Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.C[O:17]B(OC)OC.OO.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([OH:17])[CH:7]=1
Reactant: Cc1cc(C)c(Br)cc1Br
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Br)cc1O
Temperature: -70 °C
Reaction time: 1.33 h

Procedure:
In a glovebox, 1,5-dibromo-2,4-dimethylbenzene (10.000 g, 37.9 mmol) is dissolved in dry THF (140 mL) in a one-neck round bottomed flask with a thermometer well. The flask is capped with a septum, and removed from the glovebox. Nitrogen purge is provided via a needle through the septum, and the solution is cooled to −70° C. using a dry ice/acetone bath. Butyllithium (BuLi) (1.6M in hexanes, 26 mL, 42 mmol) is added slowly, maintaining the temperature below −65° C. After stirring for 80 minutes at −70° C., trimethylborate (B(OMe)3) (4.2 mL, 37.9 mmol) is added slowly, maintaining the temperature below −62° C., and then the reaction is allowed to slowly warm to room temperature overnight. Solvents are removed on a rotovap, leaving a very pale yellow oily solid, which is dissolved in tetrahydrofuran (THF) (100 mL) and treated with hydrogen peroxide (H2O2) (30% aq, 13 mL) and sodium hydroxide (NaOH) (1M, 25 mL) for two hours. The reaction is then quenched with ammonium chloride (NH4Cl) (aq) and extracted into ether (2×100 mL). The organic fractions are combined, dried over sodium sulfate, filtered and dried in vacuo. Yield=6.60 g (86.7%) of pale yellow waxy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1C=CC=Nc2ccccc21
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccccc21

Procedure:
1-[4-Nitro-2-chlorobenzoyl]-1,5-benzodiazepine (5 g) and ethyl bromoacetate (16.7 ml) are dissolved in acetonitrile (100 ml), and thereto is added dropwise 1,8-diazabicyclo[5.4.0]-7-undecene (11.3 ml). The mixture is refluxed for two days, concentrated, and thereto are added water and chloroform, and extracted. The extract is dried over sodium carbonate, and purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1→1:1) to give 1-(4-nitro-2-chlorobenzoyl)-5-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (4.4 g) as pale yellow oil.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:8]>C(#N)C.O.O.O.O.O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=3)[NH:14][CH:13]=2)[CH2:2]1
Reactant: O=C1C=CCC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 69.1 %

Procedure:
2-Cyclopenten-1-one (4.1 g, 4.2 mL, 50 mMol) was added to a stirred solution of 5-cyanoindole (1.42 g, 10 mMol) and ytterbium triflate hexahydrate (124 mg, 0.2 mMol) in acetonitrile (15 mL). After stirring at room temperature for 7d, the reaction was concentrated to an oil and diluted with ether. The red oily mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (35 g) using a gradient of 20–35% ethyl acetate in hexane. Pure product fractions were concentrated and dried under high vacuum to give 3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (1.55 g, 69%). 1H NMR (500 MHz, CDCl3) δ 8.41 (1 H, bs), 7.99 (1 H, s), 7.45 (2 H, m), 7.12 (1 H, dd, J=2.44, 0.92 Hz), 3.72 (1 H, m), 2.77 (1 H, dd, J=7.63, 18.31 Hz), 2.56 (1 H, m), 2.40 (3 H, m), 2.10 (1 H, m). MS m/e 223.2 (M−H)+. Anal. calcd. for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.75; H, 5.50; N, 12.23.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.ClCCl>>[OH:39][C:24]1[C:25]([CH3:38])=[CH:26][C:27]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:28][C:23]=1[CH3:22]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1O
Yield: 82.1 %

