solution for 16 hours at room temperature and 2 hours at 80° C. in a sealed vial. The reaction was cooled to room temperature, quenched with K2CO3 until basic, diluted with CH2Cl2, filtered, and concentrated under vacuum. The product was purified by flash chromatography (40 g SiO2, 0-10% MeOH:CH2Cl2, 60 minutes, 35 ml/min), suspended in H2O, and lyophilized to give (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol (0.46 g, 1.1 mmol, 75%) as a white solid. NMR revealed a 1.2:1 ratio of α and β anomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH:36]([CH3:38])[CH3:37])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CC(C)Br
Product: COc1ccc(CC2c3c(OC)ccc(OC(C)C)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with isopropyl bromide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:16]([C:18]2[N:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:17])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](OC)=[O:31])[CH:25]=1.C(O)C.[BH4-].[Na+]>O.CC(C)=O>[F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=2)=[CH:4][C:5]([CH2:8][N:9]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:16]([C:18]2[N:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2cc(CN(C(=O)c3ncn(C)n3)C3CCOCC3)ccc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(-c3cccc(CO)c3)c2)C2CCOCC2)n1
Yield: 5.7 %

Procedure:
A mixture of methyl 2′-fluoro-5′-([[(1-methyl-1H-1,2,4-triazol-3-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino]methyl)biphenyl-3-carboxylate (318 mg), ethanol (14 mL) and sodium borohydride (532 mg) was heated under reflux for 16 hours. After leaving the mixture to cool, water-acetone was added and extraction was conducted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; methanol/chloroform=1:99 to 3:97) to give the titled compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:37][NH:38][CH3:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([N:38]([CH3:39])[CH3:37])=[O:7]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
3-Chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (143 mg, 0.3 mmol), dimethylamine (2M in THF, 0.4 ml, 0.6 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (208 mg, 0.6 mmol), and N,N-di-iso-propylethylamine (0.1 ml, 0.6 mmol) were dissolved in DMF (2 ml). The reaction mixture was stirred at room temperature overnight. The mixture was distributed between ethyl acetate and 1 N aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel. The resulting material was dissolved in 1 ml of a 5% v/v solution of 70% perchloric acid in acetic acid and stirred overnight at room temperature. The crude was filtered and purified by mass-triggered reverse phase HPLC to afford 11 mg (63 μmol, 21%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethylbenzamide. 1H-NMR (DMSO-d6): δ2.94 (s, 6H), 3.82 (s, 3H), 7.09 (m, 1H), 7.21 (d, 1H), 7.47 (m, 2H), 7.63 (d, 1H), 7.81 (s, 1H), 8.29 (s, 1H), 8.81 (s, 1H). MS: m/z 423.0 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>ClCCl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:1]
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCc1ccccc1C=O
Reaction time: 1 h

Procedure:
A solution of 33-4 (0.5 g, 1.884 mmol) in dichloromethane (32 ml) was cooled to 0° C. in an ice bath. Dess-Martin Periodinane (1.199 g, 2.83 mmol) was then added in four portions over 20 minutes. After 1 hour, ether was added and the reaction was quenched with 30 mL of 1N NaOH (aq) followed by vigorous stirring for 30 minutes. The layers were then separated. The organic layer was dried over Sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-30% EtOAc in hexane) to yield 33-5.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CCO.O>[C:11]1([CH:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:8])[OH:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1)C(O)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 97.0 g of benzil in 1 liter of 95% EtOH was added 20 g of sodium borohydride. After stirring 10 minutes, the mixture was diluted with 1 liter of water and the mixture was treated with activated carbon. The mixture was then filtered trough supercel and the filtrate heated and diluted with an additional 2 liters of water until it became slightly cloudy. The mixture was then cooled to 0 to 5° C. and the resulting crytals were collected and washed with cold water. The crystals were then dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:43])([F:44])[F:29])[CH:32]=3)[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 62.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (501 mg, 1.15 mmol, 63%) was obtained.
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[CH3:10][C@@:11]([OH:18])([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:12]=[O:13].[OH2:19]>O1CCCC1.O.C(Cl)Cl.CSC>[CH3:10][C@@:11]([OH:18])([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]([OH:19])=[O:13]
Reactant: CC(C)(C)[C@@](C)(O)C=O
Reactant: O
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)[C@@](C)(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium chlorite (1.81 g, 20 mmol) and sulfamic acid (1.94 g, 20 mmol) were added in succession to a stirred solution of (R)-2,3,3-trimethyl-2-hydroxybutanal (2.0 g, 15.4 mmol) in 30 ml of tetrahydrofuran-water (1:1) at 0° C. The mixture was allowed to warm to room temperature, stirred for 30 minutes, diluted with methylene chloride and about 1 ml of methyl sulfide was added followed by a small quantity of water. The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the combined organic layer was dried (magnesium sulfate) and concentrated to afford a yellow gummy solid. Recrystallization from hexanes afford 1.45 g of (R) -2,3,3-trimethyl-2-hydroxybutanoic acid as a pale solid.
Reaction SMILES: [F:1][C:2]([F:29])([S:25]([OH:28])(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[Ag+2:34]>O>[F:29][C:2]([F:1])([S:25]([O-:28])(=[O:27])=[O:26])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Ag+:34]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: [Ag+]

