Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](F)[CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCC1
Reactant: Fc1cncc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Brc1cncc(NC2CCC2)c1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-5-fluoropyridine (Frontier Scientific, Logan, USA, 5.63 mmol) and cyclobutylamine (Fluka, Buchs, Switzerland, 12.38 mmol) in NMP (8 ml) was heated under microwave irradiation for 1 h at 190° C. and for 5.5 h at 200° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, with brine (3×), dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as an off-white solid. (HPLC: tR 2.31 min (Method A); M+H=227, 229 MS-ES)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-:37]>C1(C)C=CC=CC=1>[I:37][CH2:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: [I-]
Reactant: OCCC1Cc2ccccc2C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCC1Cc2ccccc2C1
Temperature: 90 °C
Yield: 87.7 %

Procedure:
A mixture of 2-(indan-2-yl)ethanol (19.3 g), imidazole (12.1 g), triphenylphosphine (34.3 g), and toluene (250 ml) was heated to 90° C. To this mixture, iodide (33.2 g) was added, and the resulting mixture was stirred at 90° C. for 20 mi. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:4) to give an oil (28.4 g, 87%).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OC[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1)=O>>[C:17]([C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11][N:6]([C:1]([O:3][CH2:4][C:5]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[O:2])[CH2:7][CH2:8]1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)N1CCC(C(=O)OCC)(C(=O)OCC)CC1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a manner analogous to that described by S. Huybrechts and G. J. Hoornaert, Synthetic Communications, 11 (1), 17-23 (1981) for the preparation of 1,4,4-tricarbethoxypiperidine but using benzyl chloroformate in place of ethyl chloroformate there was obtained benzyl 4,4-dicarbethoxypiperidine-1-carboxylate in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.B.O1CCCC1.Cl.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(CC#N)nc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCN)nc1
Temperature: 60 °C
Yield: 41 %

Procedure:
To a solution of 18 g of crude 2-(5-methylpyridin-2-yl)acetonitrile in dry THF (100 mL) was added dropwise Borane-tetrahydrofuran complex (1.0 M in THF, 232 mL, 232.5 mmol, 4 eq) at 0° C. under N2 atmosphere. The reaction mixture was then heated to 60° C. overnight. The reaction was cooled to room temperature, aq.HCl (6 N, 40 mL) was added carefully and the reaction mixture was then heated at 70° C. for 2 hrs. After cooling, water was added and the resulting solution was washed with ether. The aqueous layer was basified with aq. NaOH (10 N) at 0° C. and saturated with K2CO3 then extracted with ether (5×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 7.6 g of crude 2-(5-methylpyridin-2-yl)ethanamine. (96% crude yield)
Reaction SMILES: [CH3:1][C@H:2]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=2[C:15]([OH:23])=[C:14]2[C@@H:3]1[C@H:4]([OH:32])[C@@H:5]1[C@:11]([OH:24])([C:12]2=[O:13])[C:10]([OH:25])=[C:9]([C:26]([NH2:28])=[O:27])[C:7](=[O:8])[C@H:6]1[N:29]([CH3:31])[CH3:30].O>Cl>[CH3:1][C@@H:2]1[C@@H:3]2[C:14](=[C:12]([OH:13])[C@:11]3([OH:24])[C:10](=[O:25])[C:9]([C:26]([NH2:28])=[O:27])=[C:7]([OH:8])[C@@H:6]([N:29]([CH3:30])[CH3:31])[C@@H:5]3[C@H:4]2[OH:32])[C:15](=[O:23])[C:16]2[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]1=2
Reactant: C[C@H]1c2cccc(O)c2C(O)=C2C(=O)[C@]3(O)C(O)=C(C(N)=O)C(=O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Agent: Cl
Solvent: O
Product: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.5 g (40 mmol) doxycyclin monohydrate is dissolved in 400 ml 0.1 M HCl and by titration with 100 ml 0.05 M (5 mmol) sucrose-octa-O-sulphonic acid, precipitation of doxycyclin sucrose octa sulphate takes place. The reaction mixture is stirred for about 60 min at 25° C., filtered, washed with 3×50 ml water (by dispersion and refiltration) and vacuum dried at about 1 Torr/25° C./sicapent®/20 h.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:37])[C:23]3[C:24](=[C:26]([CH2:35][CH3:36])[N:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:38]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:16][N:15]=1)[CH3:12].[CH3:49][O:50]CCO>>[CH2:35]([C:26]1[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=[C:23]2[C:22](=[O:37])[NH:21][C:20]([C:19]3[C:14]([O:13][CH2:11][CH2:12][O:50][CH3:49])=[N:15][CH:16]=[C:17]([S:38]([N:41]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]4)(=[O:40])=[O:39])[CH:18]=3)=[N:25][C:24]=12)[CH3:36]
Reactant: COCCO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccccc3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)[nH]c(=O)c2nn1-c1ccccc1

