Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH3:11].COB(OC)OC.Br[C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=2)[CH:25]=[O:26])=[CH:8][CH:3]=1)[CH3:11]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: -11 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Under an argon atmosphere, magnesium (1.25 g, 51.5 mmol) was suspended in 100 ml of tetrahydrofuran, which was then refluxed. Under reflux, 50 ml of a tetrahydrofuran solution of bromophenetole (10 g, 50 mmol) was dropped and refluxed for 2 hours. After cooling to −11° C., a solution of trimethoxyborane (5.6 ml, 50 mmol) in 50 ml of tetrahydrofuran was dropped at −11 to −8° C. Stirring was conducted at −10° C. for 1 hour. At room temperature, palladium (II) acetate (64 mg, 0.285 mmol) and subsequently triphenylphosphine (299 mg, 1.14 mmol) were added and stirred at room temperature for 30 minutes. 5-Bromo-2-fluorobenzaldehyde (5.79 g, 28.5 mmol) and subsequently 30 ml of an aqueous solution of potassium carbonate (20.7 g, 150 mmol) were added at room temperature and heated under reflux for 5 hours. After cooling to room temperature, 170 ml of a 2N hydrochloric acid was dropped at 20 to 30° C. After phase separation had occurred, the water layer was extracted with 80 ml of toluene. The organic layers were combined and washed with two 100-ml portions of saturated brine. To the organic layer, 1.0 g of activated carbon (Shirasagi A) and tri-n-butylphosphine (0.71 ml) were added and stirred at 70° C. for 20 minutes. After filtration, the residue was washed with 50 ml of toluene and then the filtrate was concentrated under vacuum. Ten milliliters of ethanol was added and then 5 ml of water was added under reflux. After cooling, the resultant was stirred while cooling in ice. The resultant was filtered under reduced pressure and the residue was washed with 20 ml of ethanol containing 50% of water. The residue was dried under vacuum (40° C.) to yield 5.7 g (Yield 82%) of 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=3)=[CH:37][CH:36]=2)([O:14][CH2:15][C:16]2[N:20](COCC[Si](C)(C)C)[C:19]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=3)=[CH:39][CH:40]=2)([O:14][CH2:15][C:16]2[NH:17][C:18]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:19]=3[N:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2nc3cc(F)c(F)cc3n2COCC[Si](C)(C)C)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2nc3cc(F)c(F)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.8 %

Procedure:
To a solution of 0.033 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-difluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester 62 (0.05 mmol, 1 eq) in 2.5 mL of tetrahydrofuran was added 0.10 mL tetrabutylammonium fluoride (1M in THF, 0.1 mmol, 2 eq). The reaction was stirred at room temperature for 20 h and then at 60° C. for 5 h. The mixture was allowed to cool to room temperature and then partitioned between 25 mL of ethyl acetate and 20 mL of H2O. The organic layer was separated, washed with saturated brine, dried (Na2SO4), and concentrated to give the crude product which was purified by flash silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexane to yield 0.025 g of the desired product 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-difluoro-1H-benzoimidazol-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester 63 as a pale foam: 1H NMR (300 MHz, CDCl3): δ 9.96 (br. s., 1H), 7.82-7.81 (m, 1H), 7.78-7.75 (dt, 1H), 7.65-7.61 (m, 1H), 7.57-7.40 (m, 6H), 7.30-7.24 (m, 1H), 4.43 (s, 2H), 4.00 (d, 2H), 3.31-3.23 (t, 2H), 2.24-2.19 (d, 2H), 2.07-1.97 (td, 2H), 1.48 (s, 9H); MS (ESI): Calcd m/z for C31H30F2N4O3.H+=545.2. Found m/z=545 (M+1)+.
