Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][C:21](O)=[O:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:21](=[O:22])[CH2:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: Cc1c(O)cccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1OC
Temperature: 110 °C

Procedure:
2-Methylresorcinol (6.285 g, 1 equivalent) and 3,4-dimethoxyphenylacetic acid (9.251 g, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled boron trifluoride diethyl etherate, BF3.OEt2 (42 ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (110° C.). A yellow solid formed at 75 minutes indicating that the reaction had gone to completion. The reaction was heated for a further 10 minutes and cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF3.OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(3,4-dimethoxy-phenyl)ethanone in >95% purity. The solid was dried on a freeze dryer for 24 hours (6.303 g, 43%).
Reaction SMILES: [NH2:1][NH2:2].[H-].[Na+].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:12]#[N:13])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([C:12]([NH:1][NH2:2])=[NH:13])[CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([CH3:5])[CH3:7]
Reactant: NN
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
97% anhydrous hydrazine (4.8 g, 0.151 mole) is added dropwise to a stirred 0° C. suspension of sodium hydride (2.8 g of a 60% dispersion in mineral oil, 0.071 mol) in tetrahydrofuran (70 ml) under nitrogen. After 90 minutes, a solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile (6.7 g, 0.021 mole) in tetrahydrofuran (15 ml) is added dropwise. After stirring two hours at 0° C., water (2.4 ml) is added dropwise. The mixture is poured into cold, saturated aqueous sodium bicarbonate (20 ml). The product is extracted with a 1:1 ethyl acetate/ether mixture (60 ml). The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 4.9 g (7.3 g theor., 67%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide, mp 133° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1>C(O)C.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:30])[CH:12]=2)[C:14]1=[O:29]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3[N+](=O)[O-])C2=O)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3N)C2=O)cn1
Yield: 26 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-nitrobenzyl)imidazolidine-2,4-dione (example 10-23) (126 mg, 0.3 mmol) was dissolved in 2 mL ethanol. The solution was passed through the H-Cube instrument at room temperature using 10% Pd/C catalyst at a flow rate of 1 ml/minute. The collected fraction was concentrated, redissolved in 2 mL ethanol and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes). The purified fractions were combined and concentrated to afford the title compound. Yield 26%. MS M+H calculated 381.1; found 381.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 uM.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:14]([F:25])[CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br-].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH2:33]([N:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:12]1[CH:13]=[C:14]([F:25])[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([F:18])[CH:17]=1)[CH:29]=[CH2:30]
Reactant: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 3, 543 mg, 1.60 mmol) in anhydrous THF (40 ml) is treated with sodium hydride (60% dispersion in mineral oil, 128 mg, 3.19 mmol, 2 eq). The reaction is kept under an atmosphere of nitrogen at 20-25° for 0.5 hr. After this time, ally bromide (691 μl, 7.99 mmol, 5 eq) is added. Stirring is continued at 20-25° for 16 hr. After this time, the reaction is carefully quenched with water (20 ml). The layers are separated and the aqueous layer is extracted with ethyl acetate (3×25 ml). The combined organics phases are washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by silica gel chromatography (125 g of silica gel) eluting with acetonitrile/chloroform (3/97-1 l). The appropriate fractions are concentrated to give the title compound. An analytical sample is prepared by preparative TLC (SG, acetonitrile/chloroform -6/94), mp=92-93°; FTIR (mull) cm-1 3068, 3061, 1710, 1705, 1643, 1635, 1412, 1263, 1024, 733; MS (EI) m/z: 380, 336, 309, 245, 91, 65; NMR (CDCl3) 8.72, 8.62, 7.99, 7.42-7.36, 7.03, 5.94, 5.23-5.18 and 4.34 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[BH4-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:10]([CH:26]([OH:28])[CH3:27])[CH2:11][N:12]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:20][CH2:21]3)=[O:15])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CC(O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a stirred solution of 1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (XI-1) (2.00 g, 4.46 mmol) in MeOH (40 mL) at −78° C. was added LiBH4 (0.13 g, 4.68 mmol). The temperature was slowly raised to RT (over 1 hour), and the reaction mixture was quenched by addition of H2O. The product was extracted with EtOAc, the combined organic phases were dried over Na2SO4. The two diastereoisomers were separated by column chromatography (SiO2) to yield 0.31 g (16%) of [(3RS,4SR)-3-(3,4-dichloro-phenyl)-4-((RS)-1 hydroxy-ethyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (XII-A-1) as a white solid ES-MS m/e: 450.1 (M+Ht) and 1.02 g (51%) of [(3RS,4SR)-3-(3,4-dichloro-phenyl)-4-((SR)-1-hydroxy-ethyl)-pyrrolidin-1-yl]-(4 methanesulfonyl-piperazin-1-yl)-methanone (XII-1-B-1) as a white solid ES-MS m/e: 450.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][CH2:24][O:25]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1.O[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47]>>[C:46]([NH:45][CH2:44][CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[O:25][CH2:24][CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]1)(=[O:48])[CH3:47]
Reactant: CC(=O)NCCc1ccccc1O
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.24 g of tert-butyl 4-(4-methoxyphenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.17 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as an orange oil. Rf=0.50 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.85.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c(Cl)cccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 2.49 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. Then diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/15) to yield 1.40 g (53% yield) of 2-chloro-6-(pyrrolidin-1-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz (CDCl3) δ 10.49 (s, 1H), 7.20-7.25 (m, 1H), 6.73-6.78 (m, 2H), 3.14-3.19 (m, 4H), 1.94-2.02 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:57][N:51]3[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (30.36 mg, 0.044 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (82 mg, 0.44 mmol, 10 eq) and acetic acid (2.51 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl 4-[(2′-chloro-5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate. The vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator for overnight at 60° C. The reaction mixture was then concentrated and purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 23.82 mg (64.1%) of the title compound. LC-MS m/z 763 (M+H)+, 1.32 min (ret time).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH3:31])[C:23]1=[S:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:31][N:25]1[C:26](=[O:27])[CH:28]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([C:2]([F:19])([F:20])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[O:16])[C:29](=[O:30])[N:22]([CH3:21])[C:23]1=[S:24]
Reactant: O=C=Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)C(=O)N(C)C1=S