Procedure:
Potassium bis(trimethylsilyl)amide (294 mg, 1.47 mmol) was added to a solution of the compound from example 66 (200 mg, 0.37 mmol) in 2-methoxyethanol (10 ml), and the reaction heated under reflux for 18 hours. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant. The product was recrystallised from dichloromethane:iso-propanol to give the desired compound as a white solid, 82 mg.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:3][N:4]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1nccc2c1c(I)cn2C1CCOC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[3,2-c]pyridine (60.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (74.0 mg), tetrakis(triphenylphosphine)palladium(0) (20.1 mg) and potassium carbonate (48.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.6 mg).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[NH:14][NH2:15]>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]([NH:15][NH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[O:12])=[C:4]2[CH:3]=[CH:2]1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Product: O=C(NNC(=O)c1ccnc2[nH]ccc12)OCc1ccccc1
Yield: 67 %

Procedure:
In the same manner as in Reference Example 1 and using 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of benzothiazole-6-carboxylic acid and benzyl carbazate instead of tert-butyl carbazate, the title compound (yield 67%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]1[CH3:12].Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])(=O)C.[K+].C>CN(C)C(=O)C.[Pd].ClCCl>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:12])=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccn(C)c1C
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cc(Cl)ccc2C=O)n(C)c1C
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of 2-bromo-4-chlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdCl2(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130° C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (30 g) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over magnesium sulphate and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]5[C@H:27]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)[O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([OH:24])[C@H:27]([OH:26])[CH2:28][OH:29])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2ccc(OC[C@@H](O)[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ7-1, 13.7 mg, 0.0223 mmol) was dissolved in THF (0.15 mL) and methanol (0.1 mL), added with 0.5 M sulfuric acid (0.05 mL), and then stirred at 60° C. for 3 hr. After cooling, the reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with dichloromethane to obtain the title compound (white solid, 8.4 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1>CN(C=O)C.O.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>[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38]([C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[C:6]2[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:39]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2F)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
To a stirred solution of 66.6I (1.1209 g, 2.962 mmol) in dry DMF (10 mL) at 23° C. was added potassium carbonate (1.2262 g, 8.872 mmol) and then tetrakis(triphenylphosphine)palladium (0.3408 g, 0.2949 mmol). The mixture was purged with argon and placed under vacuum and the purging and vacuum process repeated three times. Before heating, 66.50A (1.6019 g, 5.888 mmol) was added via syringe and then the mixture was heated to 90° C. After 19 hours, LC-MS showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.50B as a clear oil (994.4 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, dd, J=8.0, 1.8 Hz), 7.94 (1H, d, J=1.6 Hz), 7.50 (3H, m), 7.16 (1H, t, J=9.0 Hz), 6.63 (1H, t), 5.53 (1H, s), 3.96 (3H, s), 2.25 (2H, td, J=7.0, 2.3 Hz), 1.65 (2H, t, J=7.0 Hz), 0.85 (6H, s).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:29])=[CH:31][CH:32]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cc1

