Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.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>[CH3:15][Si:16]([C:19]#[C:20][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:14])([CH3:1])[CH2:3][CH2:4][C:5]2=[O:13])=[CH:10][CH:9]=1)([CH3:18])[CH3:17]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2cc(C#C[Si](C)(C)C)ccc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 7 g (27.6 mmol) of 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound B) in 150 ml of triethylamine was added 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.3 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 39 ml (36.6 mmol) of (trimethylsilyl)acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 7-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 0.6 g (4.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O, washed with water, 10% HCl and brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3): δ 1.39 (6H, s), 2.02 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0 Hz), 3.08 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.61 (1H, dd, J=1.8, 8.2 Hz), 8.14 (1H, d, J=9 1.8 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O:12][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:11])=[CH:7][CH:8]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccc(F)cc1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
2-(4-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (255 mg, 0.93 mmol) was dissolved in dry THF (10 ml) and (R)-quinuclidin-3-ol (355 mg, 2.79 mmol), DCC (384 mg, 1.86 mmol), HOBt (285 mg, 1.86 mmol) were added. The mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2) to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (126 mg, 39.0% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].[NH2:24][OH:25].Cl>CCO.CCOC(C)=O.O>[OH:25][NH:24][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(NO)c1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
4-Cyano-N-phenyl-benzenesulfonamide (crude) (198 mg, 0.652 mmol), Sodium bicarbonate (547 mg, 6.52 mmol) and NH2OH.HCl (453 mg, 6.52 mmol) was dissolved in EtOH (2172 μL) and the resulting solution stirred overnight at 60° C. The mixture was diluted with EtOAc and water. The water phase was extracted and the combined organic phases washed with brine, then dried over magnesium sulfate. After evaporation of the solvent, 175 mg (0.571 mmol) of a white solid was obtained. The product was used without purification in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 97.1 %

Procedure:
To a solution of ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate (160.0 g, 733 mmols) in acetic acid (960 mL) was added 5% palladium on activated carbon (32.0 g, 50% hydrous). The mixture was stirred at 50° C. for 3.5 hours under hydrogen atmosphere (ambient pressure). The catalyst was filtered off and the filtrate containing 156.7 g (yield: 97%) of the title compound was obtained which was provided to the next step.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:6][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C=CCCC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 10.53 g (105 mmol) of pent-4-enoic acid in 150 ml ethanol was added 17.1 g (52.5 mmol) of Cs2CO3 and the reaction mixture was stirred at 40° C. for 2 h. The solvent was removed in vacuo, the residue coevaporated three times with toluene and then dissolved in 150 ml of DMF. 17.96 g (105 mmol) of benzyl bromide were added and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was filtered, diluted with water and extracted three times with heptane. The combined organic phases were dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 19.92 g.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1.C>CCO>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]=[N:9]1
Reactant: O=C(O)CCc1cn(Cc2ccccc2)nn1
Solvent: CCO
Product: O=C(O)CCc1c[nH]nn1
Reaction time: 24 h

Procedure:
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propanoic acid (step 1) (4.37 g, 18.90 mmol) was dissolved in EtOH and stirred for 10 mins with activated charcoal (1.13 g) and of Celite® (filter material). The reaction mixture was filtered and transferred into a 400 mL Duran Bottle. The colorless solution was set on a continuous cycle at 30 bar pressure and 70° C. through the H-Cube (continuous flow hydrogenation) for 24 hrs. The resulting material was concentrated under reduced pressure and the crude product was suspended in ether and filtered to afford the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:15])/[C:5](=[CH:18]\[N:19]([CH3:21])[CH3:20])/[C:6](=[O:14])[CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Product: CCOC(=O)/C(=C\N(C)C)C(=O)C(OCC)OCC
Reaction time: 0.5 h

