Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH2:51]([C:58]1[CH2:62][CH2:61][C:60](=[O:63])[CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCCCC>C(OCC)C>[CH2:51]([CH:58]1[CH2:62][CH2:61][C:60](=[O:63])[CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C1C=C(Cc2ccccc2)CC1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: CCCCC
Product: O=C1CCC(Cc2ccccc2)C1
Yield: 795.3 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-benzylcyclopentenone (0.11 g, 0.7 mmol) gave, after 24 h at 0° C. and flash chromatography (6:1 pentane:diethyl ether), the title compound as a clear liquid (0.97 g, 85% yield). Spectroscopic data were consistent with previously reported data for this compound.12 [α]D25° C.−96° (c 1.3, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 96% ee.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:26])=[O:27])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.72 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.CO.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:13][OH:14])=[N:6][CH:7]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
5-Bromo-pyridine-2-carbaldehyde (X. Wang et al, Tetrahedron Letters 41 (2000), 4335–4338) (60 g, 322 mmol) was added to methanol (700 ml) and then water was added (700 ml) followed by addition of hydroxylamine hydrochloride (28 g, 403 mmol). Sodium carbonate (20.5 g, 193.2 mmol) in water (200 ml) was added and the reaction was stirred for 30 minutes. Water (500 ml) was then added and the precipitate was filtered and washed with water (2×300 ml) to give the desired product (60 g).
Reaction SMILES: [H-].[Na+].[NH2:3][S:4]([CH2:7][CH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23])[C:10](OC)=[O:11])(=[O:6])=[O:5].CO>CCCCCC.O1CCCC1>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH:9]1[CH2:8][CH2:7][S:4](=[O:6])(=[O:5])[NH:3][C:10]1=[O:11]
Reactant: COC(=O)C(CCS(N)(=O)=O)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NS(=O)(=O)CCC1c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 60% sodium hydride oil dispersion (520 mg, 13.0 mmol) is washed with hexane (3×5 ml) then dry tetrahydrofuran (30 ml) added. To this stirred ice cooled mixture is added a solution of methyl .alpha.-[2-(aminosulfonyl)ethyl]-2-fluoro-4-nitrobenzeneacetate (3.20 g, 10.0 mmol) in dry tetrahydrofuran (30 ml). After stirring for 3 hr, additional sodium hydride (300 mg, 7.5 mmol) is added. Methanol (5 ml) is added after an additional 20 hr and the reaction evaporated to dryness. The residue is partitioned between 5% methanol-chloroform (150 ml) and 1N.HCl (50 ml), and the brown solid filtered. This solid is chromatographed over silica gel (150 g) eluting with 50% acetone-hexane. Recrystallization from acetone-hexane gives the title compound as solid. mp 218-219°.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7].[BH4-].[Na+]>CO.O>[C:11]([O:10][C:8]([N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:7])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of N-t-butoxycarbonyl-N-methyl-β-alanine methyl ester (3.911 g) in methanol (20 ml) and water (20 ml) was added sodium borohydride (6.81 g) portionwise at 4° C. and the mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was portioned between ethyl acetate (100 ml) and 0.5 N hydrochloric acid (100 ml). The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.48 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C=O)cccc1OC)OCC
Yield: 36.8 %

Procedure:
To a stirred suspension containing 2-hydroxy-3-methoxybenzaldehyde (4.0 g, 26.3 mmol) and K2CO3 (4.36 g, 31.60 mmol) in DMF (15 mL), bromoacetaldehyde diethyl acetal (4.86 mL, 31.60 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography eluting with hexane/EtOAc (4:1) to give 28 (2.60 g, 36%). 1H NMR (500 MHz, CDCl3): δ: 10.53 (1H, s, CHO), 7.42 (1H, m, ArH), 7.14-7.12 (2H, m, ArH), 4.83 (1H, t, J=5.30 Hz, CH), 4.21 (2H, d, J=5.35 Hz, CH2), 3.90 (3H, s, OCH3), 3.74-3.71 (2H, m, CH2CH3), 3.60-3.57 (2H, m, CH2CH3), 1.22 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13](O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C[C@@H](NC(=O)OCc1ccccc1)C1CC1
Temperature: -15 °C
Yield: 83.6 %

