Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C([Li])CCC.CCCCCC.CN([CH:27]=[O:28])C.[NH4+].[Cl-]>O1CCCC1.C(OCC)C.C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH:27]=[O:28])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2cccc(C=O)c2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 129.8 %

Procedure:
8-Bromo-2-methylquinoline (0.0675 mol) was added portionwise at −70° C. under N2 flow to a mixture of a solution of butyllithium in hexane (1.6M) (0.135 mol) in tetrahydrofuran (300 ml) and diethyl ether (300 ml). The mixture was stirred for 30 minutes. A solution of DMF (0.405 mol) in tetrahydrofuran (100 ml) was added quickly. The mixture was cooled to −70° C. and stirred for 15 minutes. Ethanol (70 ml) and a NH4Cl solution 10% were added. The mixture was brought to room temperature and stirred for 15 minutes. NH4Cl was added. The mixture was extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The product was used without further purification, yielding 15 g (>100%) of 2-methyl-8-quinolinecarboxaldehyde (interm. 12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][O:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][O:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=COCCC2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3,4-dihydro-2H-pyran (350 mg, 1.80 mmol) in ethyl acetate (8 mL) was added platinum oxide (41 mg, 0.18 mmol) and the reaction was charged with a hydrogen balloon and stirred at room temperature for 6 hours. The reaction was filtered, and the filtrate was evaporated to give crude title compound (340 mg, 96.3%) as white solid.
Reaction SMILES: C(O[C:6](=[O:18])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O)(C)(C)C.Cl.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:8]2[N:22]3[CH2:23][CH2:24][CH2:25][N:21]3[C:6](=[O:18])[CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: C1CNNC1
Reactant: CSc1nccc(C(=O)CC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid tert-butyl ester, 19, (6.8 g, 25.4 mmol), pyrazolidine-bishydrochloride (5.5 g, 38.1 mmol) and 4-angstrom molecular sieves (8.5 g) in toluene is added triethylamine (10.6 mL, 76.1 mmol). The reaction mixture is stirred for 4 hours at reflux. The solution is filtered through celite and washed with ether. The resulting yellow solid is purified over silica (10% MeOH/chloroform) to afford 5 g of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 6.08 (s, 1H), 4.26 (t, J=7.5 Hz, 2H), 3.80 (t, J=7.8 Hz, 2H), 2.62 (dddd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H), 2.60 (s, 3H); ESI+ MS: m/z (rel intensity) 249.1 (70, M++H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27])[CH:2]=C.[O:29]=[O+][O-].O=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[O:29])=[C:5]([N+:26]([O-:28])=[O:27])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reaction time: 24 h

Procedure:
A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid (2R)-8-allyl-7-nitro-2,3-dihydro-benzo (1,4)dioxin-2-ylmethyl ester in 400 mL of methylene chloride was cooled in a dry ice/isopropanol bath and saturated with ozone. It was then purged with oxygen and 2.6 g (20 mmole) of diisopropylethylamine added. The mixture was allowed to come to room temperature and stirred under nitrogen for 24 hours. It was then washed with 300 mL portions of 2 N HCl (aq), water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 3.8 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 116-120° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10](=[O:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:28])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of zinc chloride (14.8 g, 108.6 mmol) in diethyl ether (150 ml) was added sodium borohydride (8.22 g, 217 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (20 g, 54.3 mmol) in diethyl ether (50 ml), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction-solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give ethyl (2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (19.4 g, 96%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13].[OH-].[Na+].C(Cl)(Cl)Cl>C1COCC1>[O:8]=[C:1]([NH:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCC(=O)N[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-heptanoyl chloride (440 mL, 2.83 mmol) in THF (250 mL) is added dropwise, over a period of 30 min, to a cold (-5° to 0° C.), vigorously stirred mixture of D-allo-Thr (300 mg, 2.51 mmol) and 2N aq. NaOH (3.5 mL, 7.0 meq) in THF (4.0 mL). The resulting mixture is stirred for 2 h at the same temperature and overnight at room temperature. The volatiles are removed and the residue is diluted with water and acidified, using conc. HCl. The mixture is extracted with EtOAc and the combined organic solution is washed with brine, dried, filtered, and concentrated to provide crude 2c-1 (420 mg, containing 10% excess heptanoyl reagent) which solidifies upon standing. NMR δ 1.28 (d, J=6.5, 3 H), 4.20 (m, 1 H), 4.61 (dd, J=3.4, 6.6, 1 H), 6.56 (br d, J=6.9, 1 H); [α]D26 -38±2 (CHCl3).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH:30]([CH:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([CH3:42])(O)[CH3:40])[CH2:34][CH2:33]4)[CH2:29][C:28]=3[CH:43]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C1(C)C=CC=CC=1.ClCCl.CO>[F:11][C:39]([CH3:42])([CH3:40])[CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([CH:30]2[CH2:29][C:28]3[CH:43]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:19][CH:20]=4)[CH:25]=[CH:26][C:27]=3[O:31]2)[CH2:33][CH2:34]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(O)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(F)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of [bis(2-methoxyethyl)amino]sulfur trifluoride in toluene (50%; 162 μL) is added to an ice-cooled solution of 1-{4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol (100 mg) in dichloromethane (2 mL) and the resulting mixture is stirred for 16 h. The reaction mixture is diluted with methanol and concentrated in vacuo. The residue is purified by HPLC to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=C)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.C(O)CCC.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:32])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCO
Product: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reaction time: 1.5 h

