Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:31]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[O:32]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]#[C:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].O.NN>C(O)C>[NH2:20][CH2:19][C:18]#[C:17][CH2:16][O:15][C:9]1[CH:8]=[C:7]([C@H:31]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=3)[O:32]2)[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(OCC#CCN2C(=O)c3ccccc3C2=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCOc1c(OCC#CCN)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Yield: 50 %

Procedure:
To a solution of trans-2-[3-methylsulfonyl-5-(4-phthalimido-but-2-ynyloxy)-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran. (244, whole amount obtained from the previous step) in ethanol (5.0 mL) was added hydrazine hydrate (136 mL, 2.8 mmol). The resulting solution was refluxed overnight. The ethanol was removed in vacuo and the residue was diluted with methylene chloride (25 mL) and water (25 mL). The layers were separated and the water layer was extracted with methylene chloride (25 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified using PLC (eluent, 5% methanol in methylene chloride) to obtain 75 mg (50% overall from 242) of trans-2-[3-(4-amino-but-2-ynyloxy) -5-methylsulfonyl-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (244). 1H-NMR (CDCl3) δ7.55 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=2.0 Hz), 6.59 (2H, s), 5.16-5.28 (2H, m), 4.79 (2H, s), 4.12 (2H, t, J=6.6 Hz), 3.87 (6H, s), 3.81 (3H, s), 3.44 (2H, s), 3.23 (3H, s), 2.43-2.50 (2H, m), 1.83-2.03 (4H, m), 1.57 (2H, brs), 1.04 (3H, t, J=6.6 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.FC(F)(F)S(O[CH2:18][CH:19]([F:21])[F:20])(=O)=O.O>CN(C=O)C>[F:20][CH:19]([F:21])[CH2:18][N:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CSc1nc2cccnc2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2cccnc2n1CC(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (600 mg) and 2,2-difluoroethyl trifluoromethanesulfonate (816 mg) in DMF (7 mL) was stirred at 80° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound (400 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[N:33]1>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[N:33]=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cn1nncc1C=O
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.45 g, 3.37 mmol, Intermediate 5: step d) was added THF (25 mL) and the solution was cooled to −75° C. n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was then added dropwise. After 2 minutes, 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (580 mg, 5.22 mmol, in 3 mL THF) was introduced. The reaction mixture was allowed to warm to −20° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (5×40 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (5% CH3CN-DCM increasing to 30% CH3CN+2% MeOH) provided the title compound as an off white amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[N:12]=[N:13][C:14]([O:17][CH2:18][C:19]3[C:20]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])=[N:21][O:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O>C(O)C>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[C:20]1[C:19]([CH2:18][O:17][C:14]2[N:13]=[N:12][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=3)=[CH:16][CH:15]=2)=[C:23]([CH:24]([CH3:26])[CH3:25])[O:22][N:21]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(Oc2ccc(C(=O)O)cc2)nn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a suspension of 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridazin-3-yloxy}-benzoic acid methyl ester from the previous step (0.083 g, 0.155 mmol) in ethanol (5 ml) was added sodium hydroxide (0.02 g, 0.5 mmol) and water (0.2 ml). The reaction mixture was stirred at room temperature for 20 h. The volatiles were removed in vacuo and the residue was diluted with water (3 ml) and the resulting solution was acidified to pH 5 by addition of 4N HCl. The formed precipitate was collected by filtration, washed with water (3×5 ml) and dried on air to provide 0.08 g (99%) of the title product.
Reaction SMILES: CN1CCCCC1.[F:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:34]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=1)#[N:35]>C(Cl)Cl.O>[C:34]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][CH:42]([NH:44][C:21](=[O:23])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:25][CH:24]=2)=[O:15])[CH3:43])=[CH:38][CH:37]=1)#[N:35]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: CC(C)[C@H](NC(=O)Oc1ccc(F)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccc(F)cc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
1.2 g of N-methylpiperidine was added to a solution containing 3.0 g of N-(4-fluorophenoxycarbonyl)-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 1.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 2.3 g of (-)-2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 23% ).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1
Yield: 42.6 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.77 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid (145 mg, 1.15 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent 100% DCM) to yield a total of 121 mg (43%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.74 (s, 3H), 4.27 (dd, 1H), 4.41 (dd, 1H), 4.50-4.62 (m, 1H), 6.61 (d, 1H), 7.43 (d, 1H), 7.48 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.78 (dd, 1H), 7.86 (d, 1H), 8.17 (d, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:24][CH:23]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:34].[NH2:8][C@H:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:26][CH:27]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 4 h
Yield: 201.3 %

