Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9]CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:4]1.[H][H]>[Pd].CO>[NH2:9][C@H:8]1[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[CH2:4][C@H:3]1[O:2][CH3:1]
Reactant: [H][H]
Reactant: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1N
Yield: 71.4 %

Procedure:
A mixture of 53 parts of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1-piperidinyl]-1-oxobutyl]pyrrolidine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 28.3 parts (71.4%) of cis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine as a residue (int. 43).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]2[N+:17]([CH2:26][CH3:27])=[C:18]([CH3:25])[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:15]=2[CH:14]=1.CCO[CH:34]=[N:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1CCCCC1>CN(C)C(=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH:35]([CH:34]=[CH:25][C:18]1[N:19]([CH2:20][C:21]([F:23])([F:24])[F:22])[C:15]2[CH:14]=[C:13]([Cl:12])[C:29]([Cl:30])=[CH:28][C:16]=2[N+:17]=1[CH2:26][CH3:27])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC=Nc1ccccc1
Reactant: CC[n+]1c(C)n(CC(F)(F)F)c2cc(Cl)c(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCCCC1
Product: CC[n+]1c(C=CNc2ccccc2)n(CC(F)(F)F)c2cc(Cl)c(Cl)cc21
Temperature: 150 °C

Procedure:
A slurry of 30 g (0.062 mole) of the 5,6-dichloro-1-ethyl-2-methyl-3-(2,2,2-trifluoroethyl)benzimidazolium p-toluenesulfonate in 150 mL of N,N-dimethylacetamide was treated with 45 g (about 0.3 mole, a large excess) of ethyl iso-formanilide, i.e., N-(ethoxymethylene)aniline, the mixture stirred and heated to 150° C., allowed to cool to 120° C. where it was maintained for 5 minutes, and then allowed to cool slowly to 30° C. The solution was poured into 1.5 L of cyclohexane, stirred, allowed to settle, and the dark reddish oil was separated. The oil was washed with another 500 mL of cyclohexane, separated, treated with 200 mL of methyl ethyl ketone, warmed to a uniform solution and cooled in a freezer to produce a bright yellow-orange solid. The solid was collected by filtration, washed with cold methy ethyl ketone, and dried to produce 23 g melting at 215°-217° C. The mass spec. and NMR spec. are consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-benzaldehyde (6.51 g, 53.3 mmol) and 3,4-dihydro-2H-pyran (7.3 mL, 80.0 mmol) in 150 mL methylene chloride was added pyridinium p-toluenesulfonate (1.34 g, 5.33 mmol). The reaction mixture was stirred at room temperature overnight. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (5% ethyl acetate/hexanes to 10% ethyl acetate/hexanes) aforded 10.34 g (94%) of the title compound of Step A.
Reaction SMILES: [OH:1]O.[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>O.C(O)(C(F)(F)F)C(F)(F)F>[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:1])=[CH:28][CH:29]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CSc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Reactant: OO
Solvent: O
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CS(=O)c1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35% Hydrogen peroxide in water (48 μL) is added to 4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (83 mg) in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL). The resulting solution is stirred at ambient temperature for 1 h and then quenched by the addition of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [N:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)C(C)C)(C)C>>[CH2:14]([N:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:36]=[N:35][N:34]=2)=[CH:25][CH:26]=1)[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)N1CCCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N1CCCc2ccccc21
Yield: 27 %