Procedure:
Into a four-necked flask were charged 75 parts of perfluorooctanesulfonic acid and 100 parts of water, and 21.4 parts of silver carbonate was added thereto with stirring. After stirring at room temperature for 3 days, the mixture was filtered and the obtained filter-cake was washed with 10 parts of ion-exchange water, then 20 parts of diethylether and dried to give 60.3 parts of silver perfluorooctanesulfonate.
Reaction SMILES: O[C:2]1([OH:11])[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]1[OH:10].[CH3:12][CH2:13][O:14]CC.C(#N)C.Cl>[Cl-].[Zn+2].[Cl-].O>[OH:11][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:13]([CH3:12])=[O:14]
Reactant: OC1=CC(O)(O)C(O)C(O)=C1
Reactant: CCOCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1c(O)cc(O)c(O)c1O
Temperature: 0 °C
Reaction time: 13 h
Yield: 31.8 %

Procedure:
Under a stream of argon, 2.00 g (14.08 mmol) of 1,2,3,5-tetrahydroxyphenol (3) and 20 ml of ether were placed to form a suspension and 1.00 g (24.3 mmol, 1.73 equivalents) of acetonitrile was added to the suspension. While the resultant mixture was cooled with ice water, 0.70 g (5.14 mmol, 0.36 equivalent) of zinc chloride was added to the mixture and hydrogen chloride gas was bubbled at room temperature for four hours with stirring. The aeration of the mixture with the gas was stopped and the aerated mixture was left standing still at 4° C. for 13 hours. The ether layer was removed by decantation from the tarry precipitates consequently formed. The precipitates were stirred in an ice bath and 60 ml of water was added-to the stirred precipitates and they were heated under reflux for 4 hours. The product of the reflux, after adding a small amount of active carbon, was filtered while kept in hot. From the filtrate, yellow crystals were obtained as precipitates. By dissolving the crystals again in ether, removing the insoluble by filteration, and then concentrating the filtrate, 0.82 g (yield 31.8%) of the product (11) was obtained in the form of yellow platelike crystals.
Reaction SMILES: CC([O:5][C:6](=[O:42])[C@H:7]([NH:25][C@H:26]([C:31](N(C1CCS(=O)(=O)C1)C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)C.[NH:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[O:24]=[C:11]1[C:12]2[CH:13]=[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]3=[CH:16][C:17]=2[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][C@@H:7]([NH:25][C@H:26]([C:31]([N:43]1[CH2:47][CH2:46][CH2:45][C@@H:44]1[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:6]([OH:42])=[O:5]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)N(C)C1CCS(=O)(=O)C1
Reactant: c1cncc(C2CCCN2)c1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)N1CCC[C@@H]1c1cccnc1

Procedure:
Prepared as described in Example 1, Part (a) using 3-pyrrolidin-2-yl-pyridine as HNR2R3 to afford the title compound as a dark solid; 145 mg.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:20].C(OCC)(=O)C>O1CCCC1>[CH2:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(CC)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(CC)cc3)ccc12
Temperature: 67 °C

Procedure:
3.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to a solution of 240 mg of N-[6-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 17 hours, and the resulting mixture is then allowed to return to room temperature and 50 cm3 of ethyl acetate are added. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and with 2×50 cm3 of water, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 2 cm3 of ethyl acetate and then with 10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 80 mg of N-[6-(4-ethylphenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:30])=[C:27](I)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:30])=[C:25]([C:4]2[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=2[O:2][CH3:1])[CH:24]=1
Reactant: COc1cc(S(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(S(C)(=O)=O)ccc1-c1cc(Br)ccc1F
Temperature: 110 °C
Yield: 71 %