Procedure:
To (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (3.561 g, 7.42 mmol) is added a solution of 4 M HCl in 1,4-dioxane (18.55 mL, 74.2 mmol) at room temperature. After stirring for 4 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (3.11 g). HPLC retention time=1.07 minutes (condition B); MS (m+1)=380.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.81 (A of ABX, Jab=17.4 Hz, Jax=4.5 Hz, 1 H) 2.93 (B of ABX, Jab=17.4 Hz, Jbx=7.6 Hz, 1 H) 3.03-3.09 (m, 1 H) 3.50 (dd, J=4.9 and 13.5 Hz, 1 H) 3.98 (br s, 1 H) 5.09 (s, 2 H) 7.24-7.22 (m, 9 H) 7.35-7.38 (m, 1 H) 7.42 (d, J=8.1 Hz, 2 H) 7.48-7.49 (m, 1 H) 8.78 (br s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:28]([O-])=O.[Na+]>Cl.O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[C:18]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=4)[N:10]=3)=[CH:3][C:2]=2[N:1]=[N:28]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N(C)C(C)C)nc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N(C)C(C)C)nc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
To a solution of methyl 2-(3,4-diaminophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (635 mg, crude) in HCl (1N, 150 mL) was added sodium nitrite (132 mg, 1.91 mmol) in water (1 mL) at 0° C. After stirring for 15 min at 0° C., the reaction mixture was extracted with dichloromethane (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% methanol in dichloromethane) to afford methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (140 mg).
Reaction SMILES: [Cl-].[CH3:2][S:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH3:2][S:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([S:3][CH3:2])=[CH:29][CH:28]=2)=[CH:28][CH:29]=1
Reactant: CSc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CSc1ccc(/C=C/c2ccc(SC)cc2)cc1

Procedure:
Following the procedure as describe in method 1, but sustituting 4-methylthiobenzyltriphenylphosphonium chloride for benzyltriphenylphosphonium chloride, the desired residue was purified by flash chromatography (silica gel; hexane/EtOAc (90:10)) and recrystallisation from hexane.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]>CO.[Pd]>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (1.2 g, 3.02 mmol) in methanol (25 ml) was added Pd/C 10% wt (210 mg) and the mixture was stirred under hydrogen (1 atm) for 6 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (870 mg, 94%); Rt (HPLC): 3.61 min; Rf (cyclohexane:ethyl acetate=1:1): 0.18; MS: (ES/+) m/z: 329 [M+Na+]. C16H22N2O4 requires 306; 1H NMR (300 MHz, d6-DMSO) δ ppm: 9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H); 4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m, 1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)([C:23]#[N:24])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(Br)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Br)cc2)CC1
Temperature: 110 °C
Yield: 51.7 %

Procedure:
To a mixture of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester from Step 1 (7.26 g, 30 mmol, 1 eq) and 4-bromophenylacetonitrile (5.88 g, 30 mmol, 1 eq) in 38 mL of toluene and 76 mL of H2O was added NaOH (45.6 g, 114 mmol, 10M solution) followed by hexadecyltributylphosphonium bromide (3.0 g, 6.0 mmol, 0.2 eq). The resulting dark mixture was heated to 110° C. for 2 h and then allowed to cool to ambient temperature. It was extracted with three 200 mL portions of ethyl acetate and the combined organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product as a black oily residue. Purification by flash column chromatography eluting with a gradient of 5-10% ethyl acetate in hexane gave 5.67 g of 4-(4-bromo-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam. 1H NMR (300 MHz, CDCl3): δ 7.56-7.48 (d, 2H), 7.36-7.30(d, 2H), 4.40-4.10 (br. s, 2H), 3.27-3.05 (t, 2H), 2.10-1.80 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=[O:40]>CC(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1[CH:6]=[CH:5][C:4]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[CH:39]=[O:40])=[CH:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1cccc(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 67.4 %

Procedure:
Into a 2 L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of pyridin-4-ylboronic acid (30 g, 244 mmol, 1 equiv) in 2-propanol/water (800/40 mL), Na2CO3 (77.3 g, 729 mmol, 3 equiv), Pd(OAc)2 (5.46 g, 24.3 mmol, 0.1 equiv), PPh3 (12.75 g, 48.7 mmol, 0.2 equiv) and 3-bromobenzaldehyde (45 g, 243 mmol, 1 equiv). The mixture was stirred for 48 h at 80° C. in an oil bath. Then the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give 30 g of 3-(pyridin-4-yl)benzaldehyde as orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1.CC(O)C.C(O)(=O)C.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Yield: 94.4 %

