Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[N:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=[CH2:25].B(F)(F)F.CCOCC>C(#N)C>[CH3:23][C:24]1([CH3:26])[C:18]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=2)[NH:7][CH:6]([C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25]1
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of ethyl 4-(2-nitrobenzylideneamino)benzoate (18.67 g, 62.6 mmol) in acetonitrile was added 2-methylpropene (80 mL, pre-cooled to −78° C.) and boron trifluoride etherate (1 mL) at ice-bath. The reaction mixture was stirred at 90° C. for 18 h in sealed tube. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography to give ethyl 4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as yellow solid (13.4 g, yield 60.4%). %). LC/MS m/e obsd. (ESI+) [(M+H)+] 355.1.
Reaction SMILES: FC1C=CC(OC)=C(C2C=CC([C@H](NS(C3C=C(C)OC=3C)(=O)=O)C)=CC=2)C=1.[F:29][CH:30]([F:42])[N:31]1[C:35]([CH3:36])=[C:34]([S:37](Cl)(=[O:39])=[O:38])[C:33]([CH3:41])=[N:32]1.[F:43][C:44]([F:62])([F:61])[O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>>[F:43][C:44]([F:61])([F:62])[O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH:60][S:37]([C:34]2[C:33]([CH3:41])=[N:32][N:31]([CH:30]([F:42])[F:29])[C:35]=2[CH3:36])(=[O:39])=[O:38])[CH3:59])=[CH:54][CH:53]=1
Reactant: CC(N)c1ccc(-c2ccccc2OC(F)(F)F)cc1
Reactant: Cc1nn(C(F)F)c(C)c1S(=O)(=O)Cl
Agent: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Product: Cc1nn(C(F)F)c(C)c1S(=O)(=O)N[C@H](C)c1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 1-difluoromethyl-3,5-dimethylpyrazole-4-sulfonyl chloride and 1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.43-7.11 (m, 8H), 6.99 (s, 1H), 4.86 (s, 1H), 4.58 (m, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 1.54 (d, 3H), ppm; MS (ESI) m/z: 490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5](=[O:13])[C:4]=2[CH:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[Mg]Br>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[NH:7][CH2:6][C:5]([C:16]3[CH:15]=[CH:14][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: O=C1CNS(=O)(=O)c2sc(Cl)cc21
Solvent: C1CCOC1
Product: O=S1(=O)NCC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
6-chloro-2,3-dihydro-4H-thieno[3,2-e][1,2]thiazin-4-one 1,1-dioxide (0.800 g, 3.36 mmol) was dissolved in THF (30 mL) and 2-naphthylmagnesium bromide (0.5 M in THF, 33.6 mL, 16.8 mmol) was added. The solution was stirred at room temperature overnight. Reaction was quenched by addition of MeOH (20 mL) and evaporated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient 10% EA in hexane to 40% EA in hexane over 20 minutes) to give the title compound (235 mg, 18%). LCMS (FA) ES−: 364, 366. 1H NMR (400 MHz, DMSO) δ 8.46-8.42 (m, 1H), 7.97-7.89 (m, 4H), 7.55-7.52 (m, 2H), 7.35-7.32 (m, 1H), 6.74 (s, 1H), 6.63 (s, 1H), 3.90-3.84 (m, 1H), 3.69-3.64 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][C:8]3([C:11]42[NH:15][C:14](=S)[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[NH3:20]>>[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][C:8]3([C:11]42[N:15]=[C:14]([NH2:20])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CCC21CC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Yield: 81.6 %