Procedure:
4-(4'-Trifluoromethylphenoxy)phenyl isocyanate (3.7 g.) was added to a stirred mixture of 1,3-dimethyl-2-thiobarbituric acid (2.3 g.) and triethylamine (1.7 ml.) in dry benzene (30 ml.). The mixture was refluxed for 12 hours. The mixture was evaporated in vacuo. Diethyl ether (10 ml.) was added to the gummy residue and the mixture was acidified with 1N hydrochloric acid. The mixture was filtered and the solid was washed with water and then ethanol.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl[C:34]1[S:35][C:36]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]([C:34]1[S:35][C:36]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=2[N:38]=1)[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc3ccc(Cl)cc3s2)cc1)C(=O)O

Procedure:
Similarly prepared from methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2,6-dichloro benzothiazole.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([N:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:27][C:26]1=[O:42])[C:22]([OH:24])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][C:44]1[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([N:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:27][C:26]1=[O:42])[C:22]([NH:43][C:44]1[CH:45]=[CH:46][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:53][CH:54]=1)=[O:24])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cn(C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
565 mg (940 μmol) of 4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate), 155 mg (940 μmol) of ethyl 4-aminobenzoate, 134 mg (940 μmol) of Oxima and 146 μl (940 μmol) of DIC in 19 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (120 g cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 268 mg (38% of theory)
Reaction SMILES: [P:1]([O-:49])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])([O:3][CH2:4][CH:5]([O:26]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]>C(O)C.C(O)(=O)C.[Pd]>[P:1]([O-:49])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCCCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCCCC[N+](C)(C)C
Yield: 88.8 %

Procedure:
1.31 g (1.8 mmole) of the compound of Example 4 was dissolved in a mixture of 100 ml of ethanol and 50 ml of 70% acetic acid. Then, 0.6 g of 10% Pd-C was added thereto and catalytic reduction was carried out at room temperature. 19 hours later, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was solidified by acetone to give 994 mg (yield: 87.2%) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 77.5 °C
Yield: 54 %

