Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O>[CH:6](=[N:1][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](N=Cc1ccccc1)C(O)c1ccccc1

Procedure:
There are prior methods of producing β-phenylalanine derivatives. For example, there is (1) a method which comprises reacting a copper complex of glycine with a benzaldehyde (for example, West German Pat. No. 960,722). The use of the copper salt, however, gives rise to a pollution problem, and the treatment of the waste water becomes troublesome. Moreover, this method generally has the defect of low yields. Another well known method is (2) a method of producing a β-phenylserine which comprises reacting glycine and a benzaldehyde in the presence of an alkali and then treating the product with an acid. For example, according to Kenneth N. F. Shaw and Sidney W. Fox, Journal of American Chemical Society, 75, 3419 (1953), β-phenylserine is obtained in a yield of 70% by reacting glycine and benzaldehyde in the presence of sodium hydroxide in water and treating the product with hydrochloric acid. This method, however, has a serious problem. As stated in the above-cited reference, the sodium salt of N-benzylidene-β-phenylserine, the reaction product of glycine and benzaldehyde, is temporarily precipitated, and the reaction mixture solidifies wholly. As a result, it becomes impossible to stir the reaction mixture mechanically. According to the reaction mechanism as shown in the reaction scheme (1) below, first 1 mole of glycine is condensed with 1 mole of benzaldehyde to form N-benzylidene-β-phenylserine. By treating the N-benzylidene-β-phenylserine with an acid, the desired β-phenylserine is formed. ##STR1##
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=3)[O:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=3)[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:28][CH:29]=1
Reactant: COC(=O)COc1cccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(OCC(=O)O)c2)cc1
Yield: 100.3 %

Procedure:
A solution of the compound (153 mg, 0.393 mmol) of Example 1-1 in an aqueous 1N lithium hydroxide solution (1.0 ml), terahydrofuran (1.0 ml) and methanol (1.0 ml) was stirred for 30 minutes at room temperature. Thereto was added diluted hydrochloric acid and the solution was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (148 mg, 100%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:17]1[CH2:16][CH2:15][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[CH2:19][CH2:18]1)(=[O:39])[CH3:38]
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A flask was charged with 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide (0.035 g, 56 μmol) (as prepared in Example 34, step (b)), NEt3 (31.0 μL, 225 μmol), acetic anhydride (6.5 μL, 62 μmol), and DCM (0.5 mL) and stirred at RT for 1 h. The title compound was eluted from a 10-g SPE cartridge (silica) with 5% MeOH/DCM to give 18 mg (75%) of a white solid. 1H-NMR (400 MHz, CDCl3): δ 9.78 (s, 1H), 8.34 (d, 1H), 7.24 (m, 2H), 7.01 (m, 2H), 4.80 (m, 2H), 3.96. (m, 2H), 3.20 (t, 1H), 2.98 (m, 2H), 2.70 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H), 1.60 (m, 5H), 1.10 (d, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H30N4O3, 435.2 (M+H), found 435.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8](C(C(OCC)=O)C(OCC)=O)[CH3:9])=[CH:3][CH:2]=1.[C:21](=[O:24])(O)[O-:22].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH3:9])[C:21]([OH:22])=[O:24])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)Cc1ccncc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CC(Cc1ccncc1)C(=O)O
Yield: 76.9 %

