Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:39])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:18]([O:28][CH2:29][CH2:30][OH:31])=[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH3:47][O:46][C:44](=[O:45])[CH2:43][O:31][CH2:30][CH2:29][O:28][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:20][C:15]([C:14](=[O:39])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:16][C:17]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(OCCOCC(=O)OC)c(-c2cccc(Cl)c2)c1
Temperature: 60 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-dodecyl-3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzamide (Example 1, Step 2), (0.866 g, 1.52 mmol) in THF (8 mL) was added NaH (0.10 g, 80%, 3.34 mmol). The mixture was stirred at 60° C. for 50 min and was then cooled to room temperature. Methyl bromoacetate (0.158 mL, 2.67 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was cooled, quenched with 1.0 N HCl, and extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated. Crude product was purified by HPLC. Yield: 0.177 g (18%) of product as an oil. 1H NMR (CDCl2) δ 7.72 (s, 2H), 7.63 (s, 2H), 7.50 (m, 2H), 7.39 (m, 4H), 6.20 (t, 1H), 3.78 (m, 5H), 3.49 (m, 4H), 3.31 (m, 2H), 1.68 (m, 2H), 1.30 (m, 18H), 0.88 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1F)[C:5]([O:7]CC)=[O:6].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-n2cncn2)c(F)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3,4-difluoro-benzoate (1.5 g) in N,N-dimethylformamide (15 mL) is added 1,2,4-triazole (1.1 g) and K2CO3 (2.3 g) and the mixture is heated at 150° C. in a microwave oven for 30 min. After cooling to room temperature, water and ethyl acetate are added and the organic layer is dried (MgSO4) and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate/hexane 0:1→1:0). The ester is dissolved in methanol (30 mL) and 4 M aqueous NaOH (3 mL) is added and the mixture is stirred at room temperature for 1 h. The mixture is neutralized with 6 M aqueous HCl, concentrated and then acidified with 6 M aqueous HCl. The precipitate is filtered off washing with a small amount of water and dried by suction to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[CH:67]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[CH:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCCC1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/C1CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (3 g, 4.40 mmol) was dissolved in 30 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (9.6 mL, 8.80 mmol). After the mixture was stirred for 30 minutes, a solution of 1-methylpyrrolidine-2-carbaldehyde 10e (1 g, 8.80 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methylpyrrolidin-2-yl)prop-2-enamide 10 (500 mg, yield 20.8%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[CH:24][CH:23]=2)[O:18][CH2:19][CH2:20][OH:21])[CH3:14])=[CH:8][CH:7]=1)=[O:3].[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([O:18][CH2:19][CH2:20][OH:21])[C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)[CH3:14])=[CH:8][CH:7]=1)=[O:3]
Reactant: [H][H]
Reactant: CC(Cc1ccc(OCC(N)=O)cc1)NCC(OCCO)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(OCCO)c1ccc(O)cc1

Procedure:
N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (3.5 g) in glacial acetic acid (30 ml) was hydrogenated in the presence of 10% Palladium on carbon at atmospheric pressure and room temperature until hydrogen uptake was complete. The solution was filtered through diatomaceous earth and the solvent removed under vacuum. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer separated, dried (MgSO4) and evaporated to give an oil. The oil was crystallised from ethyl acetate to give the title compound, m.p. 145°-160° C. as a 40:60 mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:5]2=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:29][CH3:30]>O>[CH2:29]([O:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH3:30]
Reactant: COC(=O)c1cc(=O)c2cc(F)ccc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)OC)nc2ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8.0 g (0.036 M) of methyl 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate and 15.0 g (0.108 M) of potassium carbonate are introduced into 80 ml of DMF. The reaction mixture is stirred for 1 hour at 50° C. After addition of 3.0 ml (0.037 M) of iodoethane and heating for 12 hours at 50° C., the reaction medium is poured into 400 ml of demineralized water. A brown solid precipitates out. The solid is filtered off, washed thoroughly with water and then with isopropyl ether, and finally dried under vacuum at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccccc1C=O
Solvent: O
Solvent: NCCO
Product: COc1ccccc1C=C1NC(=O)NC1=O
