Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:23]([C:25]1([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]1)=[O:24].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]([C:25]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]2)=[O:24])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Reactant: Brc1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Br)cc1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-bromoiodobenzene (2150 mg, 7.60 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of 1.67 mol/L n-butyllithium in hexane (4.50 mL, 7.52 mmol) at −78° C. under argon atmosphere. The mixture was stirred at the same temperature for 1 hour, and then thereto was added dropwise a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (synthesized by the method of Organic Process Research and Development 2009, 13, 576, 1000 mg, 5.07 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride solution at −78° C., and then the mixture was warmed to room temperature and extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5) to give (4-bromophenyl)[1-(trifluoromethyl)cyclopropyl]methanone (783 mg, 76%) as a pale brown oil.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5](OCC)=[O:6])#[N:3].FS(O)(=O)=O.[CH:15]1([C:21]([NH2:23])=[NH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[NH2:3][C:2]1[N:22]=[C:21]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[NH:23][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC#N
Reactant: N=C(N)C1CCCCC1
Agent: O=S(=O)(O)F
Agent: [Na]
Solvent: CCO
Product: Nc1cc(=O)[nH]c(C2CCCCC2)n1
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (8.0 g.) in dry ethanol (150 ml.) was added ethyl cyanoacetate (12 ml.) followed after 15 minutes by crude cyclohexanecarboxamidine fluorosulphonate (10 g.). The mixture was heated under reflux for 20 hours, evaporated to half volume, water (100 ml.) was added and the pH adjusted to 6 by the addition of glacial acetic acid. After cooling to 0° C, the solid was filtered off and washed with water and acetone to give 4-amino-2-cyclohexylpyrimid-6-one (18 g.), m.p. 274°-276° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1)=O.OC1C=CC(C2NC(=O)C3C(=CC(OC)=CC=3OC)N=2)=CC=1>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1)=[N:1]2
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCC(=O)O)cc3)nc2c1
Yield: 21 %

