Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[C:6]([CH:14]=[C:15]([N+:17]([O-])=O)[CH3:16])=[C:7]3[CH2:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].[ClH:33]>C(OCC)C>[ClH:33].[F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[C:6]([CH2:14][CH:15]([NH2:17])[CH3:16])=[C:7]3[CH2:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CC(=Cc1c2n(c3cc(F)c(F)cc13)CCC2)[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(N)Cc1c2n(c3cc(F)c(F)cc13)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
(RS)-1-(6,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine hydrochloride was prepared from 1-(6,7-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene according to the method described in Example 1 with the following modifications: the reaction mixture was heated under reflux for 4 h, cooled to 0° C. and poured into aqueous potassium sodium tartrate solution (150 mL) and diethyl ether (100 mL). The mixture was stirred for 30 min, filtered through celite® and the filtrate was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed (brine), dried (magnesium sulfate), concentrated in vacuo, treated with ethereal hydrogen chloride (1.0 M, 2 mL, 2 mmol) and concentrated in vacuo. The residue was recrystallised (ethyl acetate, 2-propanol) to give the title compound as a white solid (0.55 g, 63%): mp 264-266° C. Found: C, 58.67; H, 6.09; N, 9.65%. C14H16F2N2.HCl requires: C, 58.64; H, 5.98; N, 9.76%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]1=[O:18].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]1=[O:18])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1oc2ccccc2n1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c(=O)oc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulfonyl chloride (2.21 ml, 3.265 g, 28.5 mmol) was added to a stirred solution of 3-(2-hydroxyethyl)benzoxazolin-2-one (5 g, 27.933 mmol) (J. Heterocyclic Chemistry 1988, 25, 1601) and triethylamine (5.947 ml, 4.318 g, 42.75 mmol) in dichloromethane (60 ml) and stirred for three days at room temperature. The solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate, washed with hydrochloric acid (2M, 5×50 ml), sodium hydrogen carbonate (2×20 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:20]([CH2:23][Cl:24])([CH3:22])[CH3:21].CCOCC>O1CCCC1.CCCCCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([Si:20]([CH2:23][Cl:24])([CH3:22])[CH3:21])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 9.9 g (0.042 mol) of 4-bromobiphenyl in 50 ml of dry tetrahydrofuran was cooled to -78° under nitrogen and stirred while 26.5 ml (0.042 mol) of 1.6 molar n-butyllithium in hexane was added dropwise over 15 minutes. A thick slurry formed, and 35 ml of tetrahydrofuran was added to facilitate stirring. With continued cooling, 5.9 ml (6.7 g, 0.046 mol) of chlorochloromethyldimethylsilane was added over 10 minutes, giving a clear solution that was allowed to warm to room temperature. Addition of 300 ml of ether, filtration to remove precipitated lithium chloride, and evaporation of the filtrate left 13.2 g of semisolid. Redissolution in ether, filtration, and evaporation of the filtrate left 11.0 g (100% crude) of the title compound as a colorless solid, m.p. 30°-40°, suitable for further reaction. Trace impurities could be removed by sublimation at 30°/0.1 mm, leaving the title compound unsublimed in 83% recovery; m.p. 37°-40°; ir (Nujol®) 1585, 1240, 1110, 830, 810, 750, 690 cm-1, nmr (CDCl3) 0.4 (6H, s), 2.9 (2H, s), 7.3-7.7 (9H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:28])[CH2:16][C:15]2[NH:14][CH:13]=[C:12]([CH2:17][CH2:18][C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=O)[C:11]=2[C:10](=O)[CH2:9]1>O1CCCC1.[OH-].[Na+]>[CH3:7][C:8]1([CH3:28])[CH2:16][C:15]2[NH:14][CH:13]=[C:12]([CH2:17][CH2:18][CH2:19][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:11]=2[CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)c2c(CCC(=O)N3CCOCC3)c[nH]c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCc2c(CCCN3CCOCC3)c[nH]c2C1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 13.5 %

