Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:6]=1)[OH:4].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[Cl:17][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:38]=[CH:37][C:28]([CH2:29][CH:30]5[S:34][C:33](=[O:35])[NH:32][C:31]5=[O:36])=[CH:27][CH:26]=4)[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: NC[C@H](O)c1cc(-c2ccc(Cl)c(Cl)c2)no1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cc(-c5ccc(Cl)c(Cl)c5)no4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1S)-2-amino-1-[3-(3,4-dichloro-phenyl)isoxazol-5-yl]ethanol (which was obtained in Example 109) and 5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 106 and was obtained as a white solid (0.22 g, 48% yield), mp 110° C.; MS (ES) m/z: 561 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.38 (m, 2H), 1.89 (m, 2H), 3.32-2.67 (m, 7H), 3.60 (m, 2H), 4.74 (m. 1H), 4.85 (m, 1H), 6.85 (d, 1H), 7.02 (d, 1H), 7.11 (s, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 8.13 (s, 1H).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[CH2:1][CH:2]([CH3:4])[CH3:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7]
Reactant: CCOC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC(C)C)c(C#N)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 33 %

Procedure:
Isobutyl bromide (56.1 mL, 512 mmol) was added to a suspension of the ethyl 3-cyano-4-hydroxybenzoate crude product (51.4 g) and potassium carbonate (70.8 g, 512 mmol) in dry DMF (200 mL), stirred at 100° C. for 10 hours, and cooled to room temperature. Ice-water (500 mL) was then added to the cooled suspension. The aqueous mixture was extracted with ethyl acetate (200 mL×2). The ethyl acetate portion was washed successively with water (500 mL×2) and aqueous saturated brine (200 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4). The resulting crystalline product was dissolved in ethyl acetate (50 mL) under heating. The mixture was kept hot, while hexane (100 mL) was added to the mixture. The hexane solution was stirred and cooled to room temperature, and further stirred for 10 min. under cooling with ice. The precipitated crystalline product was collected by filtration, washed successively with ethyl acetate/hexane (1/5, 60 mL) mixture and hexane (500 mL), and dried in air, to give 20.8 g (yield 33%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([C:23]#[N:24])=[CH:7][N:6]=1)=[O:4]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH2:24])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ncc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Reaction time: 3.5 h

Procedure:
To a solution of 5-cyano-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester (600 mg, 1.74 mmol) in concentrated glacial acetic acid (12 mL) was added 10% Pd on carbon (120 mg). The reaction mixture was evacuated with vacuum and purged with H2 (3×), then stirred under an atmosphere of H2 for 3.5 hours. The reaction mixture was then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the desired product as the HOAc salt. LCMS (method C): RT=2.51 min, [M+H]+=349.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][C:24]1([CH3:29])[CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Yield: 93 %

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (2.200 mg) was suspended in toluene (250 ml) and the flask equipped with a Dean-Stark trap. After heating to reflux, the compound dissolved. 40 ml of toluene were distilled off, PPTS (120 mg) and 2-methoxypropene (3.5 ml) were added, and distillation was continued. Further additions of 2-methoxypropene (2 ml, and then 1 ml) and toluene (50 ml, and then another 50 ml) were made, and the distillate periodically discarded. Purification on HPLC (hexane/ethyl acetate, 3:1) gave 2.3 g (93%) of the title product in a mixture with other reaction products. (Product characteristics consistent with structure of Example 1.)
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.CCOCC>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: Fc1cc2c(cc1Br)N=Cc1ccccc1O2
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 140 °C
Yield: 74.6 %