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of o-methoxybenzaldehyde (2.00 g., 14.7 moles) and hydantoin (1.47 g., 1 molar ratio) in water (12ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was heated in an oil bath (90°-92° ) and stirred magnetically for 4 hours. Usual workup gave the title compound as an orange solid (2.90 g.), m.p. 174°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:33])([F:32])[F:31].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:31])([F:33])[F:32])=[O:8])=[O:5]
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 95 mg of 3-(4-amino-3-trifluoromethoxyphenyl)-4H-[1,2,4]-oxadiazol-5-one hydrochloride and 0.054 ml of Hünig's base in 4 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>O>[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine were added to 50 ml of chloroform. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of chloroform solution containing 2.3 g of 4-methylbenzoyl chloride. After completion of addition, the reaction mixture was stirred for 30 minutes. After completion of reaction, 100 ml of chloroform and then a large amount of water was added to separate chloroform and the chloroform layer was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from chloroformether to give 1.8 g of 5-[4-(4-methylbenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 239.5°-240° C., colorless powders.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[N:25]1([S:21]([C:19]2[CH:18]=[CH:17][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:20]=2)(=[O:23])=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), azetidine (34 uL, 26 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 37 mg (46% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.52-1.65 (m, 4 H), 1.68 (s, 9 H), 1.99-2.13 (m, 2 H), 2.32-2.47 (m, 1 H), 3.32-3.43 (m, 2 H), 3.74-3.84 (m, 4 H), 3.90-4.01 (m, 2 H), 4.54 (d, J=7.42 Hz, 2 H), 7.92 (dd, J=8.79, 1.56 Hz, 1 H), 8.09 (d, J=8.79 Hz, 1 H), 8.15 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=392.0; Anal. Calcd for C20H29N3O3S+1.20 TFA+0.40 EtOAc+0.1H2O (556.60): C, 50.93; H, 5.94; N, 7.55. Found: C, 50.98; H, 5.68; N, 7.50.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1])=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Sc2ccccc2)cc1
Reactant: O=C(Cl)CCCC=C(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCC=C(F)F)Nc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling at 10°, 8.5 g of 6,6-difluorohex-5-enoic acid chloride are added to 10.0 g of 4-phenylthioaniline, 6.5 g of triethylamine and 100 mg of 4-N-pyrrolidinopyridine in 250 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and 90-95% of the amount of toluene is evaporated off in vacuo. While the mixture is still warm, a small amount of hexane is added, which causes the product to crystallise out. The mixture is cooled and filtered, and the filter residue is washed with hexane, yielding the title compound having a melting point of 80°-81° (compound no. 2-1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1C(C)C(OCC)=O.C(Cl)Cl>CCCCCC>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)Cc1c(Br)c(OC)c2ccccc2c1OC
Agent: CCOC(=O)C(C)C1=C(Br)C(=O)c2ccccc2C1=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(C)CC1=C(Br)C(=O)c2ccccc2C1=O

Procedure:
Compound 68b was prepared from 67b (0.258 g, 0.678 mmol) as described above for 68a to give 0.064 g (0.18 mmol, 27%) of the product as a yellow solid following flash chromatography (3:1 CH2Cl2:hexane).
Reaction SMILES: CS[C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH:31]1C=C(Cl)C=C(C(OO)=O)C=1.[S:42]([O-:46])([O-])(=[O:44])=S.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH3:31][S:42]([C:3]1[C:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:46])=[O:44]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC[C@H](NC(=O)c1c(SC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC(=O)c1c(S(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3-(methylthio)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (1) (40 mg, 0.097 mmol) in CH2Cl2 (1 mL) was added MCPBA (54 mg of 70-75%, 0.23 mmol) and solution allowed to stir for 1 h. Additional MCPBA (10 mg) was added and reaction heated at 40° C. for 1 h., then allowed to cool. Next was added H2O (1 mL) and a few crystals of sodium thiosulfate, CH2Cl2 (3 mL), and 1 N NaOH (2 mL-aqueous). The layers were shaken together, separated, the organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% EtOAc/CH2Cl2) to give the desired product (6 mg) as a white solid. 1H NMR (300 MHz, CDCl3, 65° C.) δ 8.13 (d, J=8.5 Hz, 1H), 7.92-7.76 (m, 2H), 7.59-7.25 (m, 11H), 6.19-6.08 (m, 1H), 5.27-5.15 (m, 1H), 2.96 (s, 3H), 2.28-1.87 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); HRMS m/z 445.1573, calcd 445.1586.