Procedure:
As described for Example 26, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as an off-white, m.p. 103°-106° C.; Mass spectrum (CI), 406 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([N:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])=[O:8])=[O:4].[CH3:15][S:16][C:17]#[CH:18].P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[C@H:6]([C:7]([N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[O:8])[C:17]([S:16][CH3:15])=[CH:18]1)=[O:4]
Reactant: COC(=O)/C=C/C(=O)N1CCOC1=O
Reactant: C#CSC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C=C(SC)[C@H]1C(=O)N1CCOC1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To 200 mg of powdery Molecular Sieves 4A, which had been dried by heating, were added 0.41 ml (0.050 mmol) of the toluene solution obtained above, 1.5 ml of toluene and 2 ml of petroleum ether (boiling point: ca. 80° C.) in an argon atmosphere. Further, 100.15 mg (0.502 mmol) of 3-[(E)-3-(methoxycarbonyl)propenoyl]-oxazolidin-2-one was added thereto and the mixture was cooled to 0° C. To the obtained suspension was added 135 mg (1.88 mmol) of 1-methylthioacetylene dissolved in 1.5 ml of petroleum ether. Next, the mixture was stirred at the same temperature for 24 hours. Then a 0.2M phosphate buffer solution (pH 7.0) was added to the reaction mixture to thereby cease the reaction. After filtering off inorganic matters with Celite, organic matters were extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by thin layer chromatography (ethyl acetate:hexane=1:1, v/v). Thus 113 mg (83%) of (-)-(3R,4R)-3-methoxycarbonyl- 1-methylthio-4-(oxazolidin-2-on-3-yl)carbonyl-1-cyclobutene was obtained. The optical purity of this compound determined by the method as will be described in Referential Example exceeded 98% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])=[O:10].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])(=[O:36])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)(=O)=O
Reaction time: 1 h
Yield: 16.6 %

Procedure:
In 100 ml of chloroform-ethanol was suspended 2.9 g of 2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Under ice-cooling, 1.72 g of m-chloroperbenzoic acid (80%) was added in small portions and the mixture was stirred for 1 hour. Then, the mixture was returned to room temperature and stirred overnight. The resulting crystals were collected by filtration, washed with ethanol and diethyl ether, and dried. Recrystallization from dimethylformamide-water to obtain 0.50 g of 2-(3-methoxy-4-methylsulfonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)NCc1ccc(O)cc1CCC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[5-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (14.8 mmol) in DMF (100 mL) was added Cs2CO3 (29.6 mmol) and benzyl bromide (16.3 mmol). The reaction mixture was stirred overnight at ambient temperature and diluted with EtOAc (200 mL). The mixture was washed with brine (100 mL) and water (100 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow oil (6.8 g). MS [ES] m/z 428 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 49 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and morpholine according to the procedure of example 25. Yield: 49%; MS: m/z=401 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][C:26]([OH:29])([CH3:28])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C=O)C>[OH:29][C:26]1([CH3:28])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[N:20]=2)[CH2:27]1
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (200 mg, 0.41 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (473 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with brine, and extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl(±)-6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (183 mg, 78%). MS (ESI) m/z=573 [M+H]+, which was separated by chiral preparative HPLC to afford (R)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (51 mg) and (S)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (48 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(#N)C.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of diethyl 3,5-pyrazoledicarboxylate (2.17 g, 10 mmol) in acetonitrile (10 ml), under nitrogen, was added potassium carbonate (2.07 g, 15 mmol), and 2-bromoethoxy-t-butyldimethylsilane (2.90 g, 12 mmol). The mixture was stirred at reflux for 18 hr. It was then cooled to room temperature, diluted with ethyl acetate (20 ml), and filtered through Magnesol. The filter pad was eluted with 2×10 ml of ethyl acetate, and the combined filtrate was evaporated. The residue was dissolved in hexanes and passed through a column of silica gel (70 g). After eluting with hexanes (100 ml), the column was eluted with ethyl acetate. The ethyl acetate eluent was evaporated to give 3.71 g of a colorless oil; MS m/e 371 (MH+).
Reaction SMILES: [CH:1]1([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[CH:1]1([O:8][C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH2:19][C:20]#[N:21])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)c1cccc(OC2CCCCCC2)n1
Product: N#CCC(=O)c1cccc(OC2CCCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cycloheptyloxy)picolinate following the method described in Example 6 gave 3-(6-(cycloheptyloxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.29 g, quant.).