Reaction SMILES: [C:1]([O:8]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].B1C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:28]1[CH:33]=[C:32]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=1>C1COCC1.CN(C=O)C>[NH2:34][C:32]1[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=[C:28]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:33]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C=CCCCC(=O)OC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(CCCCCC(=O)O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of methyl hex-5-enoate (12 mg, 0.1 mmol) in THF (0.5 ml) under argon at 0° C. was added 9-BBN (0.2 mmol, 0.4 ml of 0.5 M solution in THF). The mixture was warmed to room temperature and stirred for 16 h. Potassium phosphate (3 M in H2O, 0.2 mmol) was added followed by the addition of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmol) in DMF (0.5 ml) and Pd(dppf) Cl2—CH2Cl2 (5 mg, 0.005 mmol). The reaction mixture was heated at 90° C. for 16 h under argon. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 2:1 THF:MeOH (3 mL) and was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 4 hours followed by the addition of 2N hydrochloride solution (1.0 ml). The solution was heated at 65° C. for 2 h, cooled to room temperature, concentrated and purified by prep-LC to afford the title compound (8.2 mg): LC/MS RT=2.74 min. Mass calculated for, M+H 376.17, observed 376.17.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4](Cl)[N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][CH:17]=1.[H-].[Na+]>>[F:21][C:18]([F:19])([F:20])[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CSc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1
Yield: 85.3 %

Procedure:
A mixture of 2,6-dichloro-4-methylthiopyridine (0.97 g; 0.005 mol), 3-hydroxybenzotrifluoride (1.3 ml; 10.4 mmol) and sodium hydride (0.2 g) was reacted and worked up according to the procedure of Example 1 above to give 2,6-di-(3-trifluoromethyl phenoxy)-4-methylthiopyridine (1.9 g; 85%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([NH:12][P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:9][CH:10]=[CH2:11].[CH2:27](B1OC(C)(C)C(C)(C)O1)C=C>>[CH3:27][C:10](=[CH2:11])[CH2:9][C@@H:8]([NH:12][P:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: C=CC[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccccc1F
Product: C=C(C)C[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
The title compound is synthesized and purified analogously to 4b [except allylboronic acid pinacol ester 1b (32 μL, 0.15 mmol) is used as the nucleophile instead of 1a], affording 4m (34.4 mg, 0.0952 mmol, 95% yield) as a white solid. The analytical data are fully consistent with those reported previously.13 1H NMR (400 MHz, CDCl3): δ 7.86-7.80 (2H, m), 7.76-7.70 (2H, m), 7.50-7.46 (1H, m), 7.44-7.38 (3H, m), 7.29-7.17 (7H, m), 4.78 (1H, s), 4.69 (1H, s), 4.40 (1H, dddd, J=16.4, 16.4, 8.4, 8.4 Hz), 3.32 (1H, br dd, J=8.0, 6.0 Hz), 2.62 (1H, dd, J=13.6, 7.2 Hz), 2.53 (1H, dd, J=14.0, 7.2 Hz), 1.58 (3H, s); HRMS Calcd for C23H25NOP [M+H]+: 362.16738. Found: 362.16649. [α]20D=+39 (c=1.2, CHCl3) for a 97.5:2.5 er sample. The enantiomeric purity was determined by HPLC analysis in comparison with authentic racemic material (Chiracel OD-H, 92:8 hexanes:i-PrOH, 0.8 mL/min, 220 nm): tR of 4m: 11 min (major) and 14 min (minor).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C@@H:37]([OH:39])[CH3:38])[CH:35]=2)O1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C@@H:37]([OH:39])[CH3:38])[CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(C[C@H](C)O)c4)c3cn2)c1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (15 mg, 0.033 mmol) (Example 28, Step 4), (2S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (10 mg, 0.04 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (2 mg, 0.003 mmol), and potassium phosphate (14 mg, 0.067 mmol) in 1,4-dioxane (0.3 mL) and water (0.05 mL) in a reaction vial was degassed and sealed. It was stirred at 90° C. overnight. After cooling it was diluted with methanol, purified by RP-HPLC (pH=2) to afford the desired product (2.5 mg) as TFA salt. LCMS (M+H)+=448.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][C:8]=2[O:24][CH3:25])=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)ccc1-c1ccc(Cl)s1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1-c1ccc(Cl)s1
Yield: 83.4 %

Procedure:
A stirred mixture of 2.5 g (0.007 mole) of 2-[4-(5-chlorothien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3(2H)-dione and 0.4 g (0.007 mole) of hydrazine hydrate in 30 ml of absolute ethanol was heated at reflux for one hour. The mixture was cooled and the solvent evaporated under reduced pressure to leave a residue. The residue was subjected to column chromatography on silica gel, eluting with methylene chloride to yield 1.4 g of 4-(5-chlorothien-2-yl)-3-methoxyaniline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=O)=O)(C)(C)C.O.NN.[OH-].[K+].O>C(O)COCCO>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[CH:20][CH:19]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccc(-c2ccc(F)cc2)o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Fc1ccc(-c2ccc(CC3CCCCN3)o2)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
To a solution of (RS)-1-(tert-butyloxycarbonyl)-2-((5-(4-fluorophenyl)-furan-2-yl)carbonyl)piperidine (2.0 g, 5.36 mmol) in diethylene glycol (20 g), was added hydrazine hydrate (0.31 ml, 5.36 mmol) and the resultant mixture heated at 100° C. for 30 min. After cooling to room temperature, potassium hydroxide (1.0 g, 17.8 mmol) was added and the mixture heated at 200° C. for 18 h. The reaction mixture was then poured into water (100 ml) and extracted with diethyl ether (3×75 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as a brown oil (0.88 g, 63%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([N:8]2[CH2:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a solution of 4-acetamidopiperidine (2.5 g, 17.5 mmol) in DMF (10 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol) and K2CO3 (2.9 g, 21.2 mmol). The reaction was heated at 120° C. for 4 hours, diluted with H2O, and extracted with EtOAc. The organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (3.1 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O>C1COCC1.C(O)C.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of 81.0 g (303 mmol) of tert-butyl (2E)-3-(4-fluoro-3-nitrophenyl)acrylate in a mixture of 810 ml of THF and 810 ml of ethanol was inertized with argon, and 8.1 g of 10% palladium on carbon were added. The suspension was stirred at RT under a hydrogen atmosphere at standard pressure for 9 h. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 4:1). This gave 66.0 g (91% of theory) of the title compound.