Procedure:
7′-Bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 12, 0.688 g, 2.05 mmol) in ammonia (7 M in methanol, 18 mL, 126 mmol) was heated in a microwave reactor for 60 min at 100° C. Five times the mixture was concentrated, re-dissolved in ammonia (7 M in methanol, 18 mL, 126 mmol) and microwaved again for 40 to 60 minutes at 100° C. Purification by flash silica gel chromatography using a stepwise gradient of CHCl3/MeOH (30:1-20:1-10:1) gave the title compound (0.532 g, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.00-0.08 (m, 1 H), 0.11 (ddd, 1 H), 0.22 (ddd, 1 H), 0.51 (dt, 1 H), 1.46 (dt, 1 H), 2.17 (s, 3 H), 2.28-2.39 (m, 1 H), 2.82-2.98 (m, 2 H), 6.56 (d, 1 H), 6.58 (br. s., 2 H), 7.12 (d, 1 H), 7.30 (dd, 1 H); MS (ES+) m/z 318.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])[CH:3]=1>C(O)C.[Fe].[Fe](Cl)(Cl)Cl>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[N:5][CH:6]=1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Solvent: CCO
Product: CC(=O)N[C@@H](C)COc1cc(Cl)c(N)cn1
Yield: 91.1 %

Procedure:
To a solution of N-((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)acetamide (1.80 g) in ethanol (20 mL) were added iron powder (1.84 g) and iron(III) chloride (1.07 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (1.46 g). To a solution of N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (830 mg) and 5-(benzyloxy)pyridine-2-carboxylic acid (781 mg), diisopropylethylamine (1.19 mL) in DMF (10 mL) was added HATU (1.49 g), and the mixture was stirred at room temperature for 30 min. The precipitated solid was washed with ethyl acetate-hexane. A suspension of the obtained solid, potassium carbonate (1.22 g) and copper(I) iodide (84.0 mg) in DMF (10 mL) was stirred at 160° C. for 1.5 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), and washed with saturated brine, and the solvent was evaporated. The obtained solid was washed with ethyl acetate/hexane. A mixture of the obtained solid, 10% palladium/carbon (containing water (50%), 200 mg) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (37.4 mg).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:17]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 120.2 g (1 mole) of 4-tolualdehyde and 108.1 g (1 mole) of o-phenylenediamine in toluene is heated at reflux with azeotropic removal of water. After 20 hours at reflux, the reaction is cooled to room temperature, then 443.4 g (1 mole) of lead tetraacetate is added, and the reaction is stirred at room temperature for 20 hours The solids are removed by filtration, and the filtrate is swirled with basic alumina. The mixture is filtered, and the filtrate is evaporated to dryness The product is purified by recrystallization from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48](OS(C(F)(F)F)(=O)=O)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][CH:65]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([C:62]5[CH:63]=[CH:64][CH:65]=[C:60]([Cl:59])[CH:61]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OS(=O)(=O)C(F)(F)F)cc1)CO3
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Temperature: 90 °C
Yield: 54.5 %

Procedure:
To a solution of (3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(4-trifluoromethanesulfonyloxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.075 g) in toluene (4.0 mL) was added 3-chlorophenylboronic acid (0.0337 g), Pd(PPh3)4 (0.0052 g), and Na2CO3 (24 mg in 1.0 mL H2O). The mixture was heated at 90° C. for 3.0 hours. After completion of the reaction, the aqueous layer was drained. The organic layer was poured on to a silica gel column chromatography and eluted with 1% MeOH, 1:1 hexanes/EtOAc to provide (3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.039 g) which was deprotected according to General Procedure C to provide (S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.025 g).
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)C.[F:17][C:18]([F:26])([F:25])[CH:19]([CH3:24])[CH2:20]C(O)=O>>[OH:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[C:14]=1[CH2:20][CH:19]([C:18]([F:26])([F:25])[F:17])[CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Product: CC(CC1=C(O)C(=O)c2ccccc2C1=O)C(F)(F)F
Yield: 21.7 %

