Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[C:16](=[O:28])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)C.CO>O1CCOCC1.ClCCl>[C:14]([C:10]1[C:11]([F:13])=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:29])=[O:3])=[C:8]([C:16](=[O:28])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH:9]=1)#[N:15]
Reactant: CCOC(=O)COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(OCC(=O)O)cc1F

Procedure:
[4-Cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid was prepared in an analogous manner to that set forth in Example 45 (Steps 8–9) except that in Step 8,5-cyano-4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide was used in place of N-(4-bromo-2-fluorobenzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide. In Step 9, special care was taken in the hydrolysis of [4-cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester. The hydrolysis was performed in dioxane instead of ethanol and quenched after 15 minutes to prevent hydrolysis of the cyano functionality: mp 179–180° C.; Rf 0.22 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.12 (t, J=6.0 Hz, 1 H), 8.21 (d, J=7.8 Hz, 1 H), 8.19 (s, 1 H), 8.10 (dd, J, =8.4 Hz, J2=2.6 Hz, 1 H), 7.80 (d, J=8.4 Hz, 1 H), 7.61 (t, J=8.0 Hz, 1 H), 7.45 (d, J=11.4 Hz, 1 H), 4.99 (s, 2 H), 4.61 (d, J=6.0 Hz, 2 H); ESI-LC/MS m/z calcd for C17H12FN3O6: 373.1; Found 472.0 (M−1)−. Anal. calcd for C17H12FN3O6: C, 54.70; N, 11.26; H, 3.24. Found C, 54.43; N, 11.07; H, 3.32.
Reaction SMILES: [CH2:1]([C@@H:4]([N:14]=[C:15]=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3].[OH-].[NH4+:18]>C1COCC1>[CH2:1]([C@@H:4]([NH:14][C:15]([NH2:18])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H](N=C=O)c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (R)-α-allyl-(3,4-methylenedioxy)benzyl isocyanate (6) (400 mg, 1.84 mmol) in THF (10 mL) was added 7.4 M ammonium hydroxide (0.75 mL, 5.5 mmol). The reaction was stirred at room temperature for 1 hour and was then evaporated to dryness in vacuo. The residue was flash chromatographed using 60%-100% ethyl acetate/hexanes to obtain 400 mg (93%) of the title compound as a white solid. NMR (CDCl3): δ 2.46 (t, J=7 Hz, 2 H), 3.8-4.8 (v b s, 2 H), 4.59 (v br q, J=7 Hz, 1 H), 5.0-5.2 (m, 3 H), 5.6-5.8 (m, 1 H), 5.95 (s, 2 H), 6.76 (s, 2 H), 6.79 (s, 1 H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:26])([F:25])[CH2:22][CH2:23][I:24]>>[I-:24].[F:20][C:21]([F:26])([F:25])[CH2:22][CH2:23][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)CCI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Yield: 76.5 %

Procedure:
A solution of triphenylphosphine (Aldrich, 11.7 g) and 3,3,3-trifluoropropyl iodid (Lancaster, 10 g) was vigorously refluxed in xylenes (75 mL) for 2 days. The solid which formed was filtered and washed with xylenes then air dried to yield a white solid (16.6 g). 1H NMR and elemental analysis are consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][OH:23].O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][O:23][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)ccc3F)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
The crude (S)-(4-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 18d (150 mg, 0.45 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (94 mg, 0.45 mmol) and triphenylphosphine (177 mg, 0.68 mmol) were dissolved in 5 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (136 mg, 0.68 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 18e (150 mg, yield 65.8%) as a colorless slime.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1[CH:43]=[C:44]([CH2:53]OS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1.CN1CCNCC1>>[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[C:42]1[CH:43]=[C:44]([CH2:53][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C)CC2)c1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1 (10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 94.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCN)cc(OC)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCNC(=O)Cc2ccc(F)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(3,5-dimethoxy-phenyl)-ethylamine (1.01 g, 5.57 mmol) in anhydrous DMF (50 mL) is added 4-fluorophenyl acetic acid (860 mg, 5.57 mmol), PyBOP (3.17 g) and N-ethyldiisopropylamine (2.2 mL, 12.8 mmol). The mixture is stirred at rt for 14 h. Water (60 mL) is added, and the mixture is extracted with EtOAc (4×60 mL). The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellow oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:30])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.NCCC(OCC)OCC>>[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:29][CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:11][C:10]([O:9][C@@H:3]3[CH:4]4[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]4)[CH2:2]3)=[O:30])[CH:20]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCCO)c1)O[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: CCOC(CCN)OCC
Product: O=C(NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccc(CC3OCCO3)cc2)c1)O[C@H]1CN2CCC1CC2