Procedure:
To a suspension of 1.1 g (30 mmol) of lithium aluminum hydride in 10 mL of tetrahydrofuran was added dropwise a solution of 1.8 g (43 mmol) of 6,6-dimethyl-3-(3-morpholin-4-yl-3-oxo-propyl)-1,5,6,7-tetrahydro-indol-4-one in 10 mL of tetrahydrofuran. The mixture was stirred at 80° C. for 2.5 hours and then cooled in an ice bath. Ice cubes were added to the reaction mixture slowly until no more gas was generated. A few drops of 2 N sodium hydroxide were added and the reaction mixture was stirred at room temperature for 30 minutes, extracted with ethyl acetate, and the extract dried over anhydrous sodium sulfate and concentrated to give 1.6 g of 6,6-dimethyl-3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole as a white solid which was used without further purification. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 9.75 (br s, 1H, NH), 6.24 (s, 1H), 3.54 (m, 4H, 2×CH2), 2.23–2.31 (m, 12H, 6×CH2), 1.58 (m, 2H, CH2), 1.40 (m, 2H, CH2), 0.92 (s, 6H, 2×CH3). MS m/z 276 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][S-:11].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:10][S:11][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:9])[CH:5]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: C[S-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CSc1cc(Cl)cc(Cl)c1

Procedure:
A 4-necked, 1-liter flask equipped with a stirrer, a thermometer and a condenser tube was charged with 181.5 g (1.00 mole) of 1,3,5-trichlorobenzene and 67.9 g (0.10 mole) of an aqueous solution of 50 wt % tetra-n-butylphosphonium bromide. 233.6 g (1.00 mole) of an aqueous solution of 30 wt % sodium thiomethoxide was added dropwise at 80° C. over a period of 6 hours. After addition, the mixture was reacted at the same temperature for 10 hours. After completion of reaction, 191.9 g of a crude 1-methylthio-3,5-dichlorobenzene was obtained by separation procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cnc1N
Yield: 95.8 %

Procedure:
A suspension of 5-fluoro-3-nitro-2-pyridinamine (561 mg, 3.573 mmol) in ethanol (100 ml) was treated with added 10% Pd/C (100 mg) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 5 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH (500 ml). The filtrate was evaporated to give the desired product as a grey solid (435 mg, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH2:14]([O:21][C:22]([C:24]1([C:27](=[O:53])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([NH:42][C:43](OC4C=CC=CC=4)=[O:44])[CH:37]=3)=[CH:31][C:30]=2[F:52])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1CCCC1=O>[CH2:14]([O:21][C:22]([C:24]1([C:27](=[O:53])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]3[CH2:41][CH2:40][NH:39][CH:38]([NH:42][C:43]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH2:9][CH2:10]4)=[O:44])[CH2:37]3)=[CH:31][C:30]=2[F:52])[CH2:25][CH2:26]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: CN1CCN(C2CCN(C(=O)NC3CC(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)CCN3)CC2)CC1
Temperature: 40 °C
Yield: 60.7 %

