Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18](/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]([O:30][CH3:31])[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]3[CH2:7][CH:23]3[C:24]3[CH:25]=[C:26]([O:30][CH3:31])[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: COc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To trimethylsulfonium iodide (9.98 g, 2. eg.) in 60 mL of THF was added, at -10° C., 15 mL of n-BuLi (1.6M in hexane). The temperature was raised to room temperature for 2 hours. Then, at -10° C., the alkene (from Step 1) (7.037 g, 23.8 mmoles) in 30 mL of THF was added. After 30 minutes at -10° C., the reaction mixture was stirred overnight at room temperature. Hydrolysis with 25% aqueous NH4OAc, extractions with ethyl acetate and flash chromatography with toluene yielded the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=[O:27])[CH2:22]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55]C(Cl)=O)=[CH:52][CH:51]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](=[O:27])[CH2:55][O:54][C:53]3[CH:59]=[CH:60][C:50]([Cl:49])=[CH:51][CH:52]=3)[CH2:22]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N)nc3sc(CCc4ccc(F)cc4)nc23)C1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N[C@H]2CCN(C(=O)COc3ccc(Cl)cc3)C2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-tert-butoxycarbonyl-pyrrolidin-3-(S) -ylamino)-thiazolo[5,4-d]pyrimidine (70 mg, 0.15 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml). The reaction mixture was stirred at room temperature for 2 hours after which the solvents were removed in vacuo. The residue was dissolved in dichloromethane (3 ml) and diisopropylethylamine (1.5 mmol, 252 μL) and 4-chlorophenoxyacetyl chloride (0.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1.5% CH3OH in CH2Cl2), yielding the pure title compound (37 mg) which was characterized by its mass spectrum: MS m/z (%): 527 ([M+H]+, 100).
Reaction SMILES: [Mg].CCOCC.II.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=1.[CH:18](=[O:22])[CH:19]([CH3:21])[CH3:20]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1
Reactant: CC(C)C=O
Reactant: ClCc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Magnesium (5.02 g, 0.206 mol) was covered in dry ether (50 mL, 0.5 mol) under an atmosphere of nitrogen. Iodine (0.254 g, 0.001 mol) was added to the reaction, followed by approximately 1 mL of a solution of 1-chloro-4-(chloromethyl)-benzene (32.20 g, 0.200 mol) in ether (25.0 mL, 0.238 mol). An exotherm was noted and the mixture reached reflux. The slow addition of solution was continued over 90 minutes to maintain a gentle reflux. On completion of the addition, the reaction was heated for 30 minutes at 45° C. The reaction was then cooled to 0° C. Isobutyraldehyde (25.19 mL, 0.2774 mol) in Ether (20 mL, 0.2 mol) was then added slowly over 2 hours at 0° C. On completion of the addition the reaction was allowed to warm to room temperature and stir overnight. The reaction was then quenched with ice (200 g) and acidified with 2M HCl (100 mL). The organic phase was separated and the aqueous was extracted twice with more ether. The combined organic phase was evaporated and the residue was purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane to yield the product, 17.8 g (45%). 1H NMR (300 MHz, CDCl3, δ): 7.22 (m, 4H), 3.56 (m, 1H), 2.81 (dd, J=3.3 Hz, 13.7 Hz, 1H), 2.58 (dd, J=9.4 Hz, 13.7 Hz, 1H), 1.74 (dt, J=6.5 Hz, 12.9 Hz, 1H), 1.45 (s, 1H), 1.00 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [Na].[C:2]([O:13]CC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:11][CH2:10][O:9][C:7]([CH:6]1[C:2](=[O:13])[CH2:3][CH2:4][CH2:5]1)=[O:8]
Reactant: CCOC(=O)CCCCC(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCC1=O
Yield: 85.3 %

