Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1cccc2N1CCOCC1
Product: CC1c2cccc(N3CCOCC3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cn3)CC2)c(C)c1
Yield: 22.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 150 and (R)-4-methyloxazolidin-2-one (111 mg) described in Preparation Example 25, the title compound (88 mg) was obtained.
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+].O>O1CCCC1>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A 1M-borane/tetrahydrofuran solution (4.36 ml, 4.36 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in tetrahydrofuran (20 ml) at 0° C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After another 6 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (715 mg, 76%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:25]=[C:24]([C:26](=O)[NH2:27])[CH:23]=[CH:22][C:10]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=O)[NH2:7]>O>[C:6]([C:9]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:10]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])#[N:7]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(N)=O)cc2C(N)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2C#N)cc1
Temperature: 50 °C
Yield: 60 %

Procedure:
Phosphorus oxychloride (5.00 g) was added to 2′,4′-dicarbamoyl-p-toluenesulfonanilide (0.30 g (0.90 mmol), and the mixture was heated at 50° C. for 4 hours with stirring. After cooling, addition of water, and stirring brought about precipitation of an insoluble solid. These crystals were filtered, washed with water and recrystallized from ethyl acetate-hexane to give 0.16 g (60%) of 2′,4′-dicyano-p-toluenesulfonanilide as pale brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1>CO.[Pt]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a suspension of N-(4-bromophenyl)-2-nitro-5-chlorobenzamide (0.50 g, 1.4 mmol) in methanol (20 mL) was added 5% platinum on carbon (Degussa type, 50% water, 0.20 g), and the mixture stirred under hydrogen (balloon). After 0.5 hours, the mixture was filtered and concentrated of all volatiles in vacuo to afford 0.45 g (99% yield) of N-(4-bromophenyl)-2-amino-5-chlorobenzamide as a white solid; NMR (DMSO-d6) 10.2 (s, 1), 7.5-7.7 (m, 5), 7.2 (dd, 1), 6.8 (d, 1) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([N:19]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH3:20])[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+].CS(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([N:19]([CH3:20])[CH:14]2[CH2:13][CH:12]3[N:11]([C:9]4[C:10]5[C:2]([C:32]6[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=6)=[CH:3][S:4][C:5]=5[N:6]=[CH:7][N:8]=4)[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:24][CH2:23][CH2:22]1
Reactant: COc1ncccc1B(O)O
Reactant: CN(C1CCC1)C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1csc2ncnc(N3C4CCC3CC(N(C)C3CCC3)C4)c12
Temperature: 85 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-N-methyl-8-azabicyclo[3.2.1]octan-3-amine (82.5 mg, 0.20 mmol) in dimethoxyethane (4 mL) and 2 M sodium carbonate solution (1 mL) was treated with (2-methoxy-3-pyridyl)boronic acid (134 mg, 0.75 mmol) and palladium (II) acetate (12 mg, 0.053 mmol), triphenylphosphine (12 mg) and the reaction was stirred in a microwave at 85° C. over 1 h. The reaction was then diluted with ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give a gum. The gum was dissolved in DMSO/water 1:1 (2.5 mL) and purified by reverse phase HPLC. The main peak was collected and concentrated in vacuum to give N-cyclobutyl-8-[5-(2-methoxy-3-pyridyl)thieno[2,3-d]pyrimidin-4-yl]-N-methyl-8-azabicyclo[3.2.1]octan-3-amine as a gum (32 mg, 0.073 mmol, 36%). LCMS RT=4.76 min. M+1=436. 1H NMR (CDCl3) δ: 1.1 (2H, t, J=12 Hz), 1.3-1.9 (1H, m), 1.9 (3H, s), 2.2 (1H, br m), 2.9 (1H, br m), 3.9 (3H, s), 4.3 (2H, br s), 7.0 (1H, q, J=6 Hz, J′=4 Hz), 7.25 (1H, s), 7.55 (1H, d, J=6 Hz), 8.2 (1H, d, J=4 Hz), 8.5 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C@@H:9]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:10][C@:11]([CH3:24])([CH2:21][CH:22]=[CH2:23])[C:12]([NH:14][C@@H:15]([CH:18]2[CH2:20][CH2:19]2)[CH2:16][OH:17])=[O:13])=[CH:4][C:3]=1[F:33].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl.O.ClCCCl>[CH2:21]([C@@:11]1([CH3:24])[CH2:10][C@H:9]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:33])[CH:4]=2)[N:14]([C@@H:15]([CH:18]2[CH2:20][CH2:19]2)[CH2:16][OH:17])[C:12]1=[O:13])[CH:22]=[CH2:23]