Procedure:
2-acetyloxynaphthalene-1,4-dione (1.24 g) and 3-trifluoromethylbutanoic acid (1.08 g) were reacted using the method as descibed in Example 3 yielding the title compound (353 mg) (mp 168° C.). This compound is listed as compound 11 in the Tables below.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH:9]([C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:10][CH3:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[C:9]([CH2:10][CH3:11])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(CC)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c(-c2ccc(Cl)cc2)c1CC
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Hydrazine monohydrate (0.13 ml, 3 mmol) was added at ambient temperature to a solution of 3-(4-chloro-benzoyl)-2-oxo-pentanoic acid ethyl ester (740 mg, 3 mmol) in ethanol (4 ml) under an argon atmosphere. The solution was stirred for 8 h at reflux temperature, the solvent was removed under reduced pressure and the residue partitioned between 1 M HCl/ice water and ethyl acetate. The aqueous layer was extracted two times with ethyl acetate, the combined extracts were washed with brine (3 times) and dried over sodium sulfate. Removal of the solvent under reduced pressure left an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 355 mg (1.27 mmol, 49%) of the title compound as yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:17]C(OCC2C=CC=CC=2)=O)([CH2:14][O:15]C)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>>[ClH:28].[ClH:28].[NH2:17][C:11]1([CH2:14][OH:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCC1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: NC1(CO)CCNCC1

Procedure:
A mixture comprising 3.78 g of N-tert-butoxycarbonyl-4-benzyloxycarbonylamino-4-methoxymethylpiperidine (a compound obtained in Reference Example 6-3 (1)) and 38 ml of concentrated hydrochloric acid was refluxed for 3 days. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran to obtain 2.8 g of 4-amino-4-hydroxymethylpiperidine.dihydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])(=[O:25])[CH3:24].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([CH3:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Agent: CC(=O)OC(C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 154.8 %

Procedure:
7-Benzyl-3,8-dimethylxanthine (500 mg, 1.85 mmol) was added to a suspension of sodium hydride (50.5 mg) in anhydrous dimethylsulfoxide (20 ml). After stirring for 30 minutes, (R) 5-acetoxy-1-chlorohexane (357 mg) was added and the mixture was warmed to 70-80° C. for 12 hours. The (R) 5-acetoxy-1-chlorohexane was prepared according to methods described in U.S. Pat. No. 5,629,423 issued to Klein, J. P., Leigh, A. J., Michnick, J., Kumar, A. M., Underiner, G. E., on May 13, 1997. After cooling to room temperature, the reaction was quenched by the addition of water (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (2×50 ml), washed with saturated aqueous sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (638 mg).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].[F:25][C:26]([F:37])([F:36])[C:27]1[C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.Cl>N1C=CC=CC=1>[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH2:23][C:33]([C:32]1[C:27]([C:26]([F:37])([F:25])[F:36])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:34]
Reactant: O=C(Cl)c1cccnc1C(F)(F)F
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(CC(=O)c1cccc([N+](=O)[O-])c1O)c1cccnc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
DBU (334 mg, 2.2 mmol) was added to a solution of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (181 mg, 1 mmol) and 2-(trifluoromethyl)pyridine-3-carbonyl chloride 25 (1.1 mmol) in pyridine (3 ml). The mixture was stirred at 70° C. for 12 h, poured into 2N HCl (20 ml) and extracted with EtOAc. The organic layers were dried over Na2SO4, concentrated and purified by preparative TLC (CH2Cl2/EtOAc, 10:1) to give 26 as a yellow solid (135 mg, 38% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([C@H:22]([CH:35]([CH3:37])[CH3:36])[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si](OC[C@@H]1[C@@H](C2C=CC=CC=2)CNC1)(C(C)(C)C)(C)C>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([C@H:22]([CH:35]([CH3:37])[CH3:36])[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:24])[CH2:11]1
Reactant: COc1ccc(COC(=O)[C@@H](C(C)C)N2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccc(F)c3)C2)cc1
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C(C)C)N2C[C@H](CO)[C@@H](c3cccc(F)c3)C2)cc1
Yield: 92.4 %

