Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[O:9].[SH:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[N:19]1[CH:18]=[CH:17][N:16]2[C:11]([S:10][CH2:2][N:3]3[C:7](=[O:8])[CH2:6][S:5][C:4]3=[O:9])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: Sc1cccc2nccn12
Reactant: O=C1CSC(=O)N1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CSC(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 2.10 g (10 mmol) of 3-bromomethylthiazolidine-2,4-dione was added to a solution of 1.50 g (10 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 1.67 ml (10 mmol) of triethylamine in 50 ml of ethanol, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.41 g (50.5%, light brown solid) of the desired product.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:21]=[CH:20][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:19])[N:16]([CH2:17][CH3:18])[C:10]=2[CH:9]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:17]([N:16]1[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:21]=[CH:20][C:11]=2[CH2:12][CH2:13][O:14][C:15]1=[O:19])[CH3:18]
Reactant: CCN1C(=O)OCCc2ccc(C(=O)OC(C)(C)C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)OCCc2ccc(C(=O)O)cc21
Yield: 99.5 %

Procedure:
A solution of 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester (0.91 g, 3.12 mmol) was stirred in TFA/DCM (1:1, 3 mL) for 16 hours. The reaction was concentrated to provide 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid (0.73 g).
Reaction SMILES: [CH:1]([Si:3]([CH3:11])([CH3:10])[O:4][Si:5]([CH:8]=[CH2:9])([CH3:7])[CH3:6])=[CH2:2].C(O)(=O)C.[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>[Pt]>[CH:8]([Si:5]([CH3:7])([CH3:6])[O:4][Si:3]([CH:1]([Si:18]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:16])[CH3:2])([CH3:10])[CH3:11])=[CH2:9]
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Solvent: CC(=O)O
Product: C=C[Si](C)(C)O[Si](C)(C)C(C)[Si](OC)(OC)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A siloxane according to the present invention was prepared by charging a flask with 55.8 g (0.3 mole) of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane under a nitrogen atmosphere. A platinum/vinylsiloxane catalyst, prepared according to the method described by Hitchcock et al.(Angew. Chem. Int. Ed. Engl., 30, 1991) was added at a level of 10−6 equivalent of platinum. Acetic acid (0.06 g; 0.001 mol) was introduced and the reaction mixture heated to 60° C. Trimethoxysilane (12.2 g; 0.1 mol) and 0.24 g (0.004 mol) acetic acid were added to an addition funnel and this mixture was slowly added to the flask while the temperature was maintained below 70° C. Subsequently, the reaction mixture was kept at 70° C. for 1 hr. The product was isolated by fractional distillation at 80° C./8 mm Hg to obtain a mixture (confirmed by NMR) of 7% of an α-adduct (1-vinyl-3-(1-trimethoxysilylethyl)-1,1,3,3-tetramethyldisiloxane) having the structure
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14]([O:18][CH2:19][C@H:20]([CH3:47])[O:21][C:22]1[CH:23]=[C:24]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:25]([O:27][NH2+]C(C)(C)C)=[O:26])([CH3:17])([CH3:16])[CH3:15].CC(OC)(C)C>O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14]([O:18][CH2:19][C@H:20]([CH3:47])[O:21][C:22]1[CH:23]=[C:24]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:25]([OH:27])=[O:26])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O[NH2+]C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous citric acid was prepared by dissolving citric acid (7.35 g, 38.25 mmol) in water (100 mL). The aqueous citric acid solution was added to a reaction vessel containing ({3[(1S)-2-tert-butoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoyl}oxy)(tert-butyl)ammonium (10 g at 94.6% w/w, 19.13 mmol) and MTBE (80 mL). The two-phase mixture was stirred for 30 minutes at ambient temperature. The two phases were separated, and the aqueous phase was extracted with MTBE (80 mL). The two organic phases were combined and washed three times with brine (3×80 mL), followed by water (2×80 mL). The combined MTBE extract was distilled down to low volume, fresh MTBE (80 mL) was added and the mixture was distilled down to low volume. Acetonitrile (120 mL) was added and the mixture was distilled down to low volume at 50° C., 209 mbar. This azeodrying was repeated once more to provide a dry acetonitrile solution of the title compound, which was used directly in the next stage.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B12B3B4B1C234>C1C=CC=CC=1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: B12B3B4B1C234