Procedure:
The title compound was prepared as described in Chiral Example 11 Step 2 with (R)-quinuclidin-3-yl((3-(3-hydroxypropoxy)phenyl)(phenyl)methyl)carbamate and 4-(1,3-dioxolan-2-ylmethyl)-benzoic acid replacing 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid and 1-amino-3,3-diethoxypropane, respectively.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)C.[Br:21]C#CCCCCCCBr>>[Br:21][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC=CCCC=CCCCCCCOC(C)=O
Reactant: BrC#CCCCCCCBr
Product: CCCCC=CCCC#CCCCCCCBr

Procedure:
In particular, 7,11-hexadecadienyl acetate expressed by the formula CH3 (CH2)3CH=CH(CH2)2CH=CH(CH2)6OCOCH3 is prepared by first reacting a Grignard reagent of 1-halo-3-octene and 1,8-dibromo-1-octyne to form 1-bromohexadeca-11-en-7-yne which is then acetylated and partially hydrogenated in the presence of a Lindlar catalyst.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:15][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])(=[O:34])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Oc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Yield: 95.2 %

Procedure:
3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chloride (50 mL) was treated with diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol) at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with 200 mL of methylene chloride, washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 4.97 (s, 2 H), 6.71 (dd, 1 H, J=1.1, 4.1 Hz), 6.78 (t, 1 H, J=2.3 Hz), 6.85 (dd, 1 H, J=1.1, 4.1 Hz), 7.17 (t, 1 H, J=8.3 Hz), 7.37 (m, 5 H), 7.58 (m, 2 H), and 7.91 (dd, 1 H, J=1.1, 4.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCNCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-β-alaninate (D72) (176 mg) in tetrahydrofuran (10 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (36 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 6 hours. The reaction mixture was concentrated to about 5 mL and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-β-alanine (E46) (109 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.72 (2H, t), 3.16 (2H, t), 4.41 (2H, s), 4.90-4.93 (1H, m), 7.33 (1H, t), 7.48 (1H, d), 7.76 (1H, d), 8.02 (1H, d), 8.09 (1H, d), 8.23 (1H, dd), 8.40 (1H, d), 8.81 (1H, br), 11.36 (1H, s). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—NHC2H4COOH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[C:15]1(C)C=CC=CC=1>O1CCOCC1.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[C:7]([CH3:15])[N:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(OC)c1
Reactant: Cc1ccccc1
Agent: [CH3-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)nc(OC)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
Under argon, dimethyl zink (14.26 g, 149 mmol, 124 mL of a 1.2 M solution in toluene) is added dropwise to a solution of 2-chloro-6-methoxy-isonicotinic acid ethyl ester (5.37 g, 24.9 mmol) and Pd(dppf) (203 mg, 0.249 mmol) in dioxane (120 mL). The mixture is heated to 75° C. and stirred for 18 h before it is cooled again to rt. The reaction is quenched by carefully adding water. The mixture is diluted further with water, filtered over celite and the filtrate is extracted with EA (2×250 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-methoxy-6-methyl-isonicotinic acid ethyl ester (4.10 g) as a colourless oil; LC-MS: tR=0.92 min, [M+1]+=195.93. 1H NMR (CDCl3): δ 1.41 (t, J=7.3 Hz, 3H), 2.52 (s, 3H), 3.97 (s, 3H), 4.39 (q, J=7.3 Hz, 2H), 7.12 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:38][CH:39]=[CH2:40]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:40][CH:39]=[CH2:38])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: C=CCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred and heated to 110° C for a while. After cooling to 20° C, 3.63 parts of 3-bromo-1-propene are added dropwise. Upon completion, stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from hexane, yielding 2-propenyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 57.2° C.
Reaction SMILES: [Br-].[C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N+:9]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+]>O1CCCC1.O>[CH3:25][C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Reactant: C[Mg]Br
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccccc2)c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium bromide (353.1 g) in tetrahydrofuran (3.5 l) was added 2.0M tetrahydrofuran solution of methylmagnesium bromide (700 ml) for 1.5 hours with stirring at room temperature. After additional stirring for 1.5 hours, the mixture was poured into a solution of ammonium chloride (300 g) in water (650 ml) under ice cooling. After separation, the aqueous layer was extracted with ethyl acetate (3.5 l). The combined organic layers were washed with water (1 l), sodium chloride aqueous solution (1 l) and dried over magnesium sulfate (125 g) and evaporated in vacuo. The residue was crystallized from ethanol (500 ml) to give 1-methyl-1-phenyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline (254.0 g).
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])([CH3:8])[C:3](OCC)=[O:4].[Cl-].[OH:30][NH3+:31].[OH-].[K+]>CO>[CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])([CH3:8])[C:3]([NH:31][OH:30])=[O:4]
Reactant: CCOC(=O)C(C)(C)OCCCCCCc1nc(-c2ccc(C)cc2)oc1C
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C(=O)NO)c(C)o2)cc1
Yield: 104.8 %