Procedure:
15.0 g (0.652 mmol) of sodium was placed in 150 mL toluene, heated to reflux, shaken, and made into sodium sand. 81.6 g (0.400 mol) of diethyl adipate was added in drops to the mixture in an outside bath at 105-110° C., and the resultant solution changed into a yellow sticky product. After refluxing for 8 h, the solution was cooled by ice bath, and 400 mL of 10% acetic acid solution was added in drops. The mixture was suction filtered and washed with a small amount of toluene. The filtrate was separated into layers. The upper layer was washed with 7% sodium carbonate (260 mL×2) followed by saturated brine (200 mL×2), and dried overnight with anhydrous magnesium sulfate. The solution was filtered, concentrated and distilled under reduced pressure to collect the fractions of bp: 142-150° C./2660 Pa, yielding 53.3 g of colorless liquid with a yield of 85.6%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[O:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][O:24][C:21]3[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 2-bromo-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)ethanone (1.03 g, 4.00 mmol), 4-nitrophenol (0.57 g, 4.00 mmol), and cesium carbonate (1.63 g, 5.00 mmol) in dry N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with cold water. The resultant solid was collected by filtration gave the title compound (1.19 g, 94%). The product was used in the next step without purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:29]12[N:36]([C:37]3[N:42]=[C:41](Cl)[N:40]=[C:39]([CH2:44][N:45]([CH3:47])[CH3:46])[CH:38]=3)[CH:33]([CH2:34][CH2:35]1)[CH2:32][O:31][CH2:30]2>COCCOC.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>[CH:33]12[N:36]([C:37]3[CH:38]=[C:39]([CH2:44][N:45]([CH3:47])[CH3:46])[N:40]=[C:41]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:13][CH:12]=4)[N:42]=3)[CH:29]([CH2:35][CH2:34]1)[CH2:30][O:31][CH2:32]2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
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: COCCOC
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A microwave vial was charged with a solution of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.496 mmol) in DME (3 ml). Sodium carbonate (2M in water, 0.530 ml, 1.061 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.021 mmol), and 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.100 g, 0.354 mmol) were added and the resulting solution was sparged with nitrogen for 5 minutes and then heated to 100° C. for 90 minutes via microwave. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated sodium chloride and concentrated under reduced pressure to provide a brown oil. The crude product was added to a HPLC column and was eluted with 5-100% acetonitrile in water (0.05% TFA buffer) to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea (0.073 g, 49%) as a light yellow solid. MS; 423.2, M+H.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[CH3:13][C:14]1[C:15]([O:17][C:18](=O)[C:19]=1[CH3:20])=[O:16]>N1C=CC=CC=1>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:15](=[O:16])[C:14]([CH3:13])=[C:19]([CH3:20])[C:18]2=[O:17])=[CH:7][C:6]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: c1ccncc1
Product: CC1=C(C)C(=O)N(c2ccc(Cl)c(S(N)(=O)=O)c2)C1=O
Reaction time: 0.33 h
Yield: 93 %

Procedure:
In 3 ml of pyridine, 1 mmol of 5-amino-2-chlorobenzenesulfonamide and 1.05 mmol of 2,3-dimethylmaleic anhydride were stirred at 90-100° C. for 9 hours. Pyridine was then distilled off from the reaction mixture, followed by the addition of 20 ml of ice water and 0.1 ml of 35% hydrochloric acid to the solid residue. After the mixture thus formed was stirred for 20 minutes, the resulting precipitate was collected by filtration and then dried in air. Yield: 93%. Its physicochemical properties are shown in Table 8.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2([CH2:23][C:24]([CH3:26])=[CH2:25])[OH:22].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][C:13]12[C:19]([CH3:20])([CH3:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2([CH2:23][C:24]1([CH3:26])[CH2:25][O:9]1)[OH:22]
Reactant: C=C(C)CC1(O)CC2CCC1(C)C2(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CC2(O)CC3CCC2(C)C3(C)C)CO1

Procedure:
38.0 g (0.22 mol) of m-chloroperbenzoic acid was added portionwise to a stirred and cooled (ice bath) suspension of 28.7 g (0.14 mol) of (1RS,2SR,4RS)-1,7,7-trimethyl-2-(2-methyl-2-propenyl)bicyclo[2.2.1]heptan-2-ol and 23.1 g (0.27 mol) of sodium bicarbonate in 500 ml of methylene chloride. The temperature was maintained below 20° C. The reaction mixture was stirred at room temperature for an additional 5 hours, filtered and washed with 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of brine. After drying with MgSO4 and evaporation of the solvent the crude epoxide (30.9 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[CH:53]=1>CN(C=O)C.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:54]2[CH:53]=[C:52]([CH3:51])[CH:57]=[CH:56][N:55]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)c1
Yield: 38.6 %