Procedure:
A mixture of the 4,4-diethoxy-3-oxo-butyric acid ethyl ester (0.500 g, 2.29 mmol, prepared according to the procedure described in JACS, 1919, 41, 812) and dimethylformamide dimethyl acetal (370 μL, 2.78 mmol) in xylenes (5.0 mL) is warmed at reflux. After 30 minutes, The reaction mixture is concentrated in vacuo to afford 2-[1-dimethylamino-meth-(Z)-ylidene]-4,4-diethoxy-3-oxo-butyric acid ethyl ester, which is used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=CC=C[CH:18]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:23]([C:25]2[CH:30]=CC=C[CH:26]=2)=[O:24])=[CH:5][CH:4]=1.ClCCl.BrBr>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:16])[CH:17]([CH3:22])[CH3:18])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:23](=[O:24])[CH:25]([CH3:30])[CH3:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1-c1ccc(C(=O)c2ccccc2)cc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)cc1-c1ccc(C(=O)C(C)C)cc1
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere 4.3 grams of 1,1′-(6-methoxy-[1,1′-biphenyl]-3,4′-diyl)bis(2-methylpropan-1-one), which was prepared by following a procedure described in the below Example 4 for the synthesis of (6-methoxy-[1,1′-biphenyl]-3,4′-diyl)bis(phenylmethanone), was mixed with 80 mL of dry dichloromethane and 10 mL of CCl4 at room temperature. 4.2 grams of bromine was added and the resultant solution was continuously stirred at this temperature until the reaction completion was detected by TLC monitoring. The mixture was then concentrated and the residue was mixed with 100 mL of 2N NaOH solution. After stirring overnight the mixture was poured into 200 mL of water, and the aqueous layer was extracted by 100 mL of dichloromethane. The combined organic layer was washed by brine and dried over MgSO4. The filtered solution was then concentrated and the residue was loaded onto silica gel column and eluted by mixtures of hexane/ethyl acetate to give 3.6 grams of the light-yellow product (77% yield). 1H NMR (CDCl3, ppm): 8.13-8.09 (m, 4H), 7.63 (d, 2H, J=8.4 Hz), 7.05 (d, 1H, J=9.0 Hz), 4.17 (s, 1H), 4.16 (s, 1H), 1.68 (s, 6H), 1.65 (s, 6H); 13C NMR (CDCl3, ppm): 204.0, 202.4, 160.2, 142.2, 133.0, 132.3, 129.6, 129.5, 129.2, 126.1, 110.6, 77.4, 76.0, 55.8, 28.6, 28.1.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)(O)=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1nc(CO)co1)c1ccccc1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (500 mg, 1.65 mmole) in dry THF (8 mL) was added 4-methylmorpholine (0.22 mL, 1.99 mmole) then ethyl chloroformate (0.19 mL, 1.99 mmole) at 0° C. After 10 min, NaBH4 (249 mg, 6.59 mmole) was added all at once, then MeOH (8 mL) was added dropwise. After 30 min, the mixture was quenched with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (80% EtOAc/hexanes) to give the title compound (371 mg, 78%) as a yellow oil: MS (ES) m/e 290 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:15])=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(5-acetyl-2-hydroxyphenyl)acetate (8.0 g) was dissolved in N,N-dimethylformamide (120 ml), and benzyl bromide (5 ml) and potassium carbonate (5.8 g) were added to the solution, then the resulting mixture was stirred for 16 hours at room temperature. Ice (ca. 100 g) and hexane (200 ml) were added to the reaction mixture, and water (200 ml) was added to the resulting mixture with vigorously stirring. The precipitated crystal was collected by filtration and recrystallized from dichloromethane-hexane to give methyl 2-(5-acetyl-2-benzyloxyphenyl)acetate (10.1 g) having a melting point of 85-87° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9]4)=[CH:4][CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(N2CCC(N3CCCCC3)C2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCC(N5CCCCC5)C4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[1-(4-iodo-phenyl)-pyrrolidin-3-yl]-piperidine (120 mg, 0.34 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (73 mg, 0.34 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:28]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][C:10]([NH:9][CH2:8][CH2:7][O:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:11])[CH2:18][CH2:17]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(Cc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide. 540 mg (3.93 mmol) of potassium carbonate and 0.16 ml (1.31 mmol) of benzyl bromide were added to the solution, and they were stirred at 50° C. for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, crude 1-benzyl-N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was obtained. The crude product was stirred in 10 ml of dioxane containing 4 N hydrogen chloride. 3.5 ml of ethanol containing 30% (w/v) of hydrogen chloride was added to the resultant mixture. After the stirring at room temperature for 3 days, the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of 10% (w/v) solution of ammonia in ethanol, and the obtained solution was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was treated by the reversed-phase high-performance liquid chromatography with silica gel, containing octadodecyl group chemically bonded thereto, as the filler. After the elution with a mixed solvent of water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, the fraction of the intended product was freeze-dried to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[C:27]([OH:31])(=[O:30])[CH:28]=O.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:28][C:27]([OH:31])=[O:30])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCC(=O)O)cc1-c1ccccc1
Reaction time: 14 h
Yield: 83.3 %

