Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:23])[NH:17]2.[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1>CC#N>[Cl:24][C:25]1[N:30]=[C:29]([O:22][C:21]2[C:13]([F:12])=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH3:23])=[CH:15]3)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc2c(F)c(Oc3ccnc(Cl)n3)ccc2[nH]1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
DBU (5.48 mL, 36.3 mmol) is added dropwise to a suspension of 4-fluoro-2-methyl-1H-indol-5-ol (5.00 g, 30.3 mmol) and 2,4-dichloropyrimidine (4.60 g, 30.9 mmol) in CH3CN (60 mL) at 0° C. The resulting mixture is warmed to and stirred at 23° C. for 15 h. The reaction mixture is concentrated and the residue is partitioned between 1:1 EtOAc-CH2Cl2 (300 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to provide 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH-:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: COCC[NH-]
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCOC)s2)c(C)[nH]c1=O
Yield: 26 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-methoxyethyl)amide as described in Step 5, Example 24 to give the title compound as a solid (26% yield). LC/MS: RT 2.51 min; m/e 357 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 7.97 (1H, t), 7.54 (1H, d), 7.33 (1H, s); 7.16 (1H, d), 3.34 (2H), 3.32 (3H, s), 3.01 (2H), 2.39 (2H, q), 2.31 (3H, s), 1.07 (3H, t).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:19][C:18]1[C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cccnc1Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ncccc2Cl)c1
Temperature: 120 °C

Procedure:
7.68 g of sodium hydride dispersion (ca. 50 percent in mineral oil) was washed with pentane under nitrogen and 100 ml of N,N-dimethylformamide was then added. 21.92 g (135 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 30 minutes at room temperature. The resultant phenate solution was added dropwise over 2 hours, under nitrogen, to a solution of 20.1 g (136 mmol) of 2,3-dichloropyridine in 80 ml of N,N-dimethylformamide, heated to 120° C. After a reaction time of 3 hours, the mixture was cooled to room temperature, the precipitate of sodium chloride was filtered off and the filtrate was concentrated. The residue was extracted with toluene and 0.1 N hydrochloric acid and the organic phase was washed with saturated sodium chloride solution and concentrated. The oily residue was distilled under vacuum. The yield of the title compound was 24.75 g (67 percent) of a colorless oil, content (GC) 99.7 percent. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(Cl)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(Cl)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-chlorophenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 7) 80.0 mg (0.181 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.48 (4H, m), 7.34 (2H, d, J=8.4 Hz), 6.97 (1H, s), 6.07 (1H, t, J=4.5 Hz), 2.34 (2H, d, J=4.6 Hz), 1.29 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=1.[H-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cc(F)c(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.64 mmol), and 4-chloropicolinamide (110 mg, 0.71 mmol) in DMF (2 mL) was added NaH (80 mg, 1.3 mmol, 60% dispersed in mineral oil). The reaction mixture was microwaved at 120° C. for 1.5 hours, then cooled to rt, diluted with water (20 mL), and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccc(O)cc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(OC(=O)c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a stirred suspension of 2-methyl-1,3-benzoxazol-6-ol (2.99 g, 20 mmol) in dichloromethane (50 mL) was added triethylamine (4.05 g, 5.58 mL, 40 mmol). A solution of benzoyl chloride (3.09 g, 2.56 mL, 22 mmol) in dichloromethane (20 mL) was added dropwise over ca. 10 min. The reaction mixture was stirred at room temperature for 2.5 h, then washed with water (2×50 mL), and dried over Na2SO4, filtered and concentrated in vacuo to give the subtitled compound as a colourless solid (5.05 g, 20 mmol).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:13])[CH3:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:3][C:2]([NH:10][C:11](=[O:13])[CH3:12])([C:4]1[CH:5]=[CH:6][C:7]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)NC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NC(C)(C)c1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of N-(1-methyl-1-phenylethyl)acetamide (21.3 g, 121 mmol), phenylacetyl chloride (19.5 g, 126 mmol) and aluminum trichloride (19 g, 142 mmol) in methylene chloride (140 mL) was stirred overnight at room temperature under an atmosphere of nitrogen. The reaction was poured onto ice and stirred until the ice melted, then the layers were separated and the organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography gave the title compound. MS (M+H+): calculated=295.38, observed=296.1
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([NH:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([N:28]([CH2:29][CH2:30][OH:31])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoyl chloride (1 g, 4.21 mmol) in THF (14.04 mL) was added DIEA (1.103 mL, 6.32 mmol) and 2-(benzylamino)ethanol (0.764 g, 5.05 mmol) at room temperature. The reaction mixture was stirred for overnight. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide was used for the next step (83%). LCMS (m/z): 352/354 (MH+), 0.83 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14].C([O:20]O)(C)(C)C.[Se](=O)=O>ClCCl.CC(C)(CC(C)C)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([OH:20])/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: NC(=O)/C=C1/c2cc(F)cc(F)c2CC1O
Temperature: 25 °C

