Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:35])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C@@H:20]4[C@H:24]([C:25]=3[OH:26])[CH2:23][CH2:22][CH2:21]4)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CN(C)C=O.CO.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:35])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C@@H:20]4[C@H:24]([C:25]=3[OH:26])[CH2:23][CH2:22][CH2:21]4)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(4aR,7aS)-3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 44, 45 mg, 0.081 mmol) was dissolved in a 1:5 mixture of N,N-dimethylformamide and methanol (12 mL). 5% Palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, washed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product as an inseparable mixture of two diastereomers, (4aR,7aS)-3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (20 mg, 0.036 mmol, 44%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.44-1.60 (3H, m), 1.95-2.40 (10H, m), 3.22-3.36 (3H, m), 3.86 (1H, bs), 4.47 (1H, d, J=14.4 Hz), 4.56 (1H, dd, J=12.4, 8.0 Hz), 4.91 (1H, d, J=15.2 Hz), 7.15 (2H, t, J=8.4 Hz), 7.39 (2H, m), 7.61 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=8.4, 2.4 Hz), 7.82 (1H, s). LC-MS (ESI) calcd for C26H26FN3O6S2 559.12, found 560.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](N)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].C(ON=O)CC(C)C.C[Si](C)(C)[Br:33].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:33])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)c1cnc(N)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a suspension of 6.8 g (0.022 mol) 5-amino-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid methyl ester in 150 ml dibromomethane was added 3.50 ml (3.052 g; 0.026 mol) isoamylnitrite. To the resulting suspension was added drop wise during 30 minutes a solution of 3.38 ml (3.38 g; 0.026 mol) trimethylbromosilane in 5 ml dibromomethane at 0° C. The mixture was stirred at 0° C. for 0.5 hours and 2 hours at room temperature. To the resulting turbid reaction mixture was added ca 150 ml of a 10% aqueous sodium bicarbonate solution with stirring. The phases were separated the organic phase was dried over magnesium sulfate, evaporated and purified by chromatography on silica gel with a gradient of 100% heptane to 10% ethyl acetate in heptane to yield 6.38 g of the title compound as off white crystalline solid. MS (ISP) (M+H+)=377.0 and 379.0.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(F)cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: COC(=O)c1cc(F)cc(N2CC[C@H](N)[C@H](OC)C2)c1

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-fluorobenzoate obtained in Example (175a) (78 mg, 0.19 mmol) and a 10% palladium-carbon catalyst (100 mg), to obtain the title compound as a yellow oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>O1CCOCC1>[C:13]([C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([N:2]([CH3:1])[C:27]([NH:26][C:20]3[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:25])=[O:28])[CH:4]=2)[CH:17]=[CH:16][CH:15]=1)#[N:14]
Reactant: CNc1cc(Nc2cccc(C#N)c2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2cccc(C#N)c2)ncn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(6-methylamino-pyrimidin-4-ylamino)-benzonitrile (450.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 1.5 h at 80° C. and then evaporated in vacuo. The residue is suspended in half-concentrated aqueous K2CO3 solution, filtered off, washed with H2O and acetone and dried in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]1[N:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A solution of methyl 6-((3,4-dichlorobenzyl)amino)nicotinate (0.88 g, 2.83 mmol) in THF (18.9 mL) was cooled to −78° C. and a 1M solution of DIBAL-H (14.14 mL, 14.14 mmol) in toluene was added. The mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 45-80% ethyl acetate in hexanes. The desired fractions were concentrated to give (6-(3,4-dichlorobenzylamino)pyridin-3-yl)methanol as a white solid (0.46 g, 57%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.91 (1H, d, J=1.76 Hz), 7.40-7.52 (3H, m), 7.26 (1H, dd, J=8.28, 2.01 Hz), 6.51-6.59 (1H, m), 4.50 (2H, s), 4.44 (2H, s). LCMS: R.T.=2.74; [M+H]+=282.99.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[F:7][CH2:8][C:9]1([C:14]#[N:15])CC(=C)[CH2:10]1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[F:7][CH2:8][C:9]1([C:14]#[N:15])[CH2:5][C:6](=[O:1])[CH2:10]1
Reactant: C=C1CC(C#N)(CF)C1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: N#CC1(CF)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (6 mL, 0.08 mol), 1-(fluoromethyl)-3-methylenecyclobutanecarbonitrile (0.256 g, 0.00204 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.919 g, 0.00430 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[CH:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([CH:19]([C:17]1[N:16]=[CH:15][N:14]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[OH:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 20 °C