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2)cc1
Yield: 48.2 %

Procedure:
A mixture of 5.4 gm (0.05 moles) of anisole and 7.0 gm (0.05) moles of benzoyl chloride and 0.5 gm of boron carbide was placed in 50 ml of benzene. This mixture was allowed to react as described in Example 3. A yield of 48.2% of p-methoxy benzophenone was obtained, and 0.5 gm of the boron carbide catalysts was recovered.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1.C([Li])CCC.[CH3:15][Si:16]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)([CH3:18])[CH3:17]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[O:8]1[CH2:9][CH2:1][O:2][C:3]2=[C:4]([C:24]3[CH:25]=[CH:26][C:21]([C:20]#[C:19][Si:16]([CH3:15])([CH3:18])[CH3:17])=[CH:22][CH:23]=3)[S:5][CH:6]=[C:7]12
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: c1scc2c1OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2scc3c2OCCO3)cc1
Reaction time: 1 h
Yield: 57.7 %

Procedure:
As shown in the following Reaction 3, 580 mg (4.08 mmol) of 3.4-ethylenedioxythiophene was melted in 10 mL of tetrahydrofuran under nitrogen atmosphere at the temperature of −78° C., and 2.45 mL (6.12 mmol, 1.5 eq) of n-butyllithium was added thereto, and then the reaction solution was stirred for 1 hour. After completion of stirring, 1.37 g (6.12 mmol, 1.5 eq) of zinc bromide was again added to the reaction solution at the temperature of 0° C., and then the reaction solution was stirred for 1 hour. Next, 1.22 g (4.08 mmol, 1 eq) of 4-trimethylsilylethynyl iodobenzene and 110 mg (0.16 mmol, 0.04 eq) of dichlorobis-(triphenylphosphine)palladium(II) were added to the reaction solution, and then the reaction solution was stirred for 12 hours at room temperature. After solvents of the reaction solution were removed by distillation under reduced pressure, the compound distilled under reduced pressure was purified with an alumina column chromatography (mobile phase volume ratio: methylene chloride:n-hexane=2:3) to obtain 740 mg of [4-(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-5-yl)-phenylethynyl]-trimethyl-silane with the yield of 58%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 0.25 (s, 9H), 4.23-4.24 (m, 2H), 4.30-4.32 (m, 2H), 6.32 (s, 1H), 7.44 (d, 2H), 7.64 (d, 2H)].
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH:25]([NH:28][C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 7.0 g (0.018 mol) of product of Example 27, 3.2 ml (0.037 mol) of isopropylamine in 30 ml of DMF were reacted at room temperature for 1/2 hour affording a brown oil which was kugelrohr distilled at 78 Pa, pot temperature 95° C., to give 6.07 g (83.8%) of product as a yellow oil, nD25 1.4560.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][NH2:27])([CH3:25])[CH3:24]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Product: CCc1nn(C(C)C)c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1-isopropyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and isopropylhydrazine in analogy to Example 55 b): colourless solid; MS (ISP): 337.3 ((M+H)+.).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([OH:37])[C@@H:17]([N+:34]([O-])=O)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:11]1[CH3:44])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.[Ni](Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@@H:15]([CH:16]([OH:37])[CH:17]([NH2:34])[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:11]1[CH3:44])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)[N+](=O)[O-])N1C(=O)OC(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H](C(O)C(N)Cc2cc(F)cc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Add sodium borohydride (1.66 g, 43.87 mmol) to (2R,3S,5R)-5-[(1R,2S)-3-(3-benzyloxy-5-fluoro-phenyl)-1-hydroxy-2-nitro-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (5.89 g, 9.97 mmol) and nickel chloride (2.07 g, 15.95 mmol) in methanol (100 mL) at room temperature and stir 30 minutes. Add water (˜10 mL) and concentrate. Dilute with ethyl acetate and filter through celite. Partition between ethyl acetate and saturated aqueous sodium chloride. Wash the organic layer with saturated aqueous sodium chloride, dry (sodium sulfate), filter and concentrate to give 4.32 g (77.3%) of the desired compound as a white solid.