Procedure:
Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoate (1.488 g, 4.630 mmol) was dissolved in dry dichloromethane (50 ml) and stirred at -15° C. while adding triethylamine (1,291 μl, 9.260 mmol), and then methanesulfonyl chloride (449 μl, 5.80 mmol) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. 1,8-Diazabicyclo[5.4.0]-7-undecene (1,486 μl, 1.955 mmol) was added dropwise to the reaction solution, and the mixture was gradually warmed up to room temperature and then stirred for 15 hours. The reaction solution was washed with 10% citric acid aqueous solution (50 ml), and the organic layer was separated and then the aqueous layer was extracted with chloroform (30 ml). The organic layers were combined, washed with water (50 ml) and saturated sodium chloride aqueous solution (50 ml) in that order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a flash silica gel chromatography and eluted with n-hexane:ethyl acetate=4:1, thereby obtaining 1.174 g (87.2%) of the title compound as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1>CO.[Pt]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a suspension of N-(4-bromophenyl)-2-nitro-5-chlorobenzamide (0.50 g, 1.4 mmol) in methanol (20 mL) was added 5% platinum on carbon (Degussa type, 50% water, 0.20 g), and the mixture stirred under hydrogen (balloon). After 0.5 hours, the mixture was filtered and concentrated of all volatiles in vacuo to afford 0.45 g (99% yield) of N-(4-bromophenyl)-2-amino-5-chlorobenzamide as a white solid; NMR (DMSO-d6) 10.2 (s, 1), 7.5-7.7 (m, 5), 7.2 (dd, 1), 6.13 (d, 1) ppm.
Reaction SMILES: [Mg].[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.Br[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[CH2:25]([C:27]1[N:28]=[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[N:31][N:30]2[C:37]=1[CH:38]=[O:39])[CH3:26]>C1COCC1.CCOC(C)=O.CCCCCC>[CH2:25]([C:27]1[N:28]=[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[N:31][N:30]2[C:37]=1[CH:38]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[OH:39])[CH3:26]
Reactant: CCc1nc2c(C)cc(C)nn2c1C=O
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1nc2c(C)cc(C)nn2c1C(O)c1ccc(O)cc1
Temperature: 35 °C
Yield: 82 %

Procedure:
A 100 mL three necked round bottom flask equipped with a magnetic stir bar, septum, reflux condenser and a nitrogen inlet was dried and charged with 0.608 g (25 mmol) of magnesium turnings and 15 mL of dry THF. A solution of 7.182 g (25 mmol) of the t-butyldimethylsilylether derived from 4-bromophenol dissolved in 10 mL of dry THF was added via syringe and the reaction mixture was stirred at reflux for 3 hours. A separate 50 mL flask equipped with a magnetic stir bar, septum and containing a solution of 0.747 g (3.7 mmol) of the product of Step C was stirred at 0° C. in an ice-water bath. The Grignard reaction mixture was cooled to 35° C. and 5 mL (5 mmol) of the approximately 1.0M solution was transferred to the second reaction mixture via syringe. The reaction mixture was stirred at 0° C. for 30 min, at which point TLC analysis (50% EtOAc-hexane) indicated complete reaction of the aldehyde. The reaction mixture was quenched with 10% aqueous sodium bisulfate, then partitioned between THF and saturated brine. The organic layer was separated, evaporated in vacuo, redissolved in THF, dried (MgSO4), filtered and concentrated to an oil. The residual oil was again redissolved in 10 mL THF and treated with 5 mL of a 1.0M solution of tetra-n-butylammonium fluoride in THF. After stirring 1 h at room temperature the reaction mixture was evaporated in vacuo, and the residual oil was purified by filtration through a short plug of silica gel eluted with THF. The filtrate was concentrated and the product was precipitated from THF/hexane to afford 0.896 g (82%) of title compound as an off-white crystalline solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:48])([F:47])[C:10]1[CH:11]=[C:12]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:13][N:14]([C:34]1[N:35]=[N:36][N:37]([CH3:39])[N:38]=1)[C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:23]=2)[N:18]([C:29](Cl)=[O:30])[C@H:17]([CH2:32][CH3:33])[CH2:16]1.[CH2:49]([OH:51])[CH3:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:49]([O:51][C:29]([N:18]1[C:19]2[C:24](=[N:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)[C@@H:15]([N:14]([CH2:13][C:12]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:10]([C:9]([F:48])([F:47])[F:8])[CH:11]=2)[C:34]2[N:35]=[N:36][N:37]([CH3:39])[N:38]=2)[CH2:16][C@H:17]1[CH2:32][CH3:33])=[O:30])[CH3:50]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)nc2[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Add triethylamine (25 μL) and 4-dimethylaminopyridine (10 mg, 80 μmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carbonyl chloride (100 mg, 0.16 mmol) and ethanol (28 μL) in dichloromethane (0.9 mL). Stir the mixture at room temperature for 8 h. Evaporate the solvent and purify the crude material by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (51 mg, 51%). MS (ES+): 626 (M+H).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH2:10]=[C:11]([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)O1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)O1
Temperature: -60 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g 5-oxo-2-tetrahydrofurancarboxylic acid in 100 ml dichloromethane 0.3 ml concentrated sulfuric acid and then an excess amount of isobutene (about 50 ml) were added, while maintaining the solution at -60° C. The reaction mixture was kept standing in a tightly seald flask at room temperature overnight, and thereafter it was poured into a cooled saturated aqueous solution of sodium bicarbonate, and the dichloromethane layer was separated. After washing with water and drying (over Na2SO4), the dichloromethane layer was concentrated to yield t-butyl 5-oxo-2- tetrahydrofurancarboxylate in the form of a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)[CH3:2].[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:15])[CH:5]=3)[C:10]2=[O:14])[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CCN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1COC(C)=O)C2=O
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
6-(Ethyl-methyl-amino)-3,4-dihydro-2H-isoquinolin-1-one (2.07 g, 10.1 mmol), acetic acid 2,6-dibromo-benzyl ester (6.25, 20.3 mmol), cuprous iodide (386 mg, 2.03 mmol) and potassium carbonate (1.40, 10.1 mmol) were deposited in a sealed vessel. 30 mL DMSO was added. Argon was bubbled through the mixture for 3 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (386 mg, 2.03 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with 300 mL ethyl acetate and 300 mL water. After stirring for 20 minutes, this was filtered through a pad of celite. The layers were separated. The ethylacetate layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield acetic acid 2-bromo-6-[6-(ethyl-methyl-amino)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzyl ester (1.21 g, 2.81 mmol). MS (ESI) 433.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:13]1[C:17](O)([CH3:18])[CH:16]=[CH:15][C:14]1=[O:20])[CH2:9][CH2:10][CH2:11][CH3:12].[SH2:21]>C1(C)C=CC=CC=1>[CH2:8]([C:13]1[C:14](=[O:20])[CH2:15][CH:16]([SH:21])[C:17]=1[CH3:18])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC1=C(C)C(S)CC1=O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
Into the same flask as used in Example 1, triethylamine (5 g), 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) and toluene (30 g) were charged, and hydrogen sulfide (8 g) was introduced into the mixture at a temperature of 15° to 30° C. Thereafter, the reaction mixture was stirred at a temperature of 50° to 70° C. for 4 hours. After completion of the reaction, the mixture was washed with an acid and water in order. The organic layer was separated and concentrated to obtain 2-n-pentyl-3-methyl-4-mercapto-2-cyclopentenone (18.0 g). Yield, 91%. nD20 1.5212.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccccc1Cl
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(Cc3ccccc3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)cn1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc(=O)[nH]c2)c1C
Temperature: 55 °C
Reaction time: 1.08 h
Yield: 62.3 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (100 mg, 0.24 mmol) in CH3CN (4.75 mL) was added TMSI (68.4 μL, 0.48 mmol) drop wise. The reaction was stirred at 55° C. After 65 minutes, mainly starting material and some product observed. Two more equivalents of TMSI were added and the heating at 55° C. was continued for 3 hours 20 minutes. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×: until the yellow colour disappeared), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (60 mg, 62%). ESI-MS m/z calc. 401.5. found 402.3 (M+1)+. Retention time 1.33 minutes.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C2(O)CCN(Cc3ccccc3)C2)c1
Agent: Cl
Product: Cc1cccc(C2=CN(Cc3ccccc3)CC2)c1
Yield: 100 %