Yield: 57.8 %

Procedure:
A solution of 0.22 mole of n-butyl magnesium bromide in 75 ml of tetrahydrofuran is slowly added, under an atmosphere of argon, to 67.6 g (0.2 mole) of 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde (obtained as described in 1.b. above) in 500 ml of tetrahydrofuran. The temperature of the mixture is maintained at about 20° C. by cooling on an ice-bath. When the addition is complete, stirring is maintained for 30 minutes at ambient temperature and then 11 g of ammonium chloride and 100 ml of water are successively added. The mixture is extracted with dichloromethane. The organic phases are dried over anhydrous sodium sulfate, then evaporated under reduced pressure. The residue is recrystallized from a 2:1 v/v ethyl acetate-diethyl ether mixture. 45.8 g of alpha-n-butyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained. Yield: 58% of theory; M.P.: 119°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-Hydroxybenzoic acid (1.1 g, 7.96 mmoL) and aniline (742 mg, 7.23 mmol) were dissolved in 20 mL of dry DMF. To the above solution EDCl (1.53 g, 7.23 mmol) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using 10% EtOAc in hexane to give 450 mg (29% yield) of 4-Hydroxy-N-phenyl-benzamide. MS (ES) m/z: 214.08 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:14])[C:11]=1[CH2:12][OH:13])[C:5]([O:7][CH3:8])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]=[C:24]=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:14])[C:11]=1[CH2:12][O:13][C:24]([NH:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])=[O:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(Br)c(CO)c(Br)c1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(COC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 3,5-dibromo-4-(hydroxymethyl)benzoate (11 g, 34 mmol, 1 eq) in CH2Cl2 (50 mL) was added 2,6-dichlorophenylisocyanate (7 g, 37.2 mmol, 1.1 eq) and 4-N,N-dimethylaminopyridine (few crystals). Stirred at rt. After 15 min, the flask was thick with precipitate. Added 50 L CH2Cl2 to facilitate stirring and let stir overnight. Removed the CH2Cl2 under reduced pressure. Triturated the residue with Et2O and collected the solids giving methyl 3,5-dibromo-4-[({[(2,6-dichlorophenyl)amino]carbonyl}oxy)methyl]benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Yield: 53.9 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (49 mg, 0.108 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (46 mg, 0.162 mmol) to afford the desired product (31 mg, 54%) as a yellow solid: 1H NMR (300 MHz, CD3OD+acetic acid-d4) δ 9.31 (s, 1H), 8.06-7.99 (m, 2H), 7.91 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.35-7.26 (m, 4H), 4.41 (s, 2H), 2.93-2.86 (m, 1H), 2.13-2.03 (m, 4H), 1.23-1.06 (m, 4H); ESI MS m/z 532 [C30H27Cl2N3O2H]+; HPLC 94.9% (AUC), tR=11.43 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:23])[O:17][C:16]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:15]=2[O:14]1>>[F:23][C:13]1([F:12])[O:17][C:16]2[CH:18]=[CH:19][C:20]([NH:22][C:2]3[N:7]=[C:6]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[O:17][C:13]([F:23])([F:12])[O:14][C:15]=5[CH:21]=4)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=3)=[CH:21][C:15]=2[O:14]1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OC(F)(F)O3)nc1Nc1ccc2c(c1)OC(F)(F)O2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 2,2-difluoro-5-amino-1,3-benzodioxole gave N2,N4-bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 38.15 min.; purity: 96%; MS (m/e): 467 (M+); 1H NMR (CDCl3): δ 10.76 (1H, s), 10.49 (1H, s), 9.20 (1H, s), 7.74 (2H, s), 7.56 (1H, d, J=11.4 Hz), 7.33 (2H, m), 7.20 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(c2ccccc2C=O)CC1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 1-methylpiperazine (139.5 mL, 1.26 moles), potassium carbonate (145 g, 1.05 moles), and 2-fluorobenzaldehyde (73.7 mL, 0.7 moles) in water (700 mL) was heated at reflux for 18 hours. The solution was cooled to room temperature, extracted with methylene chloride (2×700 mL), and the combined organic layers were washed with water (2×700 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed in vacuo to afford 140 g of a dark oil. 1H NMR (400 MHz, CDCl3) 7.79 (dd, J=1.2, 7.9 Hz, 1H), 7.52 (td, J=1.5, 7.5 Hz, 1H), 7.11 (m, 2H), 3.12 (t, J=4.8 Hz, 4H), 2.63 (brs, 4H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) 191.6, 155.8, 135.2, 130.0, 128.9, 122.8, 119.2, 55.3, 54.1, 46.3.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][C:42]1[C:46](B(O)O)=[C:45]([CH3:50])[O:44][N:43]=1>>[CH3:41][C:42]1[C:46]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)=[C:45]([CH3:50])[O:44][N:43]=1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1ccc(Cn2c(CC3(C(=O)O)CCCC3)nc3cc(OCc4ccc5ccccc5n4)ccc32)cc1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 3,5-dimethylisoxazole-4-boronic acid in Step A. MS (ESI): mass calcd. for C36H34N4O4, 586.26; m/z found, 587.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.84 (d, J=8.1, 1H), 7.78-7.75 (m, 1H), 7.74-7.70 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.35 (m, 1H), 7.23-7.19 (m, 3H), 7.12-7.10 (m, 1H), 7.10-7.05 (m, 2H), 5.43 (s, 2H), 5.38 (s, 2H), 3.11 (s, 2H), 2.36 (s, 3H), 2.35-2.27 (m, 2H), 2.23 (s, 3H), 1.74-1.67 (m, 2H), 1.60-1.47 (m, 4H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([CH2:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:13])([CH3:14])[C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)[CH3:16]