Procedure:
Compound diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate (2.50 g, 9.43 mmol) was refluxed in cone. HCl (30 ml) for 16 h. The pH of the reaction mixture was adjusted to 6 by adding solid sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 1.20 g (76.9%) of 2-((pyridin-4-yl)methyl)propanoic acid as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (Yield 61%) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm: 4.45 (3H, s) 7.03–7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ ppm: 39.86, 116.28, 118.66, 118.76, 130.13, 135.73, 161.74, 163.53; LC/MS m/z 257/259.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CC1(C)CCc2cc(C=O)ccc21
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CCc2cc(CNCCc3cccc(C(F)(F)F)c3)ccc21
Yield: 97 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 1,1-dimethylindan-5-carbaldehyde (100 mg, 0.57 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (109 mg, 0.57 mmol) and sodium borohydride (33 mg, 0.86 mmol). The desired product (194 mg, 97%) was isolated without further purification as a colorless oil. MS (ISP) 348.4 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C([O-])(O)=O.[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)SCCN2CCCN1CCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)SCCN2CCCN1CCCC1)c1cccs1
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A solution of 4-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.43 g, 1.550 mmol) in dry ethanol (15 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.884 g, 3.10 mmol) at room temperature, and the resulting mixture was stirred overnight (18 hours). The reaction was diluted with saturated NaHCO3 solution (30 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2), to obtain the title product 21 (0.51 g, 85%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=4.5 Hz), 7.55 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=3.6, 4.9 Hz), 6.70 (d, 1H, J=8.7 Hz), 6.52-6.44 (m, 2H), 6.32 (brs, 2H), 3.51-3.48 (m, 2H), 3.27 (t, 2H, J=7.2 Hz), 3.04-3.00 (m, 2H), 2.48-2.40 (m, 6H), 1.80-1.60 (m, 6H); ESI-MS (m/z, %): 387 (MH+, 68), 276 (100), 194 (75); HPLC purity: 98.32% by area.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH2:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[C:11]=1[Cl:16].[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:34])[C:30](OC)=[O:31])=[CH:25][C:23]=2[N:24]=1>O1CCCC1>[Cl:16][C:11]1[C:12]([CH3:15])=[N:13][S:14][C:10]=1[NH:9][C:30](=[O:31])[CH:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([CH2:19][C:18]([CH3:35])([CH3:17])[CH3:36])=[N:24][C:23]=2[CH:25]=1)[CH3:34]
Reactant: Cc1nsc(N)c1Cl
Reactant: COC(=O)C(C)c1ccc2oc(CC(C)(C)C)nc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)C(C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (2.0 molar solution in tetrahydrofuran/ethylbenzene/heptane, 1.46 ml, 0.0029 mole) was added dropwise to a chilled solution of 5-amino-4-chloro-3-methylisothiazole (0.44 g, 0.0029 mole) [preparation as in Example 1, Step 1] in tetrahydrofuran (20 ml) and the solution was stirred at 0° C. for 1 hour. A solution of methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionate (0.80 g, 0.0029 mole) [from previous step] in tetrahydrofuran (5 ml) was added dropwise and once the addition was complete the mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The mixture was quenched with water, acidified with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Further purification by flash column chromatography, eluting with ethyl acetate:hexane at 1:4 by volume gave N-(4-chloro-3-methylisothiazol-5-yl)-2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionamide as a colourless solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[Cl:10][C:11]1[C:12](=[O:23])[C:13]2[C:18]([C:19](=[O:22])[C:20]=1Cl)=[CH:17][CH:16]=[CH:15][CH:14]=2.N>CN(C=O)C>[Cl:10][C:11]1[C:12](=[O:23])[C:13]2[C:18]([C:19](=[O:22])[C:20]=1[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:4]1=[O:3])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: O=C1CCCCN1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(N2CCCCC2=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
NaH (440 mg) was added to a solution of 2-oxopiperidine (1.0 g) in DMF (20 ml) and the mixture was stirred at room temperature for 30 minutes. This solution was added in a single portion to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (6.9 g) in DMF (150 ml) and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into saturated aqueous ammonia and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:10 solution) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-(2-oxopiperidino)naphthalene (0.49 g) as a light brown powder.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2([CH:12]3[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2(c3cccc(O)c3)CCCCC2)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC1CCC(C2(c3cccc(OC(=O)CC)c3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Under a nitrogen atmosphere, 1.7 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)cyclohexyl)phenol (3) dissolved in 10 mL of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.52 g of 3-((4-propylcyclohexyl)cyclohexyl)phenyl propanoate (4).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 51.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 11 (29 mg, yield 51.5%) as a yellow solid.