Procedure:
To a solution of 0.73 g (3 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine and 0.49 g (4 mmol) N,N-dimethylaniline in 10 mL THF is added a solution of 0.94 g (3.4 mmol) of 1-(tert-butoxycarbonyl)-4-(4-aminophenyl)-piperazine in 20 mL of 2-propanol, and the resulting mixture is heated under reflux for 2 hours. After cooling and acidification with acetic acid, the mixture is diluted with water to give 1.37 g (94%) of the title compound: mp (MeOH) 194–196° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].[F-].[K+]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 100.1 %

Procedure:
4-Bromobenzonitrile (73 mg, 0.40 mmol) reacted with 4-formylphenylboronic acid (90 mg, 0.60 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.21 mmol) in THF solvent at 40° C. to give the title compound (83 mg, 97%) as a white solid: 1H-NMR (500 MHz, CDCl3): δ 10.10 (s, 1H), 8.01 (d, 2H, J=8.25 Hz), 7.80-7.74 (m, 6H). 13C{1H}-NMR (125 MHz, CDCl3): δ 191.57, 144.90, 144.14, 136.14, 132.78, 130.41,128.03, 127.91, 118.52, 112.17. GC/MS(EI): m/z 207 (M+), 206.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:9]1=[O:13]
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(C#N)cc2)C1=O
Yield: 64.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 4-bromo-benzonitrile (154 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 151 mg of the product (64.2% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].C1C(=O)N([Cl:29])C(=O)C1>C1COCC1>[Br:1][C:2]1[C:3]([OH:21])=[C:4]([Cl:29])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.69 g, 1.90 mmol) and NCS (0.31 g, 2.3 mmol) in THF (25 mL) according to method C to yield 0.61 g (81%) of a yellow solid. An analytical sample was further prepared by reverse phase preparative HPLC to yield the title compound as a white solid: mp 176-178° C. (dec.); 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.08 (2H, d, J=8.77 Hz), 7.77 (2H, d, J=8.75 Hz), 8.00 (1H, d, J=1.84 Hz), 8.19 (1H, d, J=1.84 Hz), 8.39 (1H, s), 10.53 (1H, bs); MS (ESI) m/z39513971399 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][C:16]([C:19](O)=[O:20])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:24][C:25]1[CH:30]=[C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=[CH:27][C:26]=1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][C:16]([C:19]([NH:24][C:25]4[CH:30]=[C:29]([C:31]5[S:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=[CH:27][C:26]=4[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:20])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: N#Cc1ccc(CN2CCN(c3ncc(C(=O)O)s3)CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1cnc(N2CCN(Cc3ccc(C#N)cc3)CC2)s1
Yield: 47 %

Procedure:
A solution of acid 339 (113 mg, 0.34 mmol) amine 178 (100 mg, 0.34 mmol) and BOP (152 mg, 0.34 mmol) in pyridine (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography using gradient eluent 50%-75% EtOAc in hexanes to afford the title compound 340 (96 mg, 47% yield). MS: calc: 600.1; found: 601.3 (M+H)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[O:9]>C1COCC1.[Pd]>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CCCCC/C=C/C(=O)CCc1ccc(O)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [6]-shogaol (276 mg, 1.0 mmol) in THF (2 mL) at rt was treated with 10% Pd/C (30 mg, 10% w/w) under H2. The mixture was stirred at rt overnight and filtered. The filtrate was concentrated under reduced pressure. The residue was loaded to preparative TLC (hexane/EtOAc=8:1) to give the title compound M11 as a yellow oil (272 mg, yield 98%); 1H NMR (600 MHz, CDCl3) δ 6.69 (1H, d, J=1.6 Hz, H-2′), 6.82 (1H, d, J=8.0 Hz, H-5′), 6.66 (1H, dd, J=8.0, 1.7 Hz, H-6′), 2.69 (2H, t, J=7.4 Hz, H-1), 2.82 (2H, t, J 7.4 Hz, H-2), 2.37 (1H, t, J=7.4 Hz, H-4), 1.54 (2H, m, H-5), 1.30-1.24 (8H, m, ranged from H-6 to H-9), 0.87 (3H, t, J=6.8 Hz, H-10), and 3.87 (3H, s, OMe-3′); positive APCIMS, m/z 279 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)([CH2:21][CH3:22])[C:18](=[O:20])[CH3:19])[CH3:16]>>[CH2:15]([C:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:24]=1)([CH2:21][CH3:22])[C:18](=[O:20])[CH3:19])[CH3:16]
Reactant: CCC(CC)(C(C)=O)c1cccc(O)c1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCC(CC)(C(C)=O)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 3-ethyl-3-(3-hydroxyphenyl)pentan-2-one to give 3-ethyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pentan-2-one in 40% yield as a gum.