Procedure:
2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from 2-amino-4,6-dimethoxy-benzamide and (4-formyl phenoxy)acetic acid, using the method described for 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one. 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (135 mg, 21%) was isolated as an off-white solid. Selected data: MS (m/z): 357.04; MP 287-290° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[C:39](N)([CH3:42])([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using tert-butylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29](F)[CH:30]=1)[CH2:5][C@@H:6]([C@@H:10]([C@H:12]1[CH2:16][C@@H:15](OCC=C)[CH2:14]N1C(OC(C)(C)C)=O)O)C(O)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([CH:42]2[CH2:47][O:46][CH2:45][CH2:44][NH:43]2)[O:40][C:39](=[O:48])[NH:38]1.FC1C=C(C=C(F)C=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][C@H:45]([OH:46])[CH2:44][N:43]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:30]=[CH:29][CH:28]=2)[C:6]2[CH:10]=[CH:12][CH:16]=[CH:15][CH:14]=2)[O:40][C:39](=[O:48])[NH:38]1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H](C2COCCN2)O1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Step D (6): (4S,5S)-4-(3,5-Difluorobenzyl)-5-(morpholin-3-yl)oxazolidin-2-one. A solution of tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate (step D (5), 230 mg) in CH2Cl2 (4 mL) was treated with TFA (3 mL). This reaction mixture was stirred at rt for 1.5 h. The mixture was then concentrated in vacuo. Diethyl ether (50 mL) was added and the mixture was washed with 1N HCl solution (40 mL) twice. Aqueous layer was neutralized with 50% aqueous NaOH to pH=12. The mixture was extracted with ethyl acetate (80 mL) twice. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give 180 mg of the title compound: MS (ESI) (M+H)+ 299.17.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:23]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde (0.80 g, 4.78 mmol), in DMF (15 mls) was added ethyl 6-bromohexanoate (1.30 g, 5.82 mmol) and potassium carbonate (1.23 g, 8.91 mmol). The mixture was stirred at 70° C. for 12 hours, cooled, poured into water and extracted twice with ethyl acetate. The combined organic fractions were washed once with water and dried over anhydrous magnesium sulfate. After the solvents were removed under reduced pressure, a red oil remained which was purified by column chromatography (70% hexane/30% ethyl acetate) to give 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester as a yellow oil (1.00 g, 67%). 1H NMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.92 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=1.2 Hz), 7.54 (dd, 1H, J=8 Hz, J=1.6 Hz), 4.20 (q, 2H, J=6.8 Hz), 4.14 (t, 2H, J=7.2 Hz), 2.36 (t, 2H, J=8.0 Hz), 1.90 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.29 (t, 3H, J=6.8 Hz). 13C NMR (400 MHz, CDCl3) δ: 173.79, 169.46, 151.87, 143.23, 133.66, 125.32, 121.93, 115.88, 69.65, 60.42, 34.12, 28.54, 25.40, 24.52, 14.25. IR (neat): 3396, 3110, 3080, 3047, 2944, 2869, 2735, 1730, 1705, 1607, 1531, 1489, 1465, 1434, 1381, 1351, 1311, 1272, 1161, 1093, 1063, 1030, 961, 863 cm−1.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 95.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 1.18 ml (3.48 mmol) of stearoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.20 g of the desired compound (95.2%, colorless powder), mp: 88.0°-89.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Br)C=C.C(OCC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:34][C:33](=[O:35])[C:32]3[CH:36]=[N:37][CH:38]=[CH:39][C:31]=3[N:30]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:30][C:31]2[CH:39]=[CH:38][N:37]=[CH:36][C:32]=2[C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:35])=[O:34])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)c1ccc(-c2nc3ccncc3c(=O)o2)cc1
Agent: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (0.11 g, 0.85 mmol) in THF (12 mL) at 0° C. was added a 1 M solution of allylmagnesium bromide in diethyl ether (0.83 mL, 0.83 mmol). After 20 min, 2-[4-t-butylphenyl]-4H-6-aza-3,1-benzoxazin-4-one (0.115 g, 0.41 mmol) was added and the cold bath was removed. After 2 h, the mixture was diluted with ethyl acetate and washed three times with brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The solid was recrystallized from diethyl ether then washed several times with mixtures of ether/hexanes and dried to give 0.138 g (82%) of pale yellow needles.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([NH:49][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH:2]3[CH2:7][CH2:6]3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 26% yield: mp 142-143° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.25 (m, 5H), 5.90 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.09 (t, J=8.4 Hz, 2H), 3.67 (t, J=8.4 Hz, 2H), 3.15 (d, J=7.2 Hz, 2H), 2.60 (s, 3H), 0.97-0.86 (m, 1H), 0.58-0.49 (m, 2H), 0.25-0.19 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 157.4, 155.2, 153.0, 137.9, 128.7, 127.8, 127.6, 117.0, 48.6, 44.0, 42.2, 42.1, 17.1, 8.9, 3.4; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: C(O)C(F)(F)F.Cl.Cl.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18]2)=[N:14][C:15]=1[NH2:16].[Cl:30][C:31]([Cl:37])([Cl:36])[C:32](=N)OC>C(O)=O>[N:25]1([C:23]([C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:13]3[N:14]=[C:15]4[NH:16][C:32]([C:31]([Cl:37])([Cl:36])[Cl:30])=[N:9][C:10]4=[CH:11][CH:12]=3)[CH2:18]2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O=CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C(Cl)(Cl)Cl)[nH]c3n2)C1)N1CCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Formic acid (2.8 mL) and trifluoroethanol (61 mL) were added to (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride. Methyl 2,2,2-trichloroacetimidate (1.65 mL) was added and the reaction mixture was stirred at 60° C. for 3 h. The mixture was used for the next step without further workup or purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([NH:29]C(C)(C)C)=[O:28])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12>FC(F)(F)C(O)=O.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([NH2:29])=[O:28])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)NC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(N)=O)C1
Yield: 49.6 %

Procedure:
A solution of 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide (chiral intermediate from Example 292) (16 mg, 0.032 mmol) in trifluoroacetic acid (2 mL) was heated in the microwave at 120° C. for 10 min. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 50%). The product was isolated as a single enantiomer.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]([CH2:21][C:22]([C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1)=O)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11])(OCC)=O)C.C(O[K])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27]([C:24]1([C:22]2[CH2:21][N:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[C:10](=[O:11])[CH:9]=2)[CH2:26][CH2:25]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Agent: CC(C)(C)O[K]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Yield: 73.2 %

Procedure:
After dissolving ethyl 1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (25.0 g, 55.2 mmol) in toluene (250 ml), tert-butoxypotassium (7.40 g, 66.2 mmol) was added gradually while stirring and cooling with ice. After stirring the reaction solution for 15 minutes at room temperature, a 10% aqueous citric acid solution (250 ml) and ethyl acetate (250 ml) were added thereto, and after performing an extraction operation, the organic layer was separated. The aqueous layer was then subject to extraction with ethyl acetate (250 ml), and after washing the combined organic layer with saturated sodium bicarbonate water (250 ml) and saturated saline solution (250 ml) in that order, the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 12.1 g (73%) of the title compound was obtained as a orange syrup from an n-hexane:ethyl acetate=2:1 to 1:2 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(Cl)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Chloro-benzoic acid.