Procedure:
Nitrogen was bubbled through a mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (5.80 g, 0.0175 mol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.82 g, 0.0194 mol) and potassium carbonate (7.26 g, 0.0525 mol) in N,N-dimethylformamide (50.0 mL, 0.646 mol) for 10 min. To the reaction mixture was then added [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (1:1) (0.8 g, 0.001 mol). The resultant mixture was heated at 80 Celsius overnight. After quenched with water, the mixture was neutralized with 1N HCl, extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was applied on column, eluting with 0 to 50% EtOAc in hexane, to yield the desired product (4.36 g, 82.09%). MS (ESI): (M-Boc+2) 204.0.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14].O>CN(C=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:11][CH:10]=1)=[O:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
4-sec-butyl aniline (B) (1.49 g, 10.0 mmol) was added to a solution of isatoic anhydride (A) (1.63 g, 10.0 mmol) in anhydrous DMF (40 mL) and the reaction mixture was stirred at 115° C. for 16 hours under nitrogen. It was then cooled to room temperature and poured into water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL), 10% aqueous NaOH solution (100 mL), water (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-amino-N-(4-sec-butylphenyl)benzamide (C) as a brown solid. Yield: 1.27 g (47%).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:8]([CH3:26])=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([C@@H:18]1[CH2:20][C@@H:19]1[F:21])[CH:12]=[C:11]([C:22]([OH:24])=[O:23])[C:10]2=[O:25].Cl.Cl.[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(N(CC)CC)C>[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:16]1[CH:15]=[C:14]3[C:9]([C:10](=[O:25])[C:11]([C:22]([OH:24])=[O:23])=[CH:12][N:13]3[C@@H:18]3[CH2:20][C@@H:19]3[F:21])=[C:8]([CH3:26])[C:7]=1[F:6])[CH2:31][CH2:30]2
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: C1CN2CCC(C2)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(F)c(N2CCN3CCC2C3)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 6 ml of dried N,N-dimethylformamide were added 200 mg of 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 372 mg of 1,4-diazabicyclo[3.2.1]octane dihydrochloride, and 2 ml of triethylamine, and the mixture was stirred at 100° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution under cooling with ice. The solution was neutralized with 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of ethanol and 28% aqueous ammonia, and the crystals were collected by filtration, washed with diethyl ether, and dried at 60° C. under reduced pressure overnight to yield 131 mg of the titled compound as a yellow powder.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH:10]([OH:13])[CH2:9][CH2:8]3)=[CH:3][CH:2]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([C:7]23[CH2:12][CH:11]2[C:10](=[O:13])[CH2:9][CH2:8]3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C23CCC(O)C2C3)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C23CCC(=O)C2C3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 5-p-tolyl-bicyclo[3.1.0]hexan-2-ol (1 g, 5.3 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.6 mL, 7.4 mmol) followed by Dess-Martin periodinane (2.7 g, 6.3 mmol) and warmed to ambient temperature. After 2 h, 3 drops of H2O were added. After 0.5 h, the reaction was quenched with saturated NaHCO3 saturated Na2SO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried and concentrated in vacuo. Purification by silica gel chromatography gave the target compound (760 mg, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.47 (m, 1 H) 1.53-1.61 (m, 1 H) 2.06-2.11 (m, 1 H) 2.20-2.29 (m, 2 H) 2.30-2.36 (m, 1 H) 2.32-2.34 (m, 3 H) 2.37-2.45 (m, 1 H) 7.08-7.18 (m, 4 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH2:20][NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C(Cl)(Cl)Cl.CCCCCC>[C:22]([NH:21][CH2:20][CH2:19][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (4.81 g) in dehydrated chloroform (10 ml) were added sodium carbonate (1.06 g) and N-(2-bromoethyl)tritylamine (3.66 g), and the mixture was stirred under reflux for 3 hours. To the reaction mixture were added diethyl ether and hexane, and the solution was washed with water. The mixture was extracted with 5% aqueous citric acid solution, and the aqueous layer was washed with diethyl ether. The aqueous layer was then made alkaline with sodium hydrogencarbonate followed by extraction with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-{[2-(tritylamino)ethyl]amino}ethylcarbamate (1.86 g) as a viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[F:11].[C-:12]#[N:13].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[F:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][C:12]#[N:13]
Reactant: COc1ccc(CBr)c(F)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC#N)c(F)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 1-Bromomethyl-2-fluoro-4-methoxy-benzene (4.5 g, 21 mmol) and Tetrabutylammonium iodide (0.66 g, 2.1 mmol) in CH2Cl2 (50 mL) was added a solution potassium cyanide (4.0 g, 60 mmol) in water (50 mL). The resulting biphasic mixture was stirred vigorously for 8 hours. The reaction was poured into water (100 mL) and extracted with CH2Cl2 (2×50 mL). The organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10–30% EtOAc in hexanes) to give the product (2.6 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 3.66 (s, 2 H), 3.82 (s, 3 H), 6.69 (m, 2 H), 7.31 (m, 1 H).
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:8][C:12]([CH:9]1[CH2:11][CH2:10]1)=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C)O
Reactant: O=C(O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCC(C)OC(=O)C1CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
2-Heptanol (200 g, 1.72 mol) and cyclopropanecarboxylic acid (163 g, 1.90 mol) were added into toluene (500 mL), followed by p-toluenesulfonic acid (3.2 g, 0.0172 mol). The reaction mixture was heated to reflux for 6 hours, cooled to room temperature, and quenched with aqueous sodium bicarbonate (1 L). The reaction mixture was then washed with brine (0.5 L) and dried over sodium sulfate (50 g). The solvent was removed and the reaction mixture was distilled to provide the product cyclopropanecarboxylic acid 1-methyl-hexyl ester (253 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.ClCCl.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[CH2:20]([C:5]1[CH:4]=[CH:3][C:2]([O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=2)=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19])[CH3:21]
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Oc1cccc(F)c1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2cccc(F)c2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 160 °C