Reaction SMILES: [C:1]1([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C1COCC1>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:36][CH:35]=1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C=Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 500 ml three-neck flask was purged with nitrogen and charged with (naphthalen-1-ylmethyl)triphenylphosphonium (11.67 g, 26.6 mmol) and dry THF (200 ml). Sodium hydride (1.06 g, 26.6 mmol) was added and reaction mixture was left to stir overnight at room temperature. Solution was orange in the morning. A solution of 4-fluorobenzaldehyde (3.0 g, 24.2 mmol) in dry THF (30 ml) was added next day (16 h later) over the period of 45 minutes, bleaching the orange-red color. Reaction mixture was stirred at room temperature for 24 hours. THF was removed under reduced pressure. Crude product was purified by column chromoatography on silica gel with 5% CHCl3 in hexanes. The desired product is a mixture of cis- and trans-isomers. Yield 5.7 g (95%) of a viscous oil. The structure was confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:25][C:20]5(OCC[O:21]5)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:25][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-n2ncc3cc4c(cc32)CCCC(=O)C4)ccn1
Reaction time: 24 h
Yield: 98.9 %

Procedure:
A 200 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (82, R1=2-methylpyridin-4-yl) (3.26 g, 9.72 mmol) and PTSA (2.31 g, 12.2 mmol) in acetone (49 mL). The mixture was heated to reflux. After 24 h, the reaction was diluted with additional acetone (50 mL) and water (2.5 mL) was added. After 1 h the reaction was cooled before adding sat. aq. NaHCO3 (30 mL). The mixture was then concentrated under reduced pressure. EtOAc (70 mL) was added, and after separating the layers, the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine (75 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=2-methylpyridin-4-yl) (2.8 g, 99%); LC/MS, method 3, Rt=1.71 min, MS m/z 292 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65-8.60 (m, 1H), 8.20-8.16 (m, 1H), 7.71 (s, 1H), 7.69-7.65 (m, 1H), 7.63-7.59 (m, 2H), 3.85 (s, 2H), 3.21-3.11 (m, 2H), 2.71 (s, 3H), 2.62-2.54 (m, 2H), 2.14-1.94 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:14](O)[CH3:15]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(Cl)cc(Cl)c1N

Procedure:
A mixture of 50 parts of 2-amino-3,5-dichlorobenzoic acid and 240 parts of ethanol is saturated with gaseous hydrogen chloride. The whole is stirred and refluxed for 10 hours. The reaction mixture is allowed to cool and the solvent is evaporated. To the solid residue are added water and sodium hydroxide. The precipitated product is filtered off and dried, yielding 25 parts of ethyl 2-amino-3,5-dichlorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-4-aminopyridine (5.0 g, 30.6 mmol) in conc. H2SO4 (25 mL) at 0° C. in an ice-acetone bath was added 90% HNO3 (10 mL) dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 h then poured onto ice (100 g). The solid precipitate was isolated by filtration, washed with cold H2O and dried under high vacuum. The resulting solid was dissolved in conc. H2SO4 (50 mL) and heated at 100° C. for 20 min. The reaction mixture was poured onto ice (150 g) and neutralized with conc. NH4OH while maintaining the temperature below 20° C. The precipitate was isolated by filtration, washed with cold H2O, and dried to yield the title compound. MS: m/z=208(M+1).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N+:15]([CH3:20])[CH:14]=[CH:13]2.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.C(O)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2
Reactant: C[n+]1ccc2cc(Br)ccc2c1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of 6-bromo-2-methylisoquinolinium trifluoromethanesulfonate (371 mg, 1 mmol) in methanol (10 mL) was added bromocresol green indicator. Sodium borohydride (93 mg, 2.5 mmol) was added and the reaction was stirred at rt. HCl in acetic acid (IM) was added periodically to maintain a yellow color. After 1 h, water (50 mL) was added and the solution was basified with NaOH (1M), extracted into CH2Cl2 (100 mL), dried over MgSO4and concentrated to give the title compound as a white solid (200 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.17 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 3.51 (s, 2H), 2.93-2.82 (m, 2H), 2.65 (t, J=5.8 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C@H:11]1[C@@H:16]([CH3:17])[CH2:15][O:14][C@@H:13](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]1=[O:27]>CNS(NC)(=O)=O.O1CCCC1>[CH3:9][O:10][C@@H:11]1[C@:12]2([O:27][CH2:2]2)[C@H:13](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:14][CH2:15][C@@H:16]1[CH3:17]