Reaction SMILES: C=CC[C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([OH:17])=[C:15]([OH:18])[CH:14]=[C:13]([CH2:19][CH:20]=[CH2:21])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH3:22][CH2:23][CH2:24]CCC>CO.C(OC(=O)C)C.[Pd](Cl)Cl>[CH:22](/[C:5]1[CH:4]=[CH:9][C:8]([O:10][C:11]2[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH3:21])[CH:14]=[C:15]([OH:18])[C:16]=2[OH:17])=[CH:7][CH:6]=1)=[CH:23]\[CH3:24]
Reactant: CCCCCC
Reactant: C=CCc1cccc(Oc2cc(CC=C)cc(O)c2O)c1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C/C=C/c1ccc(Oc2cc(/C=C/C)cc(O)c2O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of obovatol (1 g) in methanol was added palladium chloride (PdCl2) (10 mg), followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer containing the active material was collected and concentrated in a vacuum. The concentrate (1.1 g) was dissolved in methylene chloride (30 ml) and loaded onto a silica gel (Merck, Art No. 9385) so as to adsorb the active material thereonto. Purification through silica gel column chromatography eluting with a gradient of a mixture of ethylacetate and hexane from 10:90 to 20:80 afforded colorless 3-(4-((E)-prop-1-enyl)phenoxy)-5-((E)-prop-1-enyl)benzene-1,2-diol (0.91 g, yield 90%)
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[O:23]=[C:24]([C:31]1[CH:35]=[CH:34][O:33][CH:32]=1)[CH2:25][C:26]([O:28]CC)=O.C[N:37](C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]1([C:8]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][CH:25]([C:24](=[O:23])[C:31]3[CH:35]=[CH:34][O:33][CH:32]=3)[C:26]([NH2:37])=[O:28])[CH2:10][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Reactant: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)C(CCCN1CCC(c2ccccc2)(c2ccccc2)CC1)C(=O)c1ccoc1

Procedure:
This compound was initially prepared according to Method A, and later according to Method B (see below). Method A: A stirred solution of 191 mg of 1-(3-aminopropyl)-4,4-diphenylpiperidine (0.676 mmol), 123 mg of ethyl 3-oxo-3-(furan-3-yl)propionate (0.676 mmol), and 83 mg of dimethylaminopyridine (0.676 mmol) in 5 mL of dry toluene were heated at reflux temperature for 18 hrs, cooled, and the residue was dissolved in 30 mL of EtOAc. The resulting solution was extracted with 2×20 mL of aqueous 1 N HCl solution. The combined aqueous extracts were washed with 20 mL of 1:1 EtOAc-ether, basified with NaHCO3 (pH=8-9), and extracted with 2×20 mL of EtOAc. The combined EtOAc extracts were dried (Na2SO4), the solvent was removed in vacuo, and the crude product was chromatographed on 100 g of silica packed with MeOH-isopropyl amine-EtOAc (1:1:98). The column was eluted with MeOH-isopropyl amine-EtOAc 1:1:98, 2:1:97, 5:1:94, 10:1:89, 20:1:79 (0.5 L each) to give N-(3-(4,4-diphenylpiperidin-1-yl)propyl 3-oxo-3-(furan-3-yl)propanamide as a slightly yellow viscous oil. The product was used in the next step after spectral characterization.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[CH3:14][NH:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[CH:18][C:17]=1[NH2:31].CCN(C(C)C)C(C)C.[Cl-].ClC1N(C)CC[NH+]1C>CC#N.O>[CH3:14][N:15]1[C:16]2[CH:30]=[CH:29][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:18][C:17]=2[N:31]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: CNc1ccc(Oc2ccnc(C#N)c2)cc1N
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(C#N)c3)ccc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