Reactant: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)C(O)c1ccc(Cl)c(F)c1)C(=O)N[C@H](CO)C1CC1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (2S)-2-((2R)-3-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide (40.2 g, 81 mmol, Example 4, Step F) in dichloromethane (80 mL) was added p-toluenesulfonic anhydride (66.3 g, 203 mmol) in dichloromethane (220 mL) at 0° C., and the reaction mixture was stirred for 10 minutes at same the temperature. 2,6-Lutidine (43.6 mL, 374 mmol, Aldrich, St. Louis, Mo.) was added dropwise via addition funnel at 0° C. The reaction mixture was slowly warmed to room temperature, and then it was stirred at reflux. After 24 hours, sodium bicarbonate (68.3 g, 814 mmol) in water (600 mL) and 1,2-dichloroethane (300 mL) were added in succession. The reaction mixture was heated at reflux for an hour and then cooled to room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with 1 N hydrochloric acid, water, and brine, then concentrated under reduced pressure. The residue was purified by flash chromatography (1.5 kg SiO2 column, gradient elution of 10% to 50% ethyl acetate in hexanes) to provide the title compound as a white solid.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([NH2:44])[C:35]=1[NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:29][C:30]1[C:35]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)=[C:34]([NH:44][C:4](=[O:6])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3])[CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(Br)c1Nc1cncc(F)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Br)c1Nc1cncc(F)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (6.36 g, 33.6 mmol) and N-methylmorpholine (3.88 mL, 35.3 mmol) in DCM (84 mL) was added isobutyl chloroformate (4.40 mL, 33.6 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 6-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine (4.7437 g, 16.81 mmol) in DCM (84 mL). The resulting mixture was allowed to warm to rt with stirring. After 20 h, satd. NH4Cl (100 mL) was added to the mixture. The cloudy organic layer was separated. The aqueous mixture was extracted with DCM (1×100 mL) and the organic extracts concentrated in vacuo to provide a crude product. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate as orange solid: LC-MS (ESI) m/z 453.0 [M+H (79Br)]+ and 455.0 [M+H (81Br)]+.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[SH:9][CH2:10][CH:11](O)[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:4][C:3]1[O:5][CH:11]([CH3:12])[CH2:10][S:9][C:2]=1[CH2:6][CH2:7][Cl:8]
Reactant: CC(O)CS
Reactant: CC(=O)C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=C(CCCl)SCC(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 0.1 mole (15.4 g.) 3,5-dichloro-2-pentanone, and 0.1 mole (9.2 g.) 1-mercapto-2-propanol was stirred in 100 ml toluene; 0.1 mole (10.4 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and reluxed with 0.5 g. PTSA, using a Dean-Stark trap to remove water for about 7 hours. The PTSA solution was washed with sodium bicarbonate, dried over magnesium sulfate and the solvent was removed. The product was distilled; bp 80°-82°/0.1 mm. Yield 47%.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=2)[CH:16]=1.C(N(CC)CC)C.C(O)(C)C>C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:23]=2)[CH:16]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl piperazine-1-carboxylate (24.0 mg, 0.125 mmol) was added to a mixture of 4-chloro-2-(2-chloropyrimidin-4-yl)phenol (Preparation 874, 30.1 mg, 0.125 mmol), and triethylamine (61.2 uL, 0.437 mmol) in isopropyl alcohol (0.2 mL, 3 mmol). The reaction mixture was stirred at ambient temperature. After 18 hours, LC/MS analysis indicated the reaction was not complete. The reaction mixture was heated 30 minutes at 70° C. then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate, filtered, and concentrated to give the product as a light brown paste (50 mg, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[NH3:26]>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Methyl 2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate (130 mg, 0.24 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 110 mg 2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 88%. 1HNMR (400 MHz, DMSO-d6): δ7.52-7.54 (t, J=6.0 Hz, 1H), 7.56-7.59 (m, 1H), 7.77-7.80 (t, J=6.0 Hz, 1H), 7.86-7.88 (dd, J=6.4 Hz, 0.8 Hz, 1H), 7.92 (brs, 1H), 7.98 (brs, 1H), 8.00-8.03 (m, 2H), 8.22-8.24 (m, 1H), 8.36-8.38 (d, J=6.4 Hz, 1H), 8.61 (s, 1H), 8.65-8.67 (m, 1H), 9.03-9.04 (d, J=1.6 Hz, 1H). LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:34])[CH:11]([NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH2:12][CH3:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:11]([NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH2:12][CH3:13])=[O:34]
Reactant: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1nc2ccccc2o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (237.6 mg, 0.48 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 76 mg of N-[1-(benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; H1 NMR(DMSO-d): 8.49(1H, d, J=5.2 Hz, NH), 7.96(11H, d, J=7.6Hz), 7.86(111, d, J=8.4), 7.6(1H, m), 7.5(1H, m), 5.14–5.04(1H, m), 3.6–3.25(8H, m), 2.9–2.75(1H, m), 2.5–2.4(1H, m), 2.25–2.15(1H, m), 2–1.8(1H, m), 1.8–1.7(2H, m), 1.7–1.6(1H, m), 1.6–1.4(5H, m), 1.35–1.2(1H, m), 1.21–1(4H, m), 0.96(3H, t); MS: 468.6(M−1), 470.5(M+1), 492.3(M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Br:13]Br>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Br:13])=[CH:11][NH:10][N:9]=1
Reactant: Clc1ccccc1-c1cc[nH]n1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccccc1-c1n[nH]cc1Br
Temperature: 25 °C
Yield: 65.3 %