Reaction SMILES: [C:1]1(C=CC(O)=CC=1)O.CC1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:28][C:29]1[C:30]([OH:38])=[C:31]([CH3:37])[C:32]([CH3:36])=[C:33]([CH:35]=1)[OH:34]>[O-2].[O-2].[Mn+4].CO>[CH3:28][C:29]1[C:30]([OH:38])=[C:31]([CH3:37])[C:32]([CH3:36])=[C:33]([OH:34])[C:35]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Oc1ccc(O)cc1
Agent: [Mn+4]
Agent: Cc1c(O)ccc(O)c1C
Agent: Cc1cc(O)ccc1O
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.105 g of hydroquinone (manufactured by Wako Pure Chemical Ind., Ltd.), 3.602 g of methanol and 1.3 mg of manganese dioxide (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 15 MPa. After 8 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of hydroquinone was 41% by mole, the selectivity of monomethylhydroquinone was 43% by mole, the selectivity of dimethylhydroquinone was 13% by mole and the selectivity of trimethylhydroquinone was 1% by mole. No tetramethylhydroquinone was produced.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][O:30]2)=[CH:25][N:24]=1>C(O)C>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([C@@H:29]([OH:30])[CH2:31][NH:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)=[CH:27][CH:28]=1
Reactant: Clc1ccc([C@@H]2CO2)cn1
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCN)cc2)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(CCCNC[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Yield: 47.6 %

Procedure:
A solution of ethyl 4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg), and 2-chloro-5-[(2R)-2-oxiranyl]-pyridine (71.5 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give ethyl 4′-[3-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-carboxylate (96 mg) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[N:3]=1
Reactant: Cc1nc2c(cc1CO)CCCC2=Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(cc1C=O)CCCC2=Cc1ccccc1
Yield: 39.9 %

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinemethanol (5.3 g) in chloroform (150 ml) is treated with three portions (4.5 g) of activated manganese dioxide at 4 hour intervals during reflux reaction. The suspension is filtered and the filtrate is evaporated to yield crude 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxaldehyde (5.3 g) as an oil. Filtration through silica gel (125 g) removes polar products and provides pure 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxaldehyde (2.1 g). Activated MnO2 (0.45 g) converts 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinemethanol (0.15 g) to 5,6,7,8-tetrahydro-2-methyl-8-methyl(phenylmethylene)-3-quinolinecarboxaldehyde (m.p. 217°-219°) within 15 minutes in toluene (15 ml) under azeotropic distillation conditions.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](SC3C(F)=C(C=CC=3)C(OCC)=O)=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.[CH2:32]1[C:37](=O)N(Cl)C(=O)[CH2:33]1>C(Cl)Cl.O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:33]3[CH2:32][CH2:37]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(Sc2cn(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of compound 3 (100 mg, 0.21 mmol) in CH2Cl2 (3 mL) under inert atmosphere was added NCS (58 mg, 0.43 mmol) at RT and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 14-17% EtOAc/Hexanes) to afford 5 (35 mg, 33%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.66 (m, 3H), 7.30 (d, J=7.6 Hz, 1H), 7.19 (dd, J=8.8, 6.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.27 (q, J=7.6 Hz, 2H), 1.58 (t, J=7.6 Hz, 3H), 1.49 (t, J=7.2 Hz, 3H); LC-MS (ESI): m/z 496.7 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobenzoate (10 g, 66.2 mmol) was dissolved in DCM (100 ml), and pyridine (8.1 ml, 99.2 mmol, 1.5 eq.) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (24.4 g, 99.2 mmol, 1.5 eq.) in DCM (150 ml) was then added dropwise at 0° C., and the reaction mixture was stirred overnight at room temperature. TLC monitoring (silica gel, DCM) showed complete conversion. When the reaction was complete, the reaction solution was diluted with DCM (250 ml) and washed with 0.5 M KHSO4 (500 ml), saturated NaHCO3 (500 ml) and saturated NaCl solution (500 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. For purification, filtration over a thin layer of silica gel was carried out (gradient: heptane/DCM (3:1) to DCM).