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)isoxazole (Preparation 56E, 0.350 g, 0.825 mmol) in THF (7.5 ml) at room temperature, was added a solution of osmium tetroxide, (2.5% in butanol, 1.7 ml, 0.017 mmol) followed by sodium periodate (0.265 g, 1.238 mmol) as a solution in 7.5 ml of water. After stirring for 90 min it was quenched with a saturated solution of sodium bisulfate. The dark colored suspension was filtered through Celite. The filter cake was washed with EtOAc. The combined EtOAc layers were washed with water, dried over anhydrous MgSO4, concentrated, and chromatographed to yield the 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde as an orange colored solid. The product had an LC ret. time=3.136 min. (condition: Start % B=50, Final % B=100, Gradient Time=4 min, Flow Rate=4 ml/min, Wavelength=220, Solvent Pair=MeOH−H2O−TFA; Solvent A=10% MeOH−90% H2O−0.1% TFA; Solvent B=90% MeOH−10% H2O−0.1% TFA; Column 1=1: Waters Sunfire C18 4.6×50 mm (4 min. grad)); LC/MS M+1=427.03.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:13](O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1.CCOC(C)=O>[O:9]1[CH2:10][CH2:13][O:8][CH:7]1[C:6]1[CH:11]=[CH:12][C:3]([CH2:1][OH:2])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: OCCO
Agent: COCCO[Al+]OCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccc(C2OCCO2)cc1
Temperature: 22 °C

Procedure:
Methyl 4-formylbenzoate (4.92 g, 30.0 mmol) was dissolved in dry toluene (50.0 mL), successively treated with ethylene glycol (1.84 mL, 33.0 mmol) and p-TsOH.H2O (57.1 mg, 0.30 mmol), then heated to reflux under Dean-Stark conditions; acetal formation was complete within 1 h. The solution was then cooled to 22° C. and treated with sodium bis(2-methoxyethoxy)aluminum hydride (45.0 mmol; 12.7 mL of a 70.3 wt. % solution in toluene) at a rate of 0.5 mL/min using a syringe pump. CAUTION: vigorous gas evolution! Upon completion of the addition, the resulting solution was further cooled to 0° C., carefully treated with a saturated aqueous solution of K,Na-tartrate (100 ml), then vigorously stirred 1 h; steady formation of a clear solution was observed. The resulting biphase was then diluted with EtOAc (50 mL), with transfer to a conical funnel, and the layers separated. The aqueous layer was then washed with EtOAc (3×50 mL) and the combined EtOAc and toluene solutions dried over MgSO4, filtered and concentrated in vacuo to a colorless oil. The crude product was then purified by chromatography on silica (50×135 mm) using 1:1 pentane/EtOAc. The main product peak eluting 425-725 mL was collected, pooled and concentrated in vacuo to a colorless oil, which solidified in the freezer (4.50 g, 83.2% over two steps).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:37]=[N-:38]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3-c3ccccc3)c2O1
Yield: 88.9 %