Procedure:
A solution containing the product from Example 23I (0.183 g, 0.259 mmol) in DMF (2.6 mL) was treated with LiCl (0.110 g, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.055 g, 0.078 mmol), and the product from Example 80A (0.495 g, 1.29 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in dichloromethane, to give the title compound (0.065 g, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a mixture of 1-(3-Chloro-phenyl)-5-(4′-methylsulfanyl-biphenyl-3-yl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (127.0 mg, 0.26 mmol) prepared in Example 24 in dichloromethane (5.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 69.0 mg, 0.31 mmol) at 0° C. The reaction mixture was stirred at room temperature 30 minutes, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5, 1/1) to give 61.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[CH3:40][S:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:38])=[O:39]
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (200 mg, 0.51 mmol) is coupled to aryl bromide 197 (127 mg, 0.51 mmol) using Method A. On filtration of the cooled reaction mixture through celite and removal of the solvents in vacuo, the crude residue obtained is used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@H:26]([CH3:27])[CH2:25][O:24][C:23]4=[O:28])=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:27][C@@H:26]1[CH2:25][O:24][C:23](=[O:28])[N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[C:4]([CH3:29])=[CH:3][C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:7][N:6]=3)[CH2:9][CH2:10]2)=[O:15])=[CH:17][CH:18]=1
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Reactant: OB(O)c1ccccc1
Product: Cc1cc(-c2ccccc2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 186 and using the obtained (R)-3-{4-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-methyloxazolidin-2-one (535 mg) and phenylboronic acid (183 mg), (R)-4-methyl-3-{4-[4-(3-methyl-5-phenylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one was obtained. The obtained compound was dissolved in ethyl acetate (10 mL), 4N hydrogen chloride/ethyl acetate (0.3 mL) was added, and the precipitate was collected by filtration to give the title compound (475 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[C:13](O)(=O)C.C=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH3:13])[C:6]=2[CH:12]=1
Reactant: Brc1ccc2c(c1)NCCCC2
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCCCc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (D50) (395 mg, 1.747 mmol) in 25 mL of MeOH and acetic acid (1 mL, 17.47 mmol) was added formaldehyde (37% aq solution) (0.780 mL, 10.48 mmol) and the reaction mixture stirred for 30 minutes followed by the addition of a solution of sodium cyanoborohydride (878 mg, 13.98 mmol) in MeOH (10 mL). The reaction mixture was stirred at RT for 1 hour, then basified by the slow addition of sodium hydrogen carbonate aqueous solution (ca. 50 mL). The aqueous layer was extracted with DCM (3×50 mL), the organic layers were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-5% ethyl acetate in cyclohexane to afford the title compound (357 mg). LCMS (A): m/z (M+H)+ 240/242, C11H14BrN requires 239/241 (acidic).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH:10](OCC1C=CC=CC=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[BH4-].[Na+]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[O:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CCNC(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCNCC(O)c2ccccc2OCc2ccccc2)cc1OC
Yield: 165.9 %

Procedure:
3 g of α-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone hydrochloride, 0.7 g of sodium borohydride and 30 ml of ethanol are treated in the same manner as described in Example 1-(b). 2.5 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzylalcohol hydrochloride are obtained. M.p. 115° - 117° C (recrystallized from a mixture of ethanol and ether).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].S(=O)(=O)(O)O>>[CH:1](=[C:19]([C@@H:17]([C@H:15]([C@@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18])[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1

Procedure:
A reactor was charged with 106 g (1 mole) of benzaldehyde, 270 g (1 mole) of a 70% aqueous solution of D-sorbitol and 20 g of 50% sulfuric acid, and they were reacted at 15° C. with stirring. Thirty minutes after the formation of fine crystals in the mixture within the reactor, the torque of the stirrer became about 3 times as high as that at the start of the reaction. At this time, the amount of monobenzylidene sorbitol formed was 42% of theory.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].O>N1C=CC=CC=1>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC(=O)Cl
Reactant: CC(CCO)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)OCCC(C)c1ccc(OCc2ccccc2)cc1
Yield: 95 %

Procedure:
2.56 (10 millimols) of (+)-3-methyl-3-(4-benzyloxyphenyl)propanol (XI-1) obtained in Preparation Example (starting material compound (V)) 1, was dissolved in 20 ml of pyridine and 1.38 g (13 millimols) of butyrylchloride was added at 30°-40° C. and reacted for 2 hours. The reaction mixture was poured into 200 ml of water and extracted with 200 ml of toluene and separated and then washed with, in the order, 1N aqueous solution of hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and water, and thereafter dried on anhydrous magnesium sulfate. After the solvent was distilled out under the reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to provide 3.1 g (yield: 95%) of (+)-4-benzyloxy-1-(1-methyl-3-butyryloxypropyl)benzene (VIII-9).
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)([O-:17])=[O:16]
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: O=[N+]([O-])O
Product: O=C1C(=O)N2CCCc3cc([N+](=O)[O-])cc1c32
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred fuming nitric acid (20 ml) at 0° C. was added 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (5 g) portionwise. The reaction mixture was stirred for additional one hour, poured into ice water and the resultant precipitate was collected by filtration. This precipitate was washed with water and dried to yield the title compound. The compound was recrystallized from ethanol-hexane to give 3.8 g (61%) as yellow needles, mp 198°-199° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:30]>CO>[NH2:30][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: N
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Solvent: CO
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (30 mg, 74 μmol) in methanol (1 mL) and ammonia (22 μL, approx. 7 N solution in methanol) is stirred at 65° C. for 4 h and at rt for 18 h. The solvent is removed in vacuo and the residue is purified by prep. HPLC to give 3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=0.87 min, [M+1]+=424.24.