Procedure:
Glutaric anhydride (7.2 g, 63 mmol) was added to a stirred solution of 8-bromo-7-fluoro-dibenz[b,f][1,4]oxazepine (46.5 mmol) in xylene (26 mL) and the mixture was heated to 140° C. for 120 h. The reaction mixture was allowed to cool to ambient temperature, ether was added and the solution extracted (3×) with 2M NaOH. The pH of the combined extracts was adjusted to pH 4 by adding 3M hydrochloric acid. The product was collected by filtration and dried to yield the title compound (14.1 g, 81%) which was used without further purification. 1H-NMR (400 MHz, CDCl3) 2.03-2.14 (m, 1H), 2.31-2.4 (m, 1H), 2.53-2.62 (m, 1H), 2.67-2.81 (m, 1H), 3.55-3.60 (m, 1H), 5.46-5.49 (m, 1H), 7.05-7.09 (d, J=8.6, 1H), 7.11-7.32 (m, 4H), 7.56-7.59 (d, J=7.8, 1H). (m/z)=406+408 (M+H)+.
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>CO>[NH2:20][C:18]1[S:19][C:2]([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CO
Product: COC(=O)CCc1sc(N)nc1-c1ccccc1
Yield: 90.6 %

Procedure:
A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (15.0 g), thiourea (3.81 g) and methanol (200 ml) was refluxed for 2 hrs. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The obtained solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-(2-amino-4-phenyl-5-thiazolyl)propionate (11.9 g, yield 90%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 130–131° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][O:26][C:27]2=[O:28])=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:30]=[C:29]2[C:24](=[CH:23][CH:22]=1)[CH2:25][O:26][C:27]2=[O:28])[CH3:14]
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)C(=O)OC4)c2cc1OCC
Temperature: 100 °C
Yield: 95 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of 6-Aminophthalide and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 535 mg of 6,7-Diethoxy-4-(3-oxo-1,3-dihydro-isobenzofuran-5-ylamino)-quinoline-3-carbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 390.1, mp=280-284° C.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31]C(=O)OC(C)(C)C)([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:28][CH2:27][C:26]([NH:31][S:43]([CH:40]6[CH2:42][CH2:41]6)(=[O:45])=[O:44])([CH2:29][CH2:30]4)[CH2:25][CH2:24]5)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)n23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To a flask containing tert-butyl 4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (0.175 g, 0.327 mmol) was added a solution of HCl (4 N in 1,4-dioxane, 5 mL). After about 2 h at ambient temperature, the reaction mixture was concentrated under reduced pressure. The crude amine hydrochloride was dissolved in DCM (10 mL) and TEA (0.36 mL, 2.6 mmol) was added to the reaction mixture followed by cyclopropanesulfonyl chloride (0.18 g, 1.3 mmol). After about 2 h at ambient temperature, DMF (3 mL) was added and the reaction mixture was concentrated under reduced pressure to remove DCM. After a further about 4 h at ambient temperature, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) was added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by chromatography on silica gel using 20-80% EtOAc in DCM to provide N-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide as a tan solid (0.025 g, 14%). LC/MS (Table 2, Method a) Rt=2.34 min; MS m/z: 540 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:11]2[O:12][C:13]=1[CH3:14].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].CCOCC>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([N+:25]([O-:26])=[O:24])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: O=[N+]=O
Reactant: Cc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate HE) (768 mg, 2.73 mmol) in MeCN (13 ml) is added nitronium tetrafluoroborate (0.5M solution in sulfolane, 6.6 ml, 3.3 mmol, 1.2 eq.). The dark orange reaction mixture is stirred at RT for 3 h then diluted into Et2O (150 ml) and washed successively with Na2CO3 1M in water (100 ml), water (100 ml) and brine (50 ml). The organic layer is dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→7:3) to yield the title compound as a greenish solid. TLC: RF=0.27 (heptane/TBME 3:1); HPLC: AtRet=2.73; MS: m/z 325.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 2.49 (s, 3H), 2.66 (s, 3H), 7.47 (dd, J 8.3, 2.0, 1H), 7.52 (d, J 8.3, 1H), 7.64 (d, J 2.0, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][C:15]=3[S:24]([CH3:27])(=[O:26])=[O:25])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([CH2:18][OH:19])=[CH:16][C:15]=3[S:24]([CH3:27])(=[O:26])=[O:25])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1c(S(=O)(=O)Nc2ccc(CO)cc2S(C)(=O)=O)sc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
Into 10 mL of toluene was dissolved 305 mg of Compound 1, and the solution was cooled to −78° C., followed by addition of 2.2 mL of 1.01 mol/L toluene solution of diisobutylaluminum hydride. After 20 minutes of stirring at the same temperature, the mixture was gradually warmed to 0° C. and stirred for 1 hour. After the reaction was terminated by adding water, the mixture was diluted with ethyl acetate and saturated aqueous potassium sodium tartrate solution were added, followed by 30 minutes of stirring at room temperature. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 230 mg of the title compound as colorless powder.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)C.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: NCCCCCCOc1ccc(Cl)cc1
Reactant: CCOc1c(Nc2ccccn2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2ccc(Cl)cc2)c(Nc2ccccn2)c1=O