Procedure:
To 20 ml of a solution of 4.84 g of ethyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate in methanol, 3.47 g of hydroxylammonium chloride was added, and then 12.5 ml of solution of 5 M potassium hydroxide in methanol was added dropwise slowly under ice-cooling with stirring. The ice-bath was removed and the mixture was stirred for 36 hours at room temperature. The reaction solution was concentrated. The residue was acidified with 50% aqueous acetic acid solution, water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine serially, dried over anhydrous magnesium sulfate and concentrated. The residue was concentrated after addition of toluene, and again concentrated after addition of ethanol to provide 4.90 g of the objective compound as pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25]I)[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:29]([NH:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32]>ClCCl>[CH2:29]([N:33]([CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]1)=[O:27])[CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Reactant: CCCCNCC
Solvent: ClCCl
Product: CCCCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21

Procedure:
3α-Hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (1.5 g) was stirred with N-butyl-N-ethylamine (3 ml) in dichloromethane (60 ml) at 20° for 21 hours. The solution was washed with water and the solvent was evaporated at reduced pressure. The residue was triturated with water giving a solid which was recrystallised from aqueous methanol to give title compound (1.2 g), m.p. 111°-112.5°, [α]D +93.5°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(OS(=O)(=O)c2ccc(I)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Iodobenzenesulfonyl chloride (604 g, 2 mol) was added with stirring to a solution of 4-methylphenol (227 g, 2.1 mol) and triethylamine (222 g, 2.2 mol) in toluene (1.5 l). The suspension was stirred at 60° C. for 2 h. The reaction mixture was added to excess dilute hydrochloric acid. The precipitate was filtered off and washed with ethanol. A second crop was obtained by concentrating the toluene mother liquor and collecting the solid material in the same manner. The combined crops were recrystallized from 2-propanol (2.5 l). Yield 680 g, 91%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[ClH:22].[CH:23]([NH:25][C@@H:26]1[C:31](=[O:32])[O:30][C:28](=[O:29])[CH2:27]1)=[O:24].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CO>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:11])[OH:12])[NH2:8].[ClH:22].[CH:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:27][C:28](=[O:29])[OH:30])=[O:24]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The present invention relates to a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride is prepared by a process comprising: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water or in water containing methanol at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture successively with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to deposit α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].O>C(OCC)(=O)C.C(O)C>[C:2]([CH:13]([C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[Cl:5])[C:14]#[N:15])(=[O:1])[CH3:3]
Reactant: CC[O-]
Reactant: N#CCc1ccc(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)c1ccc(F)cc1Cl
Temperature: 70 °C
Yield: 69.9 %

Procedure:
A suspension of dry, solid sodium ethoxide (Aldrich, 10.2 g, 150 mmol) in a mixture of xylenes (60 mL) and anhydrous ethanol (25 mL) was stirred at 70° C., and a solution of 2-chloro-4-fluorobenzeneacetonitrile (16.96 g, 100 mmol) in a mixture of ethyl acetate (30 mL) and ethanol (5 mL) was added dropwise to the hot reaction mixture over 20 minutes. The reaction mixture was heated at 75-78° C. for 3 h and then allowed to cool. Water (50 mL) was added to dissolve solids. The mixture was extracted once with ethyl acetate, and the extract was discarded. The aqueous phase was acidified to pH 2 by addition of 1 N aqueous hydrochloric acid, and then extracted with ethyl acetate (50 mL). The ethyl acetate phase was dried (MgSO4) and evaporated to provide the intermediate product α-acetyl-2-chloro-4-fluorobenzeneacetonitrile as a solid (14.8 g).