Procedure:
1-Methyl-4-(piperidin-4-yl)piperazine (1.46 g) was added to a mixture of 1-[2-fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (3.60 g) and N-methyl-2-pyrrolidone (25 ml), followed by stirring with heating at 40° C. for 1 hour and 51 minutes. The reaction mixture was partitioned after the addition of ethyl acetate (180 mL) and water (90 mL). The resultant organic layer was washed with water (36 ml, twice) and a 10% aqueous solution of sodium chloride (36 ml), dried over anhydrous magnesium sulfate (10 g), and filtered, and the filtrate was concentrated. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:isopropyl alcohol=9:1). The eluate was concentrated under reduced pressure, and the precipitate appeared after the addition of tert-butyl methyl ether (60 ml) and seed crystals obtained in (Method 1). The resultant precipitate was collected by filtration, washed with tert-butyl methyl ether (10 ml), and dried under reduced pressure at 40° C. for 2 hours to give the target title compound (2.57 g).
Reaction SMILES: [OH-].[Li+].CC1C(CC([O-])=[O:15])=CC(C)=C2C=1C=NN2.[CH3:18][C:19]1[C:27]([CH3:28])=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1CC([O-])=O.[Cl-].[NH4+]>CO>[CH3:18][C:19]1[C:27]([CH3:28])=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[OH:15]
Reactant: Cc1c(CC(=O)[O-])cc2cn[nH]c2c1C
Reactant: Cc1c(CC(=O)[O-])cc(C)c2[nH]ncc12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(O)cc2cn[nH]c2c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A 2N-aqueous lithium hydroxide solution (28.6 ml, 57.2 mmol) was added to a solution of a mixture of (4,7-dimethyl-1H-indazol-5-yl)acetate and (6,7-dimethyl-1H-indazol-5-yl)acetate (approximately 1:1, 5.30 g, 26.0 mmol) in methanol (30 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, whereby a mixture of 4,7-dimethyl-1H-indazol-5-ol and 6,7-dimethyl-1H-indazol-5-ol (4.31 g, 100%) was obtained. To this mixture were added tetrahydrofuran (200 ml) and N-chlorosuccinimide (1.74 g, 13.0 mmol), and the resulting mixture was stirred at 50° C. for 3 hours. The reaction solution was poured into water to terminate the reaction, and was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was washed three times with methanol to obtain 4-chloro-6,7-dimethyl-1H-indazol-5-ol (440 mg). On the other hand, the solvent of the filtrate was distilled off under reduced pressure and then the residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2:1) to obtain 4-chloro-6,7-dimethyl-1H-indazol-5-ol (980 mg, 1.42 g in total, 56%).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[O:11]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:19][CH:20]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Yield: 54.8 %

Procedure:
A mixture of 3,5-dichloroisonicotinonitrile (10.00 g, 57.8 mmol), 4-phenoxyphenylboronic acid (12.37 g, 57.8 mmol), palladium(II) acetate (0.389 g, 1.734 mmol), potassium phosphate (30.7 g, 145 mmol) and 1,1′-bis(di-t-butylphosphino)ferrocene (0.833 g, 1.734 mmol) was pumped and backfilled with nitrogen 3 times. Dioxane (200 mL) was added. The reaction vial was again pumped and backfilled with nitrogen 3 times, sealed and heated to gentle reflux for 20 h. The dioxane solvent was evaporated in vacuo. The residue was diluted with water (150 mL) and brine (150 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2), gave 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile as tan liquid (9.71 g, 55% yield). 1H NMR (500 CDCl3) δ ppm 8.74 (1H, s), 8.70 (1H, s), 7.50-7.59 (2H, m), 7.35-7.46 (2H, m), 7.20 (1H, t, J=7.42 Hz), 7.06-7.16 (4H, m); MS (ES+) m/z: 307 (M+H); LC retention time: 4.298 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25](O)=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:52]([CH2:54][CH2:55][NH2:56])#[N:53]>CN(C=O)C.O.C(Cl)CCl>[C:52]([CH2:54][CH2:55][NH:56][C:25](=[O:26])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:13][CH:14]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:32])#[N:53]
Reactant: N#CCCN
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)NCCC#N)cc1
Temperature: 25 °C

Procedure:
A solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (0.17 g), HOBT (0.0.08 g), DIEA (0.19 mL) and 2-cyanoethylamine (0.03 mL) in DMF (5 mL) was stirred at room temperature under N2. EDC (0.14 g) was added after 10 min and the mixture was stirred at room temperature under N2. The mixture was diluted with water and extracted with EtOAc. The extract was washed successively with water, 1 N HCl, satd. NaHCO3 and brine, dried and evaporated to give 0.17 g of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine N-(2-cyanoethyl) amide. ESMS : m/z 526 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cccc(Cl)c3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.053 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.135 g, 0.28 mmol) and methylamine (0.087 g, 2.8 mmol). mp 178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:27]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(F)c(C)cc1[N+](=O)[O-]
Yield: 60.8 %

