Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:25]([N:26]([C:28](=[O:41])[CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[CH3:27])=[CH:24][CH:23]=[C:22]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O.NN>C(O)C>[NH2:30][CH2:29][C:28]([N:26]([C:25]1[C:2]([Cl:1])=[C:3]([C:22]([Cl:42])=[CH:23][CH:24]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:27])=[O:41]
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 100.3 %

Procedure:
To a suspension of 8-[2,6-dichloro-3-(N-phthalimidoacetyl-N-methylamino)benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (1.91 g) in ethanol (19 ml) was added hydrazine monohydrate (318 mg), and the mixture was refluxed for 1 hour. After cooling, the resulting precipitates was filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in chloroform. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was pulverized with diisopropyl ether to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (1.5 g) as colorless amorphous.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:15][N:14]=1.CN(C)[CH:39]=[O:40]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[CH:20]([S:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:16]1[C:17]([CH3:19])=[CH:18][C:13]([CH:39]=[O:40])=[N:14][CH:15]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C=O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
In an argon atmosphere, a hexane solution of n-butyllithium M, 22.3 ml, 34.4 mmol) was added to a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl]-4-methylpyridine (8.10 g, 19.1 mmol) in toluene (200 ml) at −78° C. The reaction mixture was stirred for 30 minutes, and then N,N-dimethylformamide (1.63 ml, 21.0 mmol) was added at the same temperature. The reaction mixture was stirred for 30 minutes, then water was added at the same temperature, and the mixture was allowed to warm to room temperature. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with saturated aqueous ammonium chloride, and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane and then collected by filtration, thus to obtain the title compound (4.27 g, 11.4 mmol, 60%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([OH:5])=[O:4].[CH3:34][Si](C=[N+]=[N-])(C)C.CC(O)=O>ClCCl.CO>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:22])([F:23])[F:24])=[C:19]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([O:5][CH3:34])=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Yield: 97.8 %

Procedure:
To a stirred solution of 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B isomer 1, 230 mg, 0.50 mmol) in dichloromethane (5 mL) and MeOH (5 mL) was added (trimethylsilyl)diazomethane (0.42 mL, 0.84 mmol) dropwise at 0° C. The excess reagent was quenched by the slow addition of glacial AcOH (0.02 mL, 0.34 mmol) at 0° C. and the solution was concentrated. The resulting residue was mixed with ethyl acetate (30 mL). The ethyl acetate solution was washed with sat. aq. sodium bicarbonate (10 mL) and brine (10 mL), dried (sodium sulfate), filtered through a pad of silica gel, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate:hexane 45%) to yield methyl 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetate (230 mg, 0.489 mmol, 97% yield) as an oil: LC/MS M+1=471.09; 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=8.58 Hz), 7.76 (2H, d, J=7.26 Hz), 7.50-7.67 (3H, m), 7.41-7.49 (2H, m), 5.23 (1H, d, J=5.28 Hz), 3.82 (3H, s), 3.03-3.15 (4H, m).
Reaction SMILES: C([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1=[O:10])(OC(C)(C)C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O1CCOCC1>[Cl:26][CH:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]1
Reactant: CC(C)(C)OC(=O)C1CCCCNC1=O
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C1CC(Cl)CCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
Example 228 B) To a solution of 1 g (0.0047 mol) of this Boc-caprolactam product of Example 228 A in 10 mL of anhydrous THF at -78° C. was added 0.005 mol of LiHMDS. After stirring for 30 minutes, 1.2 g (0.005 mol) of hexachloroethane in 5 ml of anhydrous THF was added. The mixture was allowed to warm to 0° C. and was quenched with dilute HCl. The mixture was extracted with EtOAc and the organic layer was washed with 5% HCl, dried (MgSO4), filtered and concentrated to afford a yellow oil. The residue oil was dissolved in 40 mL of 1,4-dioxane (satd. with anhydrous HCl), stirred for 40 minutes, concentrated to afford 0.9 g of 3-chlorocaprolactam as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([N+:27]([O-:29])=[O:28])[C:24]=1[O:25][CH3:26])[C:6]([NH:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=O>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:21][C:10]([C:11]3[C:12]([C:17]([F:19])([F:18])[F:20])=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:9][N:8]=2)[CH:22]=[C:23]([N+:27]([O-:29])=[O:28])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(C(=O)NNC(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A suspension of 2-trifluoromethyl-nicotinic acid N′-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide (0.60 g, 1.44 mmol) in phosphorus oxychloride (10 mL) was stirred at 130° C. for three hours, becoming a pale yellow solution. The mixture was allowed to cool to room temperature and then poured onto ice-water (200 mL). The white precipitate was filtered off, washed with water and dried to give 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine, 0.48 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[BH4-].[Na+]>CO.[OH-].[Na+].O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CO)ccc1F
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (5 g) in methanol (25 ml) was added dropwise sodium borohydride (368 mg) in 0.1N sodium hydroxide aqueous solution (5 ml) in water bath and the whole was stirred for 1 hour. After the mixture was evaporated under reduced pressure, ethyl acetate and water were added thereto. The organic layer was separated and the water layer was further extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give 4-fluoro-3-methoxybenzyl-alcohol (5.22 g) as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].F[B-](F)(F)F.[CH2:19]([O+](CC)CC)[CH3:20]>ClCCl>[CH2:19]([O:13][C:3](=[N:2][CH3:1])[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])[CH3:20]
Reactant: CNC(=O)Cc1c(F)cccc1F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(Cc1c(F)cccc1F)=NC
Temperature: 25 °C
Reaction time: 25 h