Procedure:
Following the procedure of Example 7, Step B, 1,2,3,4-tetrahydroquinoline-1-carbonyl chloride (from Step A) was reacted with 1.2 equivalents of N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]amine (from Step D) in the presence of N,N-diisopropylethylamine. Flash chromatography of the crude product on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave two major products. (Concentration of fractions containing the pure second product afforded a 27% yield of the title compound as a stiff foam, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 723 (M+1)+. The 1H NMR spectrum indicated the presence of two isomeric forms.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=5)[CH2:18]4)[CH2:12][CH2:11]3)[C:6]=2[CH:27]=1.[Li]C(C)(C)C.[CH3:34][C:35]([CH3:37])=[O:36]>C1COCC1>[F:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:9]=[C:8]([C:35]([OH:36])([CH3:37])[CH3:34])[N:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=5)[CH2:18]4)[CH2:14][CH2:15]3)[C:6]=2[CH:27]=1
Reactant: Cc1cc2ncn(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Reactant: CC(C)=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(C(C)(C)O)n(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of 6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazole (25 mg, 0.065 mmol) in anhydrous THF (2 mL) was added tert-BuLi (0.058 mL, 1.7 M in pentane) at −78° C. After stirring for 10 minutes, anhydrous acetone (0.008 mL) was added and the reaction mixture was stirred at −78° C. for 40 minutes. After quenching with 1 M HCl (0.2 mL) the mixture was allowed to warm to rt. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic layers were washed with saturated NaHCO3, brine, and dried over Na2SO4. The extracts were removed and the residue was purified by flash chromatography (20/1 CH2Cl2/CH3OH) to afford 2-{6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (5 mg, 17%) as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.C(#N)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([NH:11][S:16]([CH3:15])(=[O:18])=[O:17])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(Br)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-methoxypyridin-3-amine hydrochloride (100 g, 1 wt, 1 eq) is charged to a CLR containing a mixture of acetonitrile (220 mL, 2.2 vols) and pyridine (101 mL, 1.01 vols, 99 g, 0.99 wt) at room temperature. Methanesulfonyl chloride (56.4 g, 0.564 wt, 1.18 eq) is then added to the mixture over 20 minutes whilst maintaining the temperature at 20° C. Having stirred at 20° C. for a further 1.5 hours, the mixture is sampled and analysed by HPLC. The completed reaction is quenched by the addition of water over 1 hour, maintaining the mixture at 20° C. and with increased stirrer speed. The resulting slurry is stirred for 17 hours and then filtered in vacuo. The cake is washed with 3:1 water:acetonitrile (2×50 mL, 2×0.5 vols) and then dried under vacuum at 40-45° C. to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7]=2[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C1CCc2c(F)ccc(O)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(F)c2c1CCC2
Yield: 85.5 %

Procedure:
4-Fluoro-7-hydroxy-1-indanone (1.0 g) was dissolved in acetic acid (15 ml) and the solution was stirred with 10% palladium-on-carbon (0.5 g) in a hydrogen atmosphere at atmospheric pressure for 12 hours. The catalyst used was removed by filtration using Celite, and the filtrate was concentrated to give 7-fluoro-4-indanol (0.783 g).
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:15][CH:16]=2)=[N:9][N:8]=[N:7]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]5[N:9]=[N:8][N:7]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:6]=5)[CH:12]=4)=[CH:36][C:21]=3[C:22]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:26][CH:27]=1
Reactant: CC(C)CBr
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(CC(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 37.6 %

Procedure:
1-bromo-2-methylpropane (23 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 38%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.63 Hz), 7.99-8.04 (2H, m), 7.87-7.94 (2H, m), 7.79-7.84 (1H, m), 7.73-7.78 (1H, m), 7.70 (1 H, t, J=7.63 Hz), 7.41 (2H, t, J=8.70 Hz), 4.62 (2H, d, J=7.32 Hz), 2.87 (3H, d, J=4.27 Hz), 2.31-2.39 (1H, m), 0.95 (6H, d, J=6.71 Hz). LC-MS retention time: 2.09 min; m/z (MH+): 470. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=16.08 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.89 min, purity=99%.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.O.C(N=C=NCCCN(C)C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=1>CN(C=O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:50][CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Yield: 82.3 %

Procedure:
A solution of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-benzoic acid (0.230 g, 0.69 mmol), 3-hydroxybenzotriazole (0.103 g, 0.76 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrate (0.146 g, 0.76 mmol) in DMF (5 mL) and 3-picolylamine (0.077 mL, 0.76 mmol) is stirred at room temperature for 21 hours. The solvent is removed in vacuo and the residue is triturated with diethyl ether, ethyl acetate and dichloromethane. A pale yellow solid is obtained, washed with water and dried to afford the title compound (241 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1>CS(C)=O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (300 mg, 1.97 mmol) in DMSO (7.5 mL) was added potassium carbonate (545 mg, 3.94 mmol) the resulting suspension was stirred under nitrogen at room temperature for 10 minutes. 4-(Bromomethyl)-1,2-dichlorobenzene was then added (commercial, 473 mg, 1.32 mmol) and the reaction mixture heated to 90° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and water (40 mL). The organic layer was washed with water (2×40 mL), dried over magnesium sulphate and evaporated in vacuo to yield the title compound as a solid (530 mg, 86%):
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH2:10][C:11]2([OH:19])[C:16]([OH:18])=[O:17])=[O:4].[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CN(C)C=O.S(Cl)(Cl)=O>C(#N)C>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH2:10][C:11]2([OH:19])[C:16]([O:18][C:24]1[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)=[O:17])=[O:4]
Reactant: O=C(Nc1cccc2c1C=CCC2(O)C(=O)O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1C=CCC2(O)C(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 82 %