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-2-yl-amino)-3-cyclobutene-1,2-dione and 6-(4-chlorophenoxy)-hexylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH:25]([Mg]Br)([CH3:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)[Mg]Br
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(O)C(C)C)c2cc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (105.3 mg) was dissolved in tetrahydrofuran (3 ml) to prepare a solution, and the solution was then cooled to −78° C. A 0.68 M tetrahydrofuran solution (0.6 ml) of isopropylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2-methyl-1-propanol (11.5 mg, yield 10%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].COC(=O)C(NC([C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[CH:37]S[C:35]=2[C:39]=1O)=O)(C)C>>[CH3:6][C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[O:20][CH2:37][CH2:38][C:34]1[CH:35]=[CH:39][CH:31]=[CH:32][CH:33]=1)=[O:9])([CH3:5])[C:3]([OH:2])=[O:21]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1O)CCCC2
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1O
Product: CC(C)(NC(=O)c1ccc2c(c1OCCc1ccccc1)CCCC2)C(=O)O

Procedure:
The following examples were prepared in analogy to example 1 via a sequence of an alkylation reaction to attach a suitably substituted alkylating agent to the aromatic hydroxy group of 2-[(1-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester or 2-[(7-Hydroxy-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester and a basic hydrolysis of the amino acid ester to the free amino acid:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[CH:18][CH:17]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
1 N Lithium bis(trimethylsilyl)amide (25 mL, 25 mmol) was added dropwise to a solution of ethyl 2-(4-(methylthio)phenyl)acetate (5.05 g, 24 mmol), prepared according to the method of Example 73A, in THF (20 mL) maintained at −78° C. After 15 minutes the mixture was treated dropwise with a solution of 4-fluorobenzoyl chloride (2.85 mL, 24 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 90 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was triturated with hexanes:ether, 15:1, to provide the desired product (yield: 7.25 g; 90%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, DMSO) δ1.18 (m, 3H), 2.45 (s, 3H), 4.15 (m, 2H), 6.15 (s, 1H), 7.23 (m, 2H), 7.35 (m, 4H), 7.85 (d, J=9 Hz, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:33]2[C:32]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][S:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[C:33]3[C:32]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][S:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccccc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a suspension of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-phenylethyl)benzo[b]thiophene (75 mg) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.025 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (42 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:32]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][C@@H:49]1[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51])[C@@H:33]1[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]1[OH:35]>CN(C=O)C>[C@@H:49]1([O:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]
Reactant: C[C@@H]1O[C@@H](OCCNCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e=616.2923 [M+1]; Rt=3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J=6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J=7.11), 2.53 (2H, t, J=7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(Br)c2ccncc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
A 3-neck flask was charged with 5-bromo-8-nitroisoquinoline (4 g, 15.8 mmol) and dissolved in MeOH (50 mL). A condenser was affixed and the mixture was heated to 100° C. Aqueous (20 mL) solution of ammonium chloride (4.12 g, 79 mmol) was added slowly, followed by iron powder (3 g, 53.7 mmol). The heterogeneous mixture was stirred at 100° C. for 3 h. LCMS confirmed complete reduction to the amine. The mixture was filtered and the solution was concentrated under reduced pressure to give a brown solid as crude product (2.4 g, 68%). LCMS showed an m/z of 225.0/223.0 with a retention time of 0.767 min, method [1].