Procedure:
5.55 g (30 mmol) of 2,6-difluorophenylacetic acid methylamide are dissolved in 70 ml of dichloromethane, 7.4 g (39 mmol) of triethyloxonium tetrafluoroborate are added thereto and the whole is stirred for 25 hours at room temperature. The reaction mixture is then extracted by shaking in succession with cold 2N sodium carbonate solution, ice-water and cold saturated sodium chloride solution, dried over magnesium sulphate and concentrated. A mixture of ether and hexane is added to the residue, the unreacted educt remaining undissolved and being filtered off. The filtrate is concentrated and subjected to distillation in a bulb tube. 4 g (62.6% of the theoretical yield) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane which boils at 70° (0.02 mm) are obtained.
Reaction SMILES: ClC1C=C[CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.CC(=C)C[N:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](=[O:18])[O-:17].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:3][C:4]1([CH2:5][O:17][C:16](=[O:18])[NH:15][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:8][O:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CN(C(=O)[O-])c1ccc(Cl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(COC(=O)Nc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.4 %

Procedure:
m-Chloroperbenzoic acid (1.6 g, 6.6 mmol) was added to a solution of 2-methyl-2-propenyl(4-chlorophenyl)carbamate (1.0 g, 4.4 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 4 hours. To which sodium thiosulfate aqueous solution was added and the mixture was filtered, and sodium hydrogencarbonate aqueous solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford (2-methyl-2-oxiranylmethyl)(4-chlorophenyl)carbamate (1.1 g, quantitative) as a pale yellow crystalline powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1.CCCCCC>[C:13]([NH:17][S:18]([CH2:21][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC(C)(C)NS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.7 ml) in tetrahydrofuran (18 ml) was added dropwise a 1.6 M solution (15 ml) of 1-butyllithium in n-hexane under a nitrogen atmosphere at an inside temperature of from −62° C. to −48° C. over 5 minutes. After stirring for 30 min under ice-cooling, a solution of N-tert-butylmethanesulfonamide(3.63 g) in tetrahydrofuran (12 ml) was added dropwise at an inside temperature of from −63° C. to −59° C. over 5 minutes. After stirring for 1 hr under ice-cooling, the mixture was cooled to an inner temperature of −60° C. again. 1-Bromo-3-(tert-butyldimethylsilyloxy)propane (3.35 ml) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and saturated brine and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give N-tert-butyl-4-(tert-butyl-dimethylsilyloxy)butanesulfonamide (618 mg) as a pale-yellow oil.
Reaction SMILES: CO.ClCCl.C(OC([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:23]3[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.C(O)C.[IH:37]>C(OCC)C>[IH:37].[CH2:25]([N:24]1[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[N:21]=[C:20]1[N:16]1[CH2:17][CH2:18][CH2:19][NH:13][CH2:14][CH2:15]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CCCCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol) portionwise. After about 30 minutes, when the gas evolution ceases, add pentyl bromide (0.34 mL, 2.74 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with dichloromethane (150 mL) and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, 5% methanol/dichloromethane/0.05% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.7 g, 1.8 mmol) and ethanol (5 mL). Add aqueous hydriodic acid (5 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOCC[O:21][CH2:20]1.C(OC=O)C.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1)=[CH:20][OH:21])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)nc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOC=O
Product: CCOC(=O)C(=CO)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.46 g (14.8 mmol) of the compound from Example 40A are initially introduced into 50 ml anhydrous toluene under argon, 712 mg (17.8 mmol) sodium hydride suspension (60% strength in paraffin oil) are added in portions and the mixture is stirred at RT for 1 h and then at 80° C. for 20 min. After cooling, 392 mg (1.48 mmol) 18-crown-6 and then, while cooling with ice, 2.20 g (29.7 mol) formic acid ethyl ester are added dropwise. The mixture is stirred first at 0° C. for 1 h and then at RT for 1 h. A mixture of 100 ml ethyl acetate and 150 ml 0.1 M hydrochloric acid is added, the phases are separated, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[Cl:16][C:17]1[S:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:20]1[S:21][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)s1
Product: Clc1ccc(CNCCCc2ccc3ccccc3c2Cl)s1
Yield: 78 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-chlorothiophen-2-carbaldehyde in 78% yield as a red oil.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:32].[OH-].[Na+]>C1COCC1.O>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[N:20][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23]4)=[N:18][CH:17]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:32]
Reactant: CCOC(=O)C1CCN(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
To a solution of Example 280 (0.11 g, 0.22 mmol) in THF (12 mL) and water (4 mL) was added 1M aqueous NaOH solution (0.22 mL). The resulting mixture was stirred for 18 h at r.t. and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound (18 mg, 17%) as a white solid. HPLC-MS (pH 10): m/z 480.8 [M+H]+, RT 1.37 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]2[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([OH:25])=[O:24])=[CH:30][CH:31]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(CN(Cc2ccccc2)c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 88.3 %