Reaction SMILES: CC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[CH:7]=[O:8].[OH-].[Na+].[OH:15][CH2:16][C:17]([C@@H:19]([C@@H:21]([C@H:23]([CH3:25])[OH:24])[OH:22])[OH:20])=[O:18].C(O)C(COP(O)(O)=O)=O.Cl.O=C[C@H]([C@@H]([C@@H]([C@H](C)O)O)O)O>O.CO>[CH3:7][O:8][CH2:25][C@H:23]([OH:24])[C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]([OH:18])[CH:16]=[O:15]
Reactant: CC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)CO
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: Cl
Agent: O=C(CO)COP(=O)(O)O
Solvent: CO
Solvent: O
Product: COC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A method for synthesizing 6-methyl-L-fucose is illustrated in Scheme 2. Compound 7e, the starting material, was synthesized according to the method of Wong et. al. (J. Am. Chem. Soc., 1986, 108, 7812, (1.21 g; 10.1 mmol). Compound 7e was dissolved in water (3 mL) and Dowex 50W-X8 (H+ form, 200-400 mesh) was added until pH 2.8. The mixture was heated at 50° C. for 8 h, then the resin was filtered off and washed with water (2×0.5 mL). A solution of 2, as synthesized by Wong, C.-H. et. al. J. Org. Chem. 1994, 59, 7182, (4.62 mL, 1.68 mmol) was added and the mixture was adjusted to pH 6.8 with 6N NaOH (0.4 mL). L-fuculose aldolase (5.2 mL, 50 units) previously prepared by Wong, C.-H. et. al. Bioorg. Med. Chem. 1995, 3, 945, was added, the mixture was stirred gently at room temperature for 17 h (DHAP analysis indicates 95% conversion) and the pH was adjusted to 4.7 with 6N HCl (0.4 mL). Acid phosphatase (0.45 mL, 225 units) was added and the mixture heated at 37° C. for 19 h. The mixture was cooled to room temperature and the pH was adjusted to 7.5 with 6N NaOH (0.6 mL). MnCl2 (30 μl, 0.7 M) and L-fucose isomerase (3 mL, 2460 units) were added. The mixture was stirred at room temperature for 24 h and adjusted to pH 7.0 with 2N HCl. Methanol (2 vol) was then added and the precipitate was filtered off through Celite. The solvent was removed under reduced pressure and the residue chromatographed on silica gel with CHCl3/methanol (3:1). The fractions containing L-fucose 8e were pooled, then concentrated and the residue chromatographed on Dowex 50W-X8 (Barium form, 200-400 mesh) with water/ethanol (1:1) to yield 8e as a white-yellowish solid (63 mg, 0.3 mmol, 25%). [α]D=−14.4 (c=1, MeOH, 4 h), [Lit, [α]25eq=−80.6 (c=1, pyridine, eq)]. 1H-NMR (400 MHz, D2O) δ: 5.10 (H1α, d, JH1α,H2α=3.6 Hz), 4.42 (H4β, d, JH1β,H2β==8 Hz), 4.08 (H5α, t, JCH2,H5α=6 Hz), 3.81 (H4α, d, JH4α,H3α=3 Hz), 3.75 (H4β, d, JH4β,H3β=3.5 Hz), 3.6-3.7 (H2α, H3α, H5β, overlapped signals), 3.58 (CH3O—, α and β), 3.47-3.52 (H3β and CH2 α and β, overlapped signals), 3.32 (H2β, dd, JH1β,H2β=8 Hz, JH2β,H3β=10 Hz) 13C-NMR (100 MHz, D2O) δ (ppm): 96.31 (C1β), 92.19 (C1α), 73.17, 72.61, 71.82, 71.61, 69.46, 68.93, 68.44, 68.19, 59.29 (CH3), 58.35 (C6β), 58.20 (C6α). HRMS Calcd for C7H14O6+Na+ 217.0688, observed 217.0647.