Procedure:
By using 3.00 g of 2,4-difluoro-5-nitrotoluene, 8.77 g of triethylamine, 40 ml of DMF, 40 ml of THF and 2.42 g of glycine ethyl ester hydrochloride, 2.70 g (61%) of N-(5-fluoro-4-methyl-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[BH4-].[Na+]>C(O)C.O1CCCC1>[C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=Cc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
1-(β-D-Glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene (84 mg) obtained in Example 249 was dissolved in a mixture of ethanol (2 ml)-tetrahydrofuran (2 ml) and added thereto was sodium borohydride (7 mg). The mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N hydrochloric acid aqueous solution (3 drops) at 0° C., and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethylphenyl)-2-thienylmethyl)benzene (82 mg) as colorless foam. APCI-Mass m/Z 494/496 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[C:28]([OH:30])=[O:29])=[CH:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2.O=O.CC(C)([O-:38])C.[K+].C(OC)(=O)C>CS(C)=O.C(O)(C)(C)C.O.C(O)(=O)C>[OH:38][CH:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:31][CH3:32])[CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]1[C:28]([OH:30])=[O:29]
Reactant: COc1ccc2ncc(Cl)c(CCCC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2ncc(Cl)c(C(O)CCC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
100 cm3 of tert-butanol are added to 5.55 g of (3RS,4RS)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid in 450 cm3 of dimethyl sulfoxide, and the reaction mixture is then saturated with oxygen for 30 minutes. A solution of 3.36 g of potassium tert-butoxide in 40 cm3 of tert-butanol is then added over 40 minutes. The mixture is allowed to stir for 2 hours while maintaining the oxygen flow rate, and then the medium is cooled to around 0° C. in order to add 1.8 cm3 of acetic acid in 30 cm3 of distilled water. 1000 cm3 of distilled water and 1000 cm3 of methyl acetate are then poured onto the reaction medium. The organic phase is then washed with 8 times 250 cm3 of distilled water then with 2 times 100 cm3 of sodium chloride. The pooled aqueous phases are re-extracted with 500 cm3 of ethyl acetate. The two organic phases are pooled and then dried over magnesium sulfate for 1 hour. Filtration is carried out through a sintered glass funnel, followed by concentration under reduced pressure (2 kPa; 45° C.). The residue is taken up in 250 cm3 of methyl acetate and 100 cm3 of distilled water. The organic phase is washed with 3 times 50 cm3 of distilled water and then with 50 cm3 of a saturated aqueous sodium chloride solution. Drying is carried out over magnesium sulfate for 1 hour, filtration is carried out through a sintered glass funnel, and then evaporation is carried out under reduced pressure (2 kPa; 45° C.). 5.08 g of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxy-carbonyl)piperidine-3-carboxylic acid are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[CH3:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(CNC2=Nc3ccc(NC(=O)CCl)cc3CO2)o1
Solvent: CC#N
Product: Cc1ccc(CNC2=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO2)o1
Yield: 71.3 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(5-methyl-furan-2-ylmethyl)-amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (100 mg, 0.300 mmol) and 1-methylpiperazine (0.333 ml 2.996 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white foam (85 mg, 71%), MS (ISP) m/e=398.2 [(M+H)+].
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:54]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:54]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Nc1ccc(CCO)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(CCO)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminophenethyl alcohol as the aniline component. (43%, MS=627.3 (M+H))
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:26]=C)[CH:3]=1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:4]1[CH:3]=[C:2]([CH3:1])[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:30]
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3ccnc(C)c3)nc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-vinylbenzoate (0.11 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.33 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.11 g) as a crude product. This compound was used in the next step without an additional purification.