Procedure:
3.5 g of 3-(2-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at room temperature and with stirring, in 20 ml of acetic acid. A solution of 3.76 g (0.0235 mol) of bromine in 20 ml of acetic acid is then run dropwise into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid and the excess bromine are driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with an aqueous bicarbonate solution, then with water and then dried over MgSO4 before being concentrated to dryness. The residue is recrystallised from pentane. 3.3 g (0.0128 mol) of 3-(2'-chlorophenyl)-4-bromo-1H-pyrazole are obtained, which melts at 80° C. (yield 65%) (compound 94)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>CN1CCCC1=O.[Cu].[Cu]I>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: Brc1ccccn1
Reactant: Oc1ccc(Br)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Brc1ccc(Oc2ccccn2)cc1
Yield: 76 %

Procedure:
A solution of copper powder (6.4 mg, 0.1 mmol, 0.1 equiv), copper (I) iodide (19 mg, 0.1 mmol, 0.1 equiv), potassium carbonate (484 mg, 3.5 mmol, 3.5 equiv), 4-bromophenol (190 mg, 1.1 mmol, 1.1 equiv), and 2-bromopyridine (158 mg, 1.0 mmol, 1.0 equiv) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated to 140° C. for 5 days. A solution of 1 M sodium hydroxide (15 mL) was added, and the mixture was extracted with ethyl acetate (1×30 mL). The organic phase was washed with 1 M sodium hydroxide (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (30% ethyl acetate in heptane) to provide a colorless oil (190 mg, 76%). MS (LCMS) m/z 250.4 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[S:41][CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[S:41][CH:42]=[CH:43][N:44]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccs4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccs4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(thiazol-2-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (57.6 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated purified by silica gel column chromatography (hexane:ethyl acetate=1:3→ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(thiazol-2-ylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (110 mg) (Compound 317) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[C:22]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCC(=O)OC)c2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 83 %

Procedure:
Using the procedure of example 11 and starting with 0.412 g (2.0 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 1.0 g (2.1 mmol) of 6-[6-[(methylsulfonyl)oxy]hexyl]-2-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester, 6-(5-methoxy-5-oxopentyloxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester was obtained in 83% yield (0.97 g) as a colorless oil. This diester (1.7 mmol) was saponified with 5 mL of 3N aqueous lithium hydroxide in 40 mL of tetrahydrofuran, at room temperature, for 20 hr. Work-up as in example 4 gave an oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.76 g (81%) of pure 2-(4-carboxybutoxy)-6-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7 -yl)oxy]hexyl]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate (2:1) gave 0.64 g (68%) of a colorless solid, mp 103°-104° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:9])[CH3:8])[CH:2]=1.O=C(CCC)OCC(OC(=O)CCC)COC(=O)CCC>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([OH:9])[CH3:8])[CH:2]=1
Reactant: CC(O)c1cccnc1
Agent: CCCC(=O)OCC(COC(=O)CCC)OC(=O)CCC
Product: C[C@H](O)c1cccnc1
Yield: 33.7 %

Procedure:
1-(3-Pyridyl)ethanol (8.9 g), tributyrin (24.0 g) and an enzyme (Lipase CES made by Amano Seiyaku K. K.) (3.6 g) were agitated at 37° C. for 190 hours, followed by filtering off the enzyme and subjecting the filtrate to silica gel column chromatography using toluene as solvent to obtain (S)-1-(3-pyridyl)ethanol (3.0 g). According to a high-speed liquid chromatography using an optical resolution column (CHIRAL CEL OB, trademark of product made by Daicel Co., Ltd.), its optical purity was 80% ee or higher.