Procedure:
In a 10 L 4 necked RB flask fitted with a mechanical stirrer, reflux condenser, was added DMF (3.5 L), 3,4-Dihydroxybenzaldehyde (1.15 Kg, 8.3M), cyclopentyl bromide (3.1 kg, 20.3 M) and powdered anhydrous potassium carbonate (1.15 kg, 20.3 M) at temperature in the range of 25-35° C. under stirring. The reaction mixture was heated to temperature of 75-80° C. under stirring and maintained under stirring for 1 hr. To the reaction mixture, powdered potassium carbonate (140 g, 1M) was added at temperature of 75-80° C. under stirring. After addition, the reaction mixture was maintained at 75-80° C. for 1 hr. The progress of the reaction was monitored by TLC and HPLC. After ascertaining the completion of the reaction, the reaction mixture was brought to 25-35° C. and filtered. The inorganic salt cake was washed with DMF (300 ml×2) and combine the washings with filtrate. The organic layer was concentrated at temperature below 75° C. under high vaccum. Add toluene (2 L) to the residue of distil of the residual DMF. Add toluene (2 L) to the resulting mass and distill off the traces of DMF. To the resulting mass, add toluene (5.7 L), celite (300 g), activated charcoal (100 g), 5% sodium hydroxide solution (1.2 L) and cool to 10-15° C. under stirring. Separate the organic and aqueous layer. The organic layer was repeatedly extracted with 5% sodium hydroxide solution (1.2 L×5) and combine the aqueous sodium hydroxide layers. The aqueous layer was washed with toluene (2 L×2) and separate the aqueous layer. The pH of the aqueous layer was adjusted to acidic 2-3 with conc. HCl (1.1 L) at 10-15° C. under stirring. The precipitated solid was filtered, washed with water(2 L×3) filtered and dried in the hot air oven below 60° C. temp. The product appear as cream color solid, weighing about 920-950 g, yield 54%-56% purity 98-99%, m.p 87-89° C. The IR (KBr) spectrum shows 3300 (OH str), 3150 (CH str), 1670 (CHO str), 1620 (C═C str). The 1H-NMR (DMSO-d6) shows δ 9.8 (s, 1H), 9.2 (s, 1H), 7.1 (d, 1H), 7.2-7.4 (m, 2H), 4.9 (m, 1H), 1.4-2.0 (m, 8H). The CI mass shows m/z 206 (M+). The elemental analysis shows calculated % C, 69.88; % H, 6.84; % O, 23.27; observed % C, 69.70; % H, 6.65; % O, 23.15.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].CS(O[CH2:23][CH2:24][C:25]1[N:30]=[C:29]([N:31]2C(C)=CC=C2C)[CH:28]=[C:27]([CH3:38])[CH:26]=1)(=O)=O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:3]([NH:6][C:7]([CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH3:38])[CH:28]=[C:29]([NH2:31])[N:30]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1cc(C)cc(N)n1)(NC(C)=O)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
Sodium hydride (52 mg of 60% oil dispersion, 1.30 mmol) was added to a solution of 310 mg (1.43 mmol) of diethyl acetamidomalonate in 2.0 mL of N,N-dimethylformamide. After 30 min, 72 mg (0.20 mmol) of tetrabutylammonium iodide was added followed by 200 mg (0.65 mmol) of 6 -(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine in 1.0 mL of N,N-dimethylformamide. The reaction was stirred at room temperature for 30 min, at 60° C. for 20 h, and at room temperature for 3 d. The reaction was diluted with 30. mL of ethyl acetate and washed with 15 mL each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The aqueous layers were extracted in succession with 30 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The crude product was purified by flash column chromatography on 15 g of silica gel, eluting with 300 mL of 10% ethyl acetate in dichloromethane to give 243 mg (87% yield) of diethyl 2-acetamido-2-(2-(6-amino-4-methylpyrid-2-yl)ethyl)malonate as a tan solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([O:42][CH2:43][CH3:44])[CH:33]=3)[C:21]([N:23]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:24])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(O)C.CO.C(NCC)C>CCCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C@H:20]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([O:42][CH2:43][CH3:44])[CH:33]=3)[C:21]([N:23]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:24])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCOc1cc(C(Nc2ccc3c(N)nccc3c2)C(=O)N(C)Cc2ccccc2)ccc1OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCO
Product: CCOc1cc([C@@H](Nc2ccc3c(N)nccc3c2)C(=O)N(C)Cc2ccccc2)ccc1OC(C)C
Reaction time: 0.43 h

Procedure:
Example 52 (34 mg) was separated from the racemic mixture (80 mg) of Example 51 using a preparative HPLC equipped with a Chiralpak® AD column (5 cm×50 cm, 20μ). The separations were performed using an isocratic method of 95% 1:1 ethanol/methanol, 5% heptane with 0.1% diethylamine for 120 min with a flow rate of 50 mL/min. Retention time for Example 52 was 26 min. Retention time for the other isomer (32 mg) was 90 min. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.33 (m, 9H) 3.01 (m, 3H) 3.98 (m, 2H) 4.59 (m, 3H) 5.61 (d, J=9.54 Hz, 1H) 6.70 (m, 2H) 7.05 (m, 6H) 7.25 (m, 3H) 7.39 (dd, J=12.96, 6.60 Hz, 1H) 7.95 (m, 1H). LC-MS 499 (M+H).