Reactant: CCc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-ethyl-3,3-dimethyl-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.45 g (91%) of (R)-1-(7-ethyl-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:27][CH:28]3[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)[C:12]3[N:13]([C:15]([C:18](=[O:26])[NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:27][CH:28]3[CH2:31][NH:30][CH2:29]3)[C:12]3[N:13]([C:15]([C:18]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:26])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Nc2cc(NC3CNC3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2A (4.0 mg, 0.008 mmol) in CH2Cl2 (1 mL) was treated with TFA (0.1 mL) and stirred at room temperature for five hours. The resulting solution was concentrated and the crude product was purified by reversed-phase preparative HPLC ((YMC ODS-A 5 um 20×100 mm, 10% to 90% MeOH/H2) containing 0.1% TFA, 30 minute gradient, 20 mL/min) to afford the title compound (2.0 mg, 61%). LC/MS, m/z 422.27 (M+1). HPLC Rt=1.405 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[CH:15]=[C:16]([C:18]3[O:23][C:22](=[O:24])[C:21]([CH3:25])=[C:20]([OH:26])[C:19]=3[CH3:27])[O:17][C:13]=2[CH:12]=1)([OH:10])=[O:9].[C:30](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:25][C:21]1[C:22](=[O:24])[O:23][C:18]([C:16]2[O:17][C:13]3[CH:12]=[C:11]([C:8]([O:10][CH3:30])=[O:9])[CH:29]=[CH:28][C:14]=3[CH:15]=2)=[C:19]([CH3:27])[C:20]=1[OH:26]
Reactant: Cc1c(-c2cc3ccc(C(=O)O)cc3o2)oc(=O)c(C)c1O
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(O)c3C)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyldiazomethane (2 M hexane solution, 85 μl) was added to a mixed solution of 6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (50 mg) in MeOH (5 ml) and toluene (1 ml), and the mixture was stirred at room temperature for 10 minutes. After adding acetic acid to the reaction solution for quenching of the excess trimethylsilyldiazomethane, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH =9/1) to obtain 3,5-dimethyl-4-hydroxy-6-(6-(methoxycarbonyl) benzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[C:14]([CH3:23])[CH:15]=2)(=[O:21])=[O:20])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1O
Reactant: CCOc1ncc(Br)cc1N
Product: CCOc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Yield: 100 %

Procedure:
5-Bromo-2-ethoxypyridin-3-amine (506 mg, 2.33 mmol) was treated with 4-hydroxy-3-methylbenzene-1-sulfonyl chloride (506 mg, 2.45 mmol, prepared as described at JP 47015818 B4 19720511) according to the method described in Preparation 15b to give 902 mg (100% yield) of the title compound as an oil. Purity 99%.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[C:2]1([CH:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccccc1

Procedure:
Grignard reaction of benzaldehyde (300.0 mg; 2.83 mmol) with phenylmagnesium bromide in anhydrous ether afforded 0.5 grams of diphenylmethanol.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+]>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a stirred, 0° C. solution of (S)-4-phenyloxazoldin-2-one (1.07 g, 6.54 mmol) in 15 mL of THF was added sodium hydride (0.32 g of a 60% oil dispersion, 8.0 mmol). When gas evolution had ceased (ca. 10 minutes), ethyl bromoacetate (0.87 mL, 7.8 mmol) was added. After 2 hours at 0° C., the mixture was treated with 50 mL of 2N aqueous NaOH, stirred rapidly for 1 hour at room temperature, and then partitioned between hexane (50 mL) and water (50 mL). The aqueous layer was separated, acidified with 6 M aqueous H2SO4, and extracted with dichloromethane (2×200 mL). The combined organic phases were dried (Na2SO4) and concentrated to a thick oil, which was dissolved in 4 mL of warm toluene, seeded, and allowed to crystallize overnight; filtration gave 1.33 g (92%) of (S)-4-phenyloxazolidin-2-one-3-ylacetic acid: mp 106°-108° C.; [α]D22 +173° (c=2.0, CHCl3); IR (CHCl3) 3500-2500 (v. br), 1760 (br), 1480, 1460, 1430, 1230 cm-1 ; 1H NMR δ11.2 (br s, 1, COOH), 7.47-7.25 (m, 5, ArH), 5.05 (t, 1, J=8.4 Hz, OCH2CH), 4.72 (t, 1, J=8.8 Hz, one of OCH2CH), 4.32 (d, 1, J=18.4 Hz, one of NCH2), 4.17 (t, 1, J=8.4 Hz, one of OCH2CH), 3.41 (d, 1, J=18.4 Hz, one of NCH2).