Procedure:
A solution of 2-(2-methoxy-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 16, 3.04 g, 9.74 mmol), 5-bromo-2-fluoro-iodobenzene (2.66 g, 8.85 mmol), and Na2CO3 (2.80, 26.55 mmol) in dioxane (60 mL) and water (15 mL) was degassed, tetrakis(triphenylphosphine)palladium(0) was added and the reaction mixture was degassed again. The reaction mixture was heated at 110° C. for 3 hours before cooling to room temperature and concentrating under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic phase was separated and the aqueous layer was re-extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude. The crude was purified by silica gel column chromatography eluting with 10-30% EtOAc/heptane to afford the title compound in 71% yield, 2.25 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CO)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (2R)-2-({[6-(hydroxymethyl)pyridin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate (430 mg, 1.4 mmol) was dissolved in DCM (15 mL) and MsCl (240 mg, 2.1 mmol) was added. The reaction mixture was cooled to 0° C. and DIPEA (0.72 mL, 4.1 mmol) were added. The reaction mixture was stirred 2 h at ambient temperature and water was added. The organic phase was separated and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound as a clear oil. Yield: 420 mg (78%). 1H NMR (399.961 MHz, CDCl3) δ 7.61 (t, J=8.2 Hz, 1H), 7.01 (d, J=6.6 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.20 (s, 2H), 4.49-4.30 (m, 1H), 4.27-4.06 (m, 2H), 3.50-3.27 (m, 2H), 3.07 (s, 3H), 2.04-1.90 (m, 3H), 1.90-1.81 (m, 1H), 1.46 (s, 9H). MS (ESI+) 387.2 (M+1H+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)C(=O)C3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:22]3[CH:17]=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[CH2:10][CH2:9]2)=[CH:26][CH:27]=1
Reactant: O=C1C(=O)N(C2CCN(CCc3ccc(F)cc3)CC2)c2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(Nc3cccc(Br)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
Under ice cooling, a 1 M solution (69 ml) of a borane/tetrahydrofuran complex in tetrahydrofuran was added dropwise into a solution of 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-2,3-dioxo-6-bromoindoline (7.4 g) in tetrahydrofuran (150 ml) followed by stirring at room temperature overnight and heating under reflux for 3 hr. Into the reaction solution was carefully added dropwise a saturated aqueous solution of sodium bicarbonate. Then ethyl acetate was added to the resultant mixture and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then diluted with pyridine (50 ml) and stirred at room temperature for 4 hr. Next, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (3.9 g) as a yellow oil (yield: 57%).
Reaction SMILES: BrC[CH2:3][CH:4]1[O:9][CH2:8][CH2:7]C[O:5]1.[Mg].[C:11]([O:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]([O:25][CH3:26])=[C:17]([CH2:27][C:28]([CH3:30])=[O:29])[C:16]=1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:13])[CH3:12].[Cl-].[NH4+].O1CCC[CH2:38]1>>[C:11]([O:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:19][C:18]([O:25][CH3:26])=[C:17]([CH2:27][C:28]([OH:29])([CH3:38])[CH2:30][CH2:3][CH:4]2[O:5][CH2:7][CH2:8][O:9]2)[C:16]=1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:13])[CH3:12]
Reactant: BrCCC1OCCCO1
Reactant: C1CCOC1
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1CC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1CC(C)(O)CCC1OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxane (50 g) in tetrahydrofuran (200 ml) was added to magnesium (6.6 g) under a nitrogen atmosphere to prepare a Grignard reagent. A solution of 4-acetoxy-2-acetonyl-3,5-di-tert-butylanisole in tetrahydrofuran (200 ml) was added dropwise to the reagent. After stirring the mixture at room temperature for 3 h, a saturated aqueous solution of ammonium chloride was added and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (33% ethyl acetate in n-hexane) to afford 4-acetoxy-2-[4-(1,3-dioxa-2-cyclopentyl)-2-hydroxy-2-methylbutyl]-3,5-di-tert-butylanisole [27.9 g (yield, 69%)] as a colorless oil.