Procedure:
A mixture of (4-amino-2-phenylbenzoyl)methionine methyl ester (compound 8, 1.51 g, 4.21 mmol), glyoxylic acid monohydrate (466 mg, 5.06 mmol), sodium cyanoborohydride (1.0 M in THF, 4.2 mL), sodium acetate (0.5 g) and acetic acid (0.5 mL) in methanol (10 mL) was stirred for 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous potassium dihydrogenphosphate, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate, then 3% methanol-ethyl acetate) to give (4-carboxymethylamino-2-phenylbenzoyl)methionine methyl ester (1.46 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H), 7.39 (m, 5H), 6.54 (dd, 1H), 6.45 9d, 1H), 5.96 (br d, 1H), 4.63 (m, 1H), 3.88 (d, 2H), 3.67 (s, 3H), 2.04 (m, 2H), 2.00 (s, 3H), 1.86 (m, 1H), 1.67 (m, 1H). MS (APCI+) m/e 417 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)N)cc1
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Methyl 4′-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-3-fluoro-1,1′-biphenyl-2-carboxylate (0.25 g, 0.59 mmol) was dissolved in 6.0 mL of anhydrous ethanol. Pd/C (90 mg) was then added and the nitrogen atmosphere was exchanged for hydrogen. The reaction mixture was allowed to stir for 72 hours. After filtration though celite, the ethanol was removed under reduced pressure to yield 0.15 grams of methyl 4′-(1-amino-1-methylethyl)-3-fluoro-1,1′-biphenyl-2-carboxylate which was of sufficient purity to use directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])[C:14]([CH3:16])=O>>[CH2:19]([O:18][C:13](=[O:17])[C@H:14]([CH3:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2)[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: CC(=O)C(=O)OCC(C)C
Product: Cc1ccc2cc(N[C@@H](C)C(=O)OCC(C)C)ccc2n1

Procedure:
Following General Procedure A above and using 6-amino-2-methylquinoline (Lancaster) and iso-butyl pyruvate (prepared by following General Procedure O above), the title compound was prepared. The reaction was monitored by silica gel tlc (Rf=0.44 in 50% EtOAc/hexanes). Purification was by flash chromatography (silica gel using 50% EtOAc/hexanes as the eluant).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]2[O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:2]=1)=[O:7]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Temperature: 95 °C
Yield: 84.9 %

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (1.27 g, 0.01 mole) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (5.04 g, 0.01 mole) was melted and then 0.095 g of p-toluenesulfonic acid was added thereto. The reaction mixture was reacted for 3 hours, while maintaining the temperature of the reaction mixture at 95±5° C. And then, the reaction mixture was crystallized with 25 ml of methanol to give 4.85 g of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (yield: 85%).
Reaction SMILES: [Li]C.CCOCC.O([NH2:10])C.[Li][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2>CCCCCC>[NH2:10][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2
Reactant: CON
Reactant: [Li]c1cccc2c1CC(N(CCC)CCC)CC2
Agent: [Li]C
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN(CCC)C1CCc2cccc(N)c2C1
Temperature: -15 °C

Procedure:
A stirred solution (9.2 ml) of 0.92M MeLi in ether (8.5 mmol) of methoxylamine in hexane (9 ml) was added dropwise (1 drop/s) followed by 2.6 ml (4.3 mmol) of a 1.55M solution of 5, 6, 7 or 8-lithio-2-(di-n-propylamino)tetralin (prepared from 5, 6, 7 or 8-bromo-2-(di-n-propylamino)tetralin and n-BuLi). The mixture was warmed to -15° C. for 2 hr and quenched with water (0.5 ml). Workup of the resulting mixture afforded the desired 5, 6, 7 or 8-amino-2-(dinpropylamino)tetralin.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mmol) was combined with acetic anhydride (0.052 mL, 0.55 mmol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give tert-butyl 4-(acetylamino)piperidine-1-carboxylate, LCMS [M+Na]+: m/z=265.1. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude HCl salt product (0.057 g), which was used directly in the next step. LCMS calculated for C7H15N2O (M+H)+: m/z=143.1; Found: 143.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:19])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-1-(1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 12 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (0.348 mL, 2.0 mmol) in dioxane (3 mL) was stirred for 24 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then crystallised from acetonitrile affording 119 as a white solid (50 mg, 34%). LCMS: RT 3.23 min [M+H]+ 370.0. 1H NMR (DMSO, 400 MHz): δ 8.21-8.07 (2H, m), 7.86-7.49 (7H, m), 7.28-7.17 (2H, m), 7.08 (1H, d, J=7.68 Hz), 5.42 (1H, br), 2.08-1.90 (2H, m), 0.83 (3H, t, J=7.32 Hz)