Procedure:
A mixture of 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (200 mg, 0.57 mmol), 3-fluorophenol (320 mg, 2.83 mmol), cesium carbonate (400 mg, 1.13 mmol), copper(II) trifluoromethanesulfonate (10 mg, 0.03 mmol), and powdered 3 Å molecular sieves (400 mg) in toluene (3.5 ml) is heated to 160° C. under microwave irradiation for 60 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid, diluted with dichloromethane and filtered through a phase separation cartridge. The organic phase is collected. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(3-fluorophenoxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH4+].[Cl-].Cl>C(OCC)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:14]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCCCCCCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCC=Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.7 %

Procedure:
To dry diethyl ether (50 mL) containing Mg turnings (1.22 g; 50 mmol) under N2 was added 1-bromononane (8.6 mL; 50 mmol) at a rate sufficient to maintain slow reflux. The reaction mixture was stirred for 45 minutes after the end of addition, cooled on an ice/water bath and 3-methoxy benzaldehyde (6.1 mL; 50 mmol) was then added drop wise. The reaction mixture was allowed to warm to room temperature overnight, added saturated aqueous NH4Cl (50 mL) and then 4 M HCl (aq.; 10 mL). The organic phase was isolated, dried (MgSO4), filtered and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:10) to yield 7.4 g (64%) pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]=O)[CH:28]=1)[CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:38][C:29]3[CH:28]=[C:27]([CH2:24][CH2:25][CH3:26])[N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:30]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: CCCc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 95 %

Procedure:
Compound 94 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:25][CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:22][CH2:23][CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:25]([CH:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH3:27])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNC(C)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCN(C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)C(C)c1ccccc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and butyl-(1-phenyl-ethyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO5 [M+H]+414.
Reaction SMILES: C([O:4][C@H:5](/[CH:7]=[CH:8]\[C:9]([NH:11][C@@H:12]1[CH2:17][C@H:16]([CH3:18])[C@H:15]([CH2:19]/[CH:20]=[C:21](\[CH3:24])/[CH:22]=[CH2:23])[O:14][C@@H:13]1[CH3:25])=[O:10])[CH3:6])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.[NH4+].[Cl-]>[CH3:25][C@@H:13]1[C@H:12]([NH:11][C:9](=[O:10])/[CH:8]=[CH:7]\[C@@H:5]([OH:4])[CH3:6])[CH2:17][C@H:16]([CH3:18])[C@H:15]([CH2:19]/[CH:20]=[C:21](\[CH3:24])/[CH:22]=[CH2:23])[O:14]1
Reactant: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(C)=O)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)O)C[C@@H]1C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a stirred solution of (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl acetate (26.5 mg, 0.0758 mmol) in MeOH (380 μL) was added K2CO3 (26.3 mg, 0.190 mmol) at 0° C. under an open atmosphere. After 2 h at the same temperature the reaction was diluted with saturated aqueous NH4Cl (60 μL) and stirred for 5 min. The resulting reaction mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (20→50% EtOAc in hexanes) on silica gel (3 mL) to give (S,Z)—N-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-yl)-4-hydroxypent-2-enamide (19.2 mg, 82%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][CH:10]=[N:9][C:8]2=O)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:36][C:35]1[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[C:34]=1[F:40])(=[O:3])[CH3:2]
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2[nH]cnc(=O)c2cc1OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Acetoxy-7-methoxy-4(1H)-quinazolinone (150 g; prepared as described in WO96/15118, Example 39 thereof), N,N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70° C., under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70° C. The mixture was held at 70° C. for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70° C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70° C. for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2×300 ml), aqueous IMS (2×450 ml and IMS (2×450 ml). The solid was left to pull dry on the filter overnight to give 6-acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline.HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H); 7.58 (s, 1H); 7.64 (t, 1H); 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum: M+H362.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:29])[CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:28])[CH2:4][CH2:3]1.[C:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH4-].[Na+]>ClCCl.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:30]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:29])[CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:28])[CH2:4][CH2:3]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(NC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)-3,3-diphenylpiperidin-2-one (Example 87B, 0.1 g, 0.25 mmol) and benzophenone (0.056 g, 0.3 mmol) is stirred in dichloromethane (3 mL) with titanium(IV) isopropoxide (0.012 g, 0.4 mmol) for 3 hours. The reaction mixture was then diluted with methanol (10 mL) and sodium borohydride (0.4 g, 0.4 mmol) was added. The mixture was stirred at ambient temperature for 16 hours and then concentrated. The residue was partition in ethyl acetate/H2O (100 mL/20 mL). The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with 5-10% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.26-7.38 (m, 16H), 7.15-7.24 (m, 4H), 4.99 (s, 1H), 4.36-4.44 (m, 1H), 4.21 (s, 2H), 3.70-3.77 (m, 1H), 3.48 (t, J=6.4 Hz, 2H), 2.93-3.03 (m, 1H), 2.69-2.79 (m, 1H), 2.61-2.69 (m, 3H), 1.89-2.00 (m, 2H), 1.77-1.89 (m, 2H), 1.24-1.41 (m, 3H); MS (ESI+) m/z 558 (M+H)+.