Procedure:
A mixture of 8 parts of 3-(3-methylphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride and 150 parts of a hydrochloric acid solution 6N was stirred and refluxed for 3 hours. After cooling, the reaction mixture was evaporated, yielding 7.4 parts (100%) of 2,3-dihydro-4-(3-methylphenyl)-1-(phenylmethyl)-1H-pyrrole hydrochloride as a residue (intermediate 47).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[N:28]C=C(N2CCC=CC2)[N:25]=1.[CH3:36][N+:37]1([O-])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.OS([O-])=O.[Na+].[CH3:49][C:50](C)=[O:51]>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:25]=[C:42]([N:37]2[CH2:36][CH2:49][C@H:50]([OH:51])[C@H:39]([OH:40])[CH2:38]2)[CH:41]=[N:28][CH:29]=1
Reactant: CC(C)=O
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(N3CC=CCC3)n1)nn2C1CCCCO1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O[C@@H]1CN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)CC[C@@H]1O
Yield: 41.5 %

Procedure:
To a bright yellow slurry of 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.225 g, 0.475 mmol) and NMO (aldrich) (0.083 g, 0.713 mmol) in 3 mL acetone and 1 mL water was added osmium tetroxide 4% solution in water (aldrich) (0.151 mL, 0.024 mmol). The reaction was sealed and stirred rapidly over the weekend. The heterogeneous reaction was refreshed with NMO (aldrich) (0.083 g, 0.713 mmol) and osmium tetroxide 4% solution in water (aldrich) (0.151 mL, 0.024 mmol) and stirred rapidly for 36 h. The heterogeneous reaction was refreshed with NMO (aldrich) (0.083 g, 0.713 mmol) and osmium tetroxide 4% solution in water (Aldrich) (0.151 mL, 0.024 mmol) and stirred rapidly 48 h. The reaction was treated with 2 mL sat'd aqueous NaHSO3, and partitioned between water and DCM. The aqueous layer was extracted with DCM 4 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM and adsorbed onto 2 g silica gel, then purified by silica gel chromatography (40 g column) using 0-75% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford racemic cis-1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidine-3,4-diol (0.10 g, 0.197 mmol, 41.5% yield) as a yellow solid: MS (ESI, pos. ion) m/z: 508 (M+1).