Procedure:
Treatment of ((2R)-8-(biphenyl-2-yl)-6-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (1.30 g, 2.66 mmol) with sodium azide (1.04 g, 15.96 mmol) in DMSO (30 mL) according to the procedure described for Example 69, Step 9 provided 0.85 g (89%) of (2R)-2-(azidomethyl)-8-(biphenyl-2-yl)-6-fluorochroman as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[C:13]3([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:14][N:15]4[CH:21]=[CH:20][CH:19]=[C:16]4[C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)=[O:8])=[CH:5][O:4][N:3]=1.[OH:28]O.O>C(Cl)Cl.C[Re](=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]([N:9]2[C:13]3([C:22]4[CH:23]=[N+:24]([O-:28])[CH:25]=[CH:26][CH:27]=4)[CH2:14][N:15]4[CH:21]=[CH:20][CH:19]=[C:16]4[C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)=[O:8])=[CH:5][O:4][N:3]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1cccnc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Solvent: O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (15 mg, 0.041 mmol) in CH2Cl2 (0.5 mL) was added methyltrioxorhenium (VII) (1 mg, 0.004 mmol) followed by hydrogen peroxide (30% aqueous solution, 70 μL, 0.62 mmol). The resulting solution was stirred vigorously at room temperature. After 4.5 hours the reaction was complete (monitored by LCMS). Water (2 mL) was then added and the mixture extracted with CH2Cl2 (3×1 mL). The extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oil that was purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 0 to 10% methanol in CH2Cl2). The compound 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(1-oxidopyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (78) was isolated as a colourless oil (2 mg, yield 12%).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C:19](=[O:21])[CH:18]=[CH:17]1.O1CCC[CH2:26]1.C[Li]>CCOCC>[CH3:24][Si:2]([CH3:23])([CH3:1])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C@@:19]([CH3:26])([OH:21])[CH:18]=[CH:17]1
Reactant: C[C@H](C[C@@H]1C=CC(=O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Product: C[C@H](C[C@@H]1C=C[C@](C)(O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 84 %

Procedure:
A 1.76 g amount of the compound (1-10), (4S)-4-{(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-2-cyclopenten-1-one was placed into a 300 ml eggplant-shaped flask. A 150 ml amount of tetrahydrofuran was added and the solution stirred and cooled to -78° C., and then, 6.5 ml of an ether solution of methyllithium (1.16 mol/liter) was added, followed by stirring for 15 minutes. A 50 ml amount of saturated saline was added, the excess methyllithium was broken down, then 100 ml of ether was added for separation. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (Merck gel: 300 g, hexane/ethyl acetate=15/1 to 9/1) to obtain the desired product (1-11), (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 1.55 g (yield 84%) and the desired product (1-12), (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol, in an amount of 0.27 g (yield 14%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27](F)=[CH:26][C:25]([NH:29][C:30]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)=O)=[C:24]([N+:38]([O-])=O)[CH:23]=1)(=[O:16])[CH3:15]>>[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[CH:6][CH:7]=2)=[CH:26][C:25]2[N:29]=[C:30]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[NH:38][C:24]=2[CH:23]=1)(=[O:16])[CH3:15]
Reactant: O=C1OCCN1c1ccc(O)cc1
Reactant: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccc(N2CCOC2=O)cc1