Procedure:
A suspension of (E)-2-(4,6-difluoro-1-indanylidene)acetamide (10.0 g, 0.05 mol, prepared as in Example 5 g in dichloromethane (250 mL) was added portionwise over a 10 min. period to a mixture of 70% aqueous t-butylhydroperoxide (19.8 mL, 0.15 mol, Aldrich) and selenium dioxide (3.7 g, 0.03 mol, Aldrich) in dichloromethane (500 mL) at ambient temperature. After 18h, additional t-butylhydroperoxide (10 mL of a 5.0M solution in 2,2,4-trimethylpentane, 0.05 mol, Aldrich) and selenium dioxide (1.8 g, 0.02 mol) were added and the mixture was stirred at ambient temperature. After 18h, additional t-butylhydroperoxide (10 mL of 70% aqueous solution, 0.08 mol) and selenium dioxide (3.7 g, 0.05 mol) were added and the mixture was stirred at ambient temperature for 8 days. The resulting solid was filtered off and washed with dichloromethane to give 5.85 g of crude (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide. After 7 days at ambient temperature a second crop of crude (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide was obtained from the filtrate. Column chromatography on silica gel using ethyl acetate as the eluent followed by a second column chromatography on silica gel using ethyl acetate:hexanes (3:2) as eluent and trituration of the resulting solid with pentane gave 2.38 g of (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide as a pink solid: m.p. 235-237° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:29]=[CH:28][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[S:20][C:19]=4[CH3:27])[CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C=O.[C:32]([BH3-])#N.[Na+]>C(O)C>[CH3:27][C:19]1[S:20][C:21]2[CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]=2[C:18]=1[CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[C:6]3[CH:28]=[CH:29][C:3]([F:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:11][CH2:12]1
Reactant: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C)C2
Temperature: 25 °C

Procedure:
To a solution of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine hydrochloride in ethanol was added 0.3 ml of 37% formaldehyde solution and the mixture was stirred at room temperature for an hour. To the mixture was added 0.2 g of sodium cyanoborohydride, the mixture was stirred for an hour, and then concentrated. To the residue was added water and extracted with chloroform. The extract was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography and recrystallized from isopropyl ether to give 2,6-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine 1/2hydrate as white crystals, m.p. 100°-103° C.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[CH:11]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:2][CH3:3])[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1
Reactant: [Li]CCCC
Reactant: COc1cc(C=O)cc(OC)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyltriphenylphosphonium bromide (4.69 g) was dissolved in anhydrous THF (70 mL) and the mixture cooled to 0-5° C. n-BuLi (5.05 mL of 2.5 M in hexane) was added dropwise and the resulting mixture was stirred at room temperature for 3 h. The mixture was cooled to −78° C. and a solution of 3,5-dimethoxybenzaldehyde (2 g) in anhydrous THF (14 mL) was added. The mixture was allowed to warm up to room temperature then stirred overnight. The mixture was concentrated, and the residue was taken up with AcOEt, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 10:1) to give 3,5-dimethoxy-1-(1-propenyl)benzene as a mixture of cis and trans isomers (2.15 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:10])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:18])[N:3]=1.[CH3:24][C:25]([NH2:31])([C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:26]>>[CH3:24][C:25]([NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:10])([CH3:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:18])[C:19]([CH3:22])([CH3:20])[CH3:21])[N:3]=1)([CH3:26])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(C)(C)N
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(NC(C)(C)C(C)(C)C)n1
Temperature: 185 °C

Procedure:
3.3 g. (9.6 mmole) of 2-chloro-4,6-di(2,3,3-trimethyl-2-butyl)amino-s-triazine and 3.3 g. (30 mmoles) of 2,3,3-trimethyl-2-butylamine are heated at reflux (oil bath 185° C.) for 21 hours. Thin layer chromatography of a sample of the reaction mixture indicates a mixture of starting material and product in a ratio of 3:7. Heating is terminated and the reaction mixture is treated with excess aqueous NaOH. Filtration affords a 4.9 g. of crude beige product. This is digested with 15 ml. of hot acetone, filtered and 2.6 g. of beige solid collected, m.p. 278° C. dec. Recrystallization of this product from hot ethanol gives the pure product, m.p. 317°-321° C. dec.
Reaction SMILES: [CH2:1]([C:8]([NH2:11])(C)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(O)C(C)(N)C)C=CC=CC=1.[IH:24]>>[C:2]1([CH2:1][CH:8]([NH2:11])[CH2:9][I:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: I
Reactant: CC(C)(N)Cc1ccccc1
Agent: CC(C)(N)C(O)c1ccccc1
Product: NC(CI)Cc1ccccc1
Yield: 31 %