Procedure:
The title compound was prepared from 14.84 g of α-(R)-(3-(S)-((tert-butyldimethylsilyloxy)methyl)-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-isopropylacetic acid, para-methoxybenzyl ester (from Step B above) and 125 mL of 1M solution of tetrabutylammonium fluoride in 125 mL of THF using a procedure analogous to that described in Example 1, Step B, Aldehyde 1. After purification with flash chromatography on silica gel, 10.75 g of the title compound was obtained as a colorless oil. RF: 0.23 (30% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.33˜7.36 (m, 2H), 7.22˜7.26 (m, 1H), 6.88˜6.98 (m, 5H), 5.14 (AB d, 12.3 Hz, 1H), 5.13 (AB d, 12.3 Hz, 1H), 3.82 (s, 3H), 3.68 (dd, 4.6 & 10.6 Hz, 1H), 3.57 (dd, 6.1 & 10.5 Hz, 1H), 3.25˜3.29 (m, 1H), 3.05˜3.16 (m, 3H), 2.73˜2.77 (m, 1H), 2.60˜2.64 (m, 1H), 2.29˜2.35 (m, 1H), 2.02˜2.10 (m, 1H), 1.03 (d, 6.6 Hz, 3H), 0.91 (d, 6.7 Hz, 3H).
Reaction SMILES: [OH-].[K+].CI.[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].N1C=C[CH:29]=N1>CC(C)=O>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:24])[F:25])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([O:10][CH3:29])=[O:9]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Yield: 48 %

Procedure:
A KOH powder (0.1 g, 1.8 mmoles) and methyl iodide (0.26 g, 1.8 mmols) were added to a solution of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid (0.30 g, 0.8 moles) in 20 ml acetone and reacted with this pyrazole derivative under reflux 3 hours. Then the extraction with ethylacetate, washing with water, dehydration, and concentration of the extract solution, and purification of the residue by column chromatography gave the title compound (0.15 g), yield 48%.
Reaction SMILES: C([Al:3](CC)CC)C.[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[CH3:9].O>C(COC)OC>[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[Al+3:3]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC[Al](CC)CC
Solvent: O
Solvent: COCCOC
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Product: [Al+3]
Temperature: -5 °C
Yield: 93.1 %

Procedure:
3.8 g of triethyl aluminum were dissolved in 100 ml of dimethoxyethane, and the solution was cooled to -5° C. Under nitrogen gas current, a solution of 10.8 g of o-acetoxybenzoic acid dissolved in 100 ml of dimethoxyethane was added dropwise little by little to the above solution. After completion of the dropwise addition, the temperature of the mixture was returned to room temperature, and the reaction mixture was thrown into a great quantity of water. The precipitated crude crystals were recovered by filtration and dried under reduced pressure to yield 10.5 g of white aluminum tris-(o-acetoxybenzoate) having a molecular weight of about 550 and an average degree of polymerization of about 1. The infrared absorption spectrum of the resulting aluminum salt was as follows:
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH2:30][CH:31]=O>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:31][CH2:30][C:22]4[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=4[O:20][CH3:19])[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Product: COc1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc3nonc3c2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and (2-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 426 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[O:5][CH3:6].[OH:16][CH:17](C1OC=CC=1)C1C=CC=CC=1OC>>[CH3:6][O:5][CH:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[O:16][CH3:17]
Reactant: COC(c1ccco1)c1ccccc1Cl
Reactant: COc1ccccc1C(O)c1ccco1
Product: COc1ccccc1C(OC)c1ccco1

Procedure:
(±) 2-(α,2-Dimethoxybenzyl)furan (b.p. 112°-115° C./0.1 mm.Hg) was prepared in a manner similar to that described in Example 3(k) for the preparation of (±) 2-(2-chloro-α-methoxybenzyl)furan but replacing the (±) 2-(2-chloro-α-hydroxybenzyl)furan by (±) 2(α-hydroxy-2-methoxybenzyl)furan.