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)C1=O
Reactant: C[S+](C)(C)=O
Agent: CNS(=O)(=O)NC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]12CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Trimethylsulfoxonium iodide (74 mg) was added to a suspension of sodium hydride (14 mg, 60% oil suspension) in dry dimethylsulfamide (1 ml) . The mixture was stirred for 1 hr at room temperature. A solution of (2S,4S,5S)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-one (30 mg) in dry tetrahydrofuran (0.2 ml) was added dropwise. After stirring for 2 hrs at room temperature, the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography (n-hexane: ethyl acetate=10:1) gave (3S,4S,7S,8S)-8-methoxy-7-methyl-4-[(E)-1-nonenyl]-1,5-dioxaspiro[2,5]octane (23 mg, 72% yield) as colorless oil; EI-MS: m/z 282 (M+); 1H-NMR (CDCl3)d: 0.87 (3 H,t,J=7 Hz), 1.10 (1H,d,J=7 Hz), 1.2~1.4 (10H,m), 2.0 (2H,m), 2.2 (1H,m), 2.43 (1H,d,J=5 Hz), 2.80 (1H,d,J=5 Hz), 3.37 (3H,s), 3.52 (1H,d,J=3 Hz), 3.66 (1H,dd,J=3 & 12 Hz), 3.90 (1H,dd,J=4 & 12 Hz), 3.94 (1H,d,J=8 Hz), 5.56 (1H,dd,J=8 & 15 Hz), 5.71 (1H,m).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)[C:3]1=[O:16].BrBr.O>ClCCl>[OH:15][C:11]1[CH:10]=[C:9]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]2=[O:16])[CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCCCC(C2=CC(=O)CCC2)C1=O
Agent: BrBr
Solvent: O
Solvent: ClCCl
Product: CN1CCCCC(c2cccc(O)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A solution of hexahydro-1-methyl-3-(3-oxocyclohexen-1-yl)-2H-azepin-2-one (150 g) in dichloromethane (750 ml) was warmed to 25° C. Bromine (97.5 g) was added over 40 minutes at 25°-32° C. (occasional water cooling being applied) and the mixture stirred for 2 hours at about 25° C. Water (200 ml) was added and the dichloromethane layer washed with water (100 ml). The aqueous phases were combined and extracted into dichloromethane (2×100 ml). The dichloromethane extracts were combined and the solvent distilled off and replaced with ethyl acetate to keep temperature of 72° C. (750 ml ethyl acetate added; 90 ml distillate collected). The mixture was cooled to room temperature and filtered. The product was washed with 100 ml ethyl acetate and dried to give the title compound (134.3 g) as a crystalline fawn powder, m.p. 184°-189° C. Identical to product of Example 4.
Reaction SMILES: [F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]2[CH:3]1[CH2:4][CH2:5][C:6]2=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C>CCCCCC.O1CCCC1>[F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]2[CH:3]1[CH:4]=[CH:5][C:6]2=[O:8]
Reactant: CCOC(=O)C1(F)C2CCC(=O)C21
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)C2C=CC(=O)C21
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Under a nitrogen atmosphere, 19.5 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate dissolved into 230 ml of tetrahydrofuran at −78° C. was added dropwise to 230 ml of a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide which was prepared from 78 ml of n-butyllithium (1.61M hexane solution) and 20.3 g of 1,1,1,3,3,3-hexamethyldisilazane. After stirring at this temperature for 1 hour, 19.8 ml of chlorotrimethylsilane was added thereto, and this was stirred at room temperature for 1.5 hours. After carrying out of concentration of the reaction solution under reduced pressure, anhydrous hexane was added to the residue, the resulting inorganic salt was filtered off, and the filtrate was further concentrated under reduced pressure. After the residue was dissolved into 240 ml of acetonitrile, 25.9 g of palladium acetate was added thereto, and then it was stirred at room temperature for one day. The reaction solution was diluted with 240 ml of diethyl ether, the palladium was filtered off by use of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=9:1 to 5:1), yielding 17.1 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hex-3-en-6-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2F)c1

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 50 mg, 0.124 mmol), (2-fluoropyridin-3-yl)boronic acid (26 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation 140° C. for 30 min, filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=1.71 min, m/z=463.0 [M+H]+.