Procedure:
There are many possible methods for hydrogenating the hydroxyl group at benzyl position of APPD. For example, U.S. Pat. No. 3,084,099 issued to Hays et al. describes a method of preparing 1-benzyl-iso-propyl amine from 1phenyl-2-methyl-2-amino-propanol by hydrogenation in 57% hydriodic acid with red phosphorous. However, the strongly acidic condition of this system may induce iodination of other hydroxyl groups. In fact, the hydrogenation of APPD in the above conditions produced 1-phenyl-2-amino-3-iodopropane instead of phenylalaninol, as disclosed in Japanese Patent 3910914. Other approaches were made by two independent groups, Boerner et al. prepared D-phenylalaninol from L(+)-APPD by 4 steps with a total yield of 31% (Pharmazie 45, 531 (1990)). On the other hand, the hydrogenation of L(+)-APPD in the presence of sulfuric acid was found to give D-phenylalaninol (D-PAO)in 73-85% yield (Hashizume, Japanese Patent 63255254). It is obvious that the latter is quite cost-effective. However, in this process, it is necessary to use excess amounts of base to neutralize the reaction mixture for the recovery of D-PAO because an excess amount of sulfuric acid is used. When the pH of the reaction mixture is adjusted to above 11, large amounts of salts are produced and some of them, including small amount of D-PAO, are precipitated. This phenomenon makes the work-up process very complicated. Furthermore, it makes it impossible to derivatize phenylalaninol into desired forms such as N-terminal blocked phenylalaninols without isolation of phenylalaninol.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].CO[CH:22](OC)[CH2:23][CH:24](OC)OC>C(O)C.CO>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]2[CH:24]=[CH:23][CH:22]=[N:1][C:2]=12
Reactant: COC(CC(OC)OC)OC
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c(N)[nH]1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12

Procedure:
50 mg (0.19 mmol) of ethyl 5-amino-4-(2-fluorobenzyl)-1H-imidazole-2-carboxylate from example 9A are heated in 0.5 ml of ethanol to reflux and a solution of 34 mg (0.21 mmol) of 1,1,3,3-tetramethoxypropane in 1.0 ml of methanol is added dropwise. The mixture is then stirred under reflux for 45 min. The product is purified directly by preparative HPLC. 37 mg (65% of theory) of the desired compound are obtained.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:49]([C:46]2[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)(=[O:50])=[O:51])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (129 μL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 6-methoxypyridine-3-sulfonyl chloride (129 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:6) to give the title compound as a pale-yellow oil (yield 247 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(F)ccc1C(=O)OC
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of methyl 2-bromo-4-fluorobenzoate (1 g, 4.29 mmol), allyltributylstannane (1.464 mL, 4.72 mmol), lithium chloride (0.364 g, 8.58 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.151 g, 0.215 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-fluorobenzoate (330 mg, 1.699 mmol, 39.6% yield) as an white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=8.6, 6.1 Hz, 1H), 7.09-6.87 (m, 2H), 6.01 (ddt, J=16.9, 10.3, 6.6 Hz, 1H), 5.19-4.96 (m, 2H), 3.90 (s, 3H), 3.80 (d, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[C:4]([F:14])[CH:3]=1.C1(C)C=CC(S(O[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[C:4]([F:14])[CH:3]=1
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 93.1 %

Procedure:
A 10-L three-necked flask equipped with a mechanical stirrer and a Dimroth condenser was charged with methyl N-(4-chloro-2-fluoro-5-hydroxyphenyl)carbamate (1.64 kg, 7.47 mol), cyclopentyl p-toluenesulfonate (1.80 kg, 7.48 mol), potassium carbonate (1.03 kg, 7.46 mol) and potassium iodide (12.3 g, 1.0 mol %), followed by the addition of solvent acetone (7,500 mL). The mixture was heated under reflux for 4 h. After completion of the reaction, the reaction mixture was recovered and 0.5N HCl (20 L) was added with vigorous stirring. The precipitating methyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate as white solids (2.00 kg, 6.95 mol; yield=93.1%) was isolated by filtration and dried thoroughly. MP: 120.0°-123.0° C. 1H-NMR(CDCl3,TMS,ppm): δ1.40-2.10(8H,m), 3.77(3H,s), 4.77(1H,m), 6.82(1H,brs), 7.07(1H,d,JHF =10.5Hz), 7.83(1H,d,JHF =7.5Hz). IR (KBr disk, cm-1): 1714, 1535, 1500, 1415, 1255, 1190.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].C(OC(C)C)(C)C>ClCCl>[Cl:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=1)=[O:16]
Reactant: COC(=O)CCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(=O)CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetyl chloride and 250 ml of dichloromethane was cooled to 0° C. Then at 0° to 10° C. with stirring, 122 g of aluminum chloride was added slowly, stirred at a room temperature for 2 hours and allowed to stand overnight. The reaction mixture was poured into an ice-concentrated hydrochloric acid and extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation to obtain the residue, then isopropyl ether was added to the residue to effect crystallization. The crystals were collected by filtration, and recrystallized from ethanol to obtain 53.4 g of methyl 3-(4-chloroacetylphenyl)-propionate. Colorless needle-like crystals. Melting point: 90°-92° C.