4-(Trifluoromethyl)phenyl isothiocyanate (9.65 g, 0.0475 moles) was added to a solution of 4-(4-methylamino-3-amino-phenoxy)-pyridine-2-carbonitrile (12.0 g, 0.05 moles) in MeCN (60 mL). HPLC analysis indicated complete conversion of the amine after 40 min. The mixture was filtered and the removed solids washed with MeCN (2×12 mL). DIPEA (17.5 mL, 0.1 moles) was added to the filtrate. 2-Chloro-1,3-dimethylimidazolinium chloride (DMC) was added in 4×2.11-g portions (8.44 g, 0.05 moles) every 10 min. After the final addition, the mixture was allowed to stir an additional 10 min when HPLC analysis indicated complete conversion. The mixture was then heated to 50° C. (internal temperature). After 45 min at 50° C., HPLC analysis indicated complete conversion to the product. The mixture was allowed to cool to ambient temperature and then H2O (45 mL) was added. The reaction mixture was initially homogeneous before compound began to precipitate from the mixture. After stirring for 2 h, the solid was collected by filtration and washed with 2:1 MeCN/H2O (2×20 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 16.10 g (78%) of the title compound 1H NMR (400 MHz, DMSO-d6) δ 9.5 (m, 1 H), 8.5 (m, 1 H), 8.0 (m, 2 H), 7.7 (m, 2H), 7.6 (m, 1H), 7.4 (m, 1 H), 7.3 (m, 1 H), 7.1 (m, 1 H), 6.9 (m, 1 H), 3.7 (m, 3 H); APCI MS [M+H]+=410; HPLC >99% (LCAP).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)C>CO.ClCCCl>[CH2:36]([NH:43][CH:16]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1
Yield: 68.8 %

Procedure:
Add sodium triacetoxyborohydride (0.2301 g, 1.086 mmol) to a stirred solution of 6-[4-(3-oxo-butyl)-phenoxy]-nicotinamide (0.2051 g, 0.7214 mmol), benzylamine (0.079 mL, 0.723 mmol), glacial acetic acid (0.045 ml 0.786 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Add methanol (1.5 mL) and load the reaction mixture directly onto a 2 g prepacked SCX cartridge. Wash the cartridge with methanol (100 mL) and elute the product off of the cartridge with 2 M ammonia in methanol (50 mL). Concentrate the eluant on a rotary evaporator to yield 0.1863 g (69%) of 6-[4-(3-benzylamino-butyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.09 minutes, Purity: 99.9%; mass spectrum (ion spray): m/z=376.4 (M+1).
Reaction SMILES: S(=O)(=O)(O)N.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[CH:10]=[O:11].Cl([O-])=[O:18].[Na+]>O.C(O)(C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[C:10]([OH:18])=[O:11]
Reactant: Cc1cc(C=O)cc(Cl)c1O
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C(=O)O)cc(Cl)c1O
Temperature: 12 °C
Yield: 52 %

Procedure:
A solution of sulfamic acid (11.8 g, 121.5 mmol) in water (25 mL) was added with vigorous stirring to 3-chloro-4-hydroxy-5-methylbenzaldehyde (16.00 g, 93.8 mmol) in tert-butanol (100 mL). The mixture was cooled (˜12° C.) and a solution of sodium chlorite (12.00 g, 106.1 mmol) in water (25 mL) was added in5 mL portions with vigorous stirring. The reaction was exothermic and the temperature at the end of the addition was approximately 50° C. The two layers were separated and the aqueous layer was extracted with ether (2×50 mL). The organic layers were washed with brine and evaporated to dryness. Water was added, and the mixture was stirred and filtered. The solid was dissolved in warm ether (250 mL), and the solution was dried, filtered, concentrated to 100 mL, and cooled in the freezer (approx. −20 ° C.). Filtration and washing with cold ether gave 3-chloro-4-hydroxy-5-methylbenzoic acid (9.10 g, 52%), as a yellow solid, mp 242-244° C.