Procedure:
In 1.5 liters of acetonitrile were dispersed 200 g of 5-trifluoroacetamido-1-hydroxynaphthoic acid and 100 g of p-nitrophenol, and the mixture was stirred under heating. To the dispersion was added 15 ml of dimethylformamide, and 110 ml of thionyl chloride was added thereto dropwise. After the dropwise addition, the mixture was heated while stirring for 1 hour, followed by cooling. The precipitate thus formed was collected by filtration, washed with acetonitrile, and dried to obtain 230 g of p-nitrophenyl 5-trifluoroacetamido-1-hydroxynaphthoate.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.608 g, 13.9 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (2.0 g, 9.29 mmol, from example 114, step A) in THF (7 mL) at 0° C. After 15 min, a solution of 1-(bromomethyl)-4-chlorobenzene (1.72 g, 8.37 mmol) in THF (7 mL) was added to the reaction mixture. The resulting mixture was stirred at RT for 6 h. The reaction was quenched with pellets of ice. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (0-15% EtOAc/hexanes) to afford (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one (1.34 g, 42% yield): LCMS (M+H)+ 340.2; 1H NMR (500 MHz, chloroform-d) δ 1H NMR (500 MHz, chloroform-d) δ 7.36-7.29 (m, J=8.4 Hz, 2H), 7.23-7.16 (m, J=8.4 Hz, 2H), 4.51-4.33 (m, 3H), 3.31-3.22 (m, 1H), 3.11 (dt, J=9.7, 7.4 Hz, 1H), 2.37-2.25 (m, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.21 (s, 3H), 0.18 (s, 3H).
Reaction SMILES: C(O)(=[O:8])CCCCCC.[OH:10][CH:11]([CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][CH:15]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[OH:10][CH:11]([CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16](=[O:8])[CH:15]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCOCC(O)CCN1C(=O)CSC1CCCCCCC(=O)O
Reactant: CCCCCCC(=O)O
Product: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the same method as described in Example 2 except that the 7-3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoic acid is replaced by 7-[3-(3-hydroxy-4-propoxybutyl)-4-oxo-2-thiazolidinyl]heptanoic acid. This method provides the title compound as an essentially colorless, viscous oil.
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH3:26])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[O:28]1CCOCC1>>[CH2:19]([O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][C:5](=[O:28])[C:6]([OH:8])=[O:7])=[CH:12][C:13]=1[CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(C)c1)NC(C)=O
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(CC(=O)C(=O)O)cc(C)c1OCc1ccccc1
Reaction time: 7 h

Procedure:
31.1 g (88.1 mmol) methyl 2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate in 150 mL 1,4-dioxane were combined with 125 mL 4 M HCl, stirred for 7 h at reflux temperature and stirred overnight at RT. The precipitate was suction filtered, washed with water and dried at 45° C. in the vacuum drying cupboard.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][OH:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of compound 101 (350 mg, 0.63 mmol) in methanol (4.0 mL) was added toluene-4-sulfonic acid (60 mg, 0.32 mmol) and the mixture was stirred for 7 h at RT. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with NaOH (aq., 2 M), water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:8][CH:7]=1)=[O:5])C.[CH:23]([Li])([CH2:25][CH3:26])[CH3:24].Cl>C1(C)C=CC=CC=1.CCCCCC.C1CCCCC1>[CH3:24][CH:23]([CH2:25][CH3:26])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:19][CH:20]=1)=[O:5]
Reactant: [Li]C(C)CC
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCC(C)C(=O)c1ccc(Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)anisole (100 mg) obtained in the process of Reference Example 1(d) was dissolved in toluene (2 ml), added with a solution of sec-butyl lithium in n-hexane and cyclohexane (1.0 M, 0.47 ml) at 0° C. under argon atmosphere and stirred at room temperature for 1 hour. After the reaction mixture was slowly poured into 1 N aqueous hydrochloric acid (5 ml) with ice cooling to quench the reaction and the layers were separated, the aqueous layer was extracted with ether (10 ml). The organic layer was washed with saline and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 58.3 mg of the title compound. Yield: 61%.