Procedure:
The entitled compound was obtained as a yellow oily substance in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using 3-(4-hydroxyphenyl)-1,3-oxazolidin-2-one and N-(4-(1-acetylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazin-2-carboxamide enantiomer B obtained in Example 569 (step 5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:11])=[O:10])=[C:4](Br)[CH:3]=1.[F:13][C:14]1([F:26])[O:18][C:17]2[CH:19]=[CH:20][C:21](B(O)O)=[CH:22][C:16]=2[O:15]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:26][C:14]1([F:13])[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[NH:8][C:9](=[O:10])[CH3:11])=[CH:19][C:17]=2[O:18]1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: CC(=O)Nc1ccc(C)cc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(C)cc1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
To a mixture of 2-bromo-4-methylacetanilide (1.5 g, 6.6 mmol) and the title compound of Step B (2.0 g, 9.9 mmol) in ethylene glycol dimethyl ether (20 mL) were added a solution of sodium carbonate (2.1 g, 20 mmol) in water (20 mL) and bis(triphenylphosphine) palladium (II) chloride (230 mg, 0.33 mmol). The mixture was heated at reflux overnight, and then additional title compound of Step B (1.0 g, 4.9 mmol) and sodium carbonate (1.0 g, 9.4 mmol) as a solution in water (approximately 10 mL) were added. The mixture was heated at reflux an additional 6 h and then allowed to come to room temperature. The mixture was poured into water and the aqueous mixture was extracted with ethyl acetate four times. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give a dark-brown oil. The oil was purified by flash chromatography on silica gel, eluting with 1:4 ethyl acetate/hexane to afford the title compound of Step C, a compound of the invention, as a light brown solid melting at 105°-107° C. (205 mg, 10%). 1H NMR (CD3COCD3): δ1.95 (s,3H), 2.36 (s,3H), 7.2(m,2H), 7.25(m,3H), 7.8(m, 1H), 8.55(br s, 1H).
Reaction SMILES: [Na].[N:2]1([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:20]1[S:21][C:22]2[C:23]([N:28]=1)=[N:24][CH:25]=[CH:26][N:27]=2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:2]1([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C:20]4[S:21][C:22]5[C:23]([N:28]=4)=[N:24][CH:25]=[CH:26][N:27]=5)=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Oc1ccc2c(CN3CCOCC3)c[nH]c2c1
Reactant: Clc1nc2nccnc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Product: c1cnc2sc(Oc3ccc4c(CN5CCOCC5)c[nH]c4c3)nc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.4 %

Procedure:
To a solution of 3-morpholin-4-ylmethyl-1H-indol-6-ol sodium salt (130 mg, 0.51 mmol) and 2-chloro-thiazolo[4,5-b]pyrazine (70 mg, 0.41 mmol) in DMF (1.4 mL) was added Cs2CO3 (43 mg, 0.12 mmol) and the resulting suspension was stirred (rt, 16 h). The reaction mixture was filtered and the solid was rinsed with EtOAc. The reaction mixture was concentrated in vacuo. The resulting residue was purified via reverse phase HPLC to provide the title compound as a white powder (38.3 mg, 26%). MS (ESI): mass calculated for C18H17N5O2S, 367.1; m/z found, 368.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.51 (d, J=2.6, 1H), 8.32 (d, J=2.6, 1H), 8.21 (s, 1H), 7.83 (d, J=8.6, 1H), 7.45 (d, J=2.2, 1H), 7.21 (d, J=2.3, 1H), 7.12 (dd, J=8.6, 2.2, 1H), 3.75-3.69 (m, 6H), 2.51 (s, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([OH:20])=O)[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32].NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=3[F:32])=[O:20])[C:12]2=[O:22])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)O)C2=O)cc1
Reactant: N#Cc1ccc(N)c(F)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3F)C2=O)cc1

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.2 g) derived from compound 52-4 and 4-amino-3-fluorobenzonitrile (81.7 mg) were used instead of 1-2 and 6-amino-1-bis(tert-butoxy carbonyl)aminoisoquinoline, under high concentration condition (1M), to obtain compound 67-1 (130 mg) as a colorless amorphous solid.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[NH2:62][CH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:6][C:5](=[O:14])[CH2:4][CH2:3][C@H:2]([NH:1][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15](=[O:17])[NH:69][CH2:68][C:67]1[CH:70]=[CH:71][C:64]([C:63]#[N:62])=[CH:65][CH:66]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
A solution of Boc-Glu(OBzl)-OH (7.08 g, 21.0 mmol), BOP (9.72 g, 22.0 mmol) and DIEA (12.18 ml, 70.0 mmol) in DMF (50 ml) was maintained at room temperature for 20 min, followed by the addition of 4-(aminomethyl)benzonitrile hydrochloride (3.38 g, 20.0 mmol). The reaction mixture was stirred at room temperature for an additional 1 h and diluted with EtOAc (500 ml). The obtained solution was extracted with water (100 ml), 5% aq. NaHCO3 (100 ml) and water (2×100 ml). The organic layer was dried over MgSO4, evaporated and dried in vacuo to provide compound Q (9.65 g, yield exceeded quantitative) as yellowish oil. LC-MS [M+H] 452.0 (C25H29N3O5+H, calc: 452.4). Compound Q was used without further purification.