Procedure:
In 40 ml of ethanol is dissolved 2.3 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate, and 25 ml of 1 N aqueous solution of sodium hydroxide is added to the solution. The mixture is refluxed under heating for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue is dissolved in water. The solution is adjusted to pH 4 with 10% hydrochloric acid. The resulting crystals are collected by filtration and dried to give 1.9 g of 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid, mp 65° to 67° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[C:36]([NH:44][C:45]1[CH:50]=[CH:49][NH:48][C:47](=[O:51])[N:46]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>[Cl-].[Na+].O>[C:16]([O:15][C@@H:8]1[C@H:7]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:14][C@H:9]1[N:48]1[CH:49]=[CH:50][C:45]([NH:44][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:46][C:47]1=[O:51])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: O
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the anomeric mixture 33 (4.0 g, 8.22 mmol) and 4-N-benzoylcytosine (2.79 g, 13.0 mmol) was added N,O-bis(trimethylsilyl)acetamide (8.16 cm3, 33.0 mmol). The reaction mixture was stirred for 1 h at room temperature and cooled to 0° C. Trimethylsilyl triflate (3.0 cm3, 16.2 mmol) was added dropwise and the mixture was stirred at 60° C. for 2 h. Saturated aqueous solutions of sodium hydrogencarbonate (3×20 cm3) and brine (2×20 cm3) were successively added, and the separated organic phase was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give compound 54 as a white solid material (3.9 g, 74%). δH (CDCl3), 8.28 (1H, d, J 7.5, 6-H), 7.94-7.90 (2H, m, Bz), 7.65-7.25 (13H, m, Bn, Bz), 7.16 (1H, d, J 7.1, 5-H), 6.22 (1H, d, J 2.8, 1′-H), 5.51 (1H, dd, J 2.8, 5.8, 2′-H), 4.62 (1H, d, J 11.6, Bn), 4.51 (1H, d, J 12.3, 1″—Ha), 4.49-4.34 (4H, m, 3′-H, Bn), 4.21 (1H, d, J 12.3, 1″-Hb), 3.85 (1H, d, J 10.3, 5′-Ha), 3.47 (1H, d, J 10.3, 5′-Hb), 2.13 (3H, s, COCH3), 2.06 (3H, s, COCH3). δC (CDCl3) 170.52, 169.61 (C═O), 166.83, 162.27 (C-4, C═O), 154.26 (C-2), 145.26 (C-6), 137.25, 136.93, 133.18, 129.0, 128.75, 128.51, 128.45, 128.18, 128.10, 127.89, 127.71 (Bn, Bz), 96.58 (C-5), 89.42, 86.52 (C-1′, C-4′), 76.21, 75.10, 74.17, 73.70, 69.70, 63.97 (C-2′, C-3′, Bn, C-5′, C-1″), 20.82 (COCH3). FAB-MS m/z 664 [M+Na]+, 642 [M+H]+. Found: C, 65.0; H, 5.7; N, 6.5; C35H35N3O9 requires C, 65.5; H, 5.5; N, 6.5%.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21](I)[CH3:22]>CN(C=O)C.O>[CH2:21]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1)[CH3:22]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2[nH]cc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF (1.0 mL) was added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture was stirred for 20 min at 0° C. under N2. Ethyl iodide (14.8 μL, 0.185 mmol) was added dropwise and the reaction mixture was stirred for an additional 3 hours. The reaction mixture was diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase was washed with water (250 mL) and was then dried over MgSO4 and the solvent was removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole was obtained as a yellow powder (40.0 mg, 89.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[NH:14]C(=O)C(C)(C)C)=[O:7])=[CH:4][CH:3]=1>Cl>[NH2:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccc(F)cc1
Agent: Cl
Product: Nc1ccncc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-[3-(4-fluorobenzoyl)pyridin-4-yl]-2,2-dimethylpropanamide (2.85 g, 9.5 mmol) in 3 N aqueous HCl (15 ml) was warmed at reflux overnight. After cooling to room temperature, the reaction mixture was washed with ether, the aqueous layer was separated and neutralized with potassium carbonate. The product was extracted into ethyl acetate, dried over potassium carbonate/sodium carbonate and concentrated. The residue was purified by flash chromatography (5% methanol/methylene chloride gradient) to afford 4-amino-3-(4-fluorobenzoyl)pyridine (1.58 g).