Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:45][C:46]([O:49][C:50]([NH:52][C@@H:53]([C:65](O)=[O:66])[CH2:54][C:55]1[C:60]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])([CH3:48])[CH3:47]>ClCCl.O>[C:46]([O:49][C:50](=[O:51])[NH:52][C@@H:53]([C:65](=[O:66])[NH:1][CH:2]1[C:3](=[O:13])[NH:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8]1)[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:60]=1[C:61]([F:64])([F:63])[F:62])([CH3:45])([CH3:48])[CH3:47]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1C(F)(F)F)C(=O)NC1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic 3-amino-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (0.100 g, 0.57 mmol) in dichloromethane (5.0 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.218 g, 1.13 mmol), 1-hydroxybenzotriazole (0.153 g, 1.13 mmol), diisopropylethylamine (0.20 mL, 1.13 mmol) and N-Boc-D-2-trifluoromethyl phenylalanine (0.189 g, 0.57 mmol). The resulting mixture was stirred at room temperature for 18 hours, then diluted with H2O and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via prepatory thin-layer chromatography on silica gel (50% ethyl acetate/hexanes) to give the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:25][C:26]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34](Cl)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.O>CN(C=O)C>[Cl:25][C:26]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.2 %

Procedure:
Triethylamine (12.5 mL, 0.0889 mol) and 1-(N-Boc-aminomethyl)-3-(aminomethyl)benzene (17.71 g, 74.94 mmol) were sequentially added to a solution of 2,4-dichloro-3-nitroquinoline (18.2 g, 0.0750 mol) in DMF (90 mL), and the reaction was stirred at room temperature under nitrogen for 1.5 hours. The reaction was poured into water (2 L), and the suspension was stirred for 15 minutes. Most of the water was decanted away from the resulting precipitate, which was dissolved in ethyl acetate (600 mL). The ethyl acetate was separated from a small amount of remaining water and then removed under reduced pressure. The resulting solid was dried under vacuum to provide 38.24 g of tert-butyl 3-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a sticky, amber solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=2)[O:7][C:6]=1[C:29](O)=[O:30])(=[O:3])[CH3:2].Cl.[CH:33]12[CH2:40][CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34]2.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:33]12[CH2:40][CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]2[C:29]([C:6]1[O:7][C:8]2=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=[C:13]2[C:5]=1[NH:4][C:1](=[O:3])[CH3:2])=[O:30]
Reactant: CC(=O)Nc1c(C(=O)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: C1CC2CCC1CN2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1c(C(=O)N2CC3CCC2CC3)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.027 g (0.0568 mmol) of the product from Step A in CH2Cl2 (0.6 mL) was treated with 2-azabicyclo[2.2.2]octane hydrochloride (0.009 g; 0.0625 mmol), EDC (0.016 g; 0.0852 mmol), DMAP (0.007 g; 0.0568 mmol), and 1-methylmorpholine (19 μL; 0.170 mmol), then stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 568.0 (M+1), 570.0 (M+3); Rt=4.68 min.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C@H:62]([CH2:64][C:65]([NH2:67])=[O:66])[OH:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C@H:62]([CH2:64][C:65]([NH2:67])=[O:66])[OH:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)N[C@@H](CC(C)C)[C@@H](O)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](CC(C)C)[C@@H](O)CC(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 125 mg of Z-Phe-His-OH, 110 mg of H-Leu-Val-Ile-Sta-NH2, 44 mg of HOBt and 68 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.20, Rf (B11)=0.64.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([O:20]CC)=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)cnn2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixed solution of the compound (2.86 g, 9.46 mmol) obtained in step 1 in THF (15 mL) and ethanol (15 mL) was added 1N aqueous sodium hydroxide solution (14.19 mL, 14.19 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added thereto. The precipitate was collected by filtration to give 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (2.59 g, 9.44 mmol, 100%) as a white powder.
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9](=[O:19])[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(O)=[O:2].CC[N:22]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.N>ClCCl.O>[C:1]([C:4]1[C:8]2[C:9](=[O:19])[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(=[O:2])[NH2:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1coc2c1C(=O)CC(c1ccccc1)C2
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
To a suspension of 3-carboxy-4-oxo-6-phenyl-4,5,6,7-tetrahydrobenzofuran (1.28 g) in dichloromethane (25 ml) were added, under ice-cooling, WSC (1.15 g) and N-hydroxybenzotriazole (0.92 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added concentrated ammonia solution (4.1 g), and the mixture was stirred at room temperature overnight (12 hours). To the reaction solution was added water, and the mixture was subjected to extraction. The lower layer was washed with saturated brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure, and the residue was washed with ethyl acetate and isopropylether to give 3-carbamoyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.36 g).
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([I:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[SH:62]>CN(C1C=CN=CC=1)C>[I:22][C:20]1[C:18]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[SH:62])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Nc1ccccc1S
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(Nc3ccccc3S)nc2=O)C[C@@]1(O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of 3′,5′-diacetyl-5-iodo-2′-deoxyuridine (2.19 g, 5.00 mmol) acetonitrile (ACN, 75 ml), triethylamine (TEA, 6.96 ml, 50.0 mmol) and DMAP (0.15 g, 1.25 mmol) was added mesitylsulfonyl chloride (2.19 g, 10.0 mmol). After stirring at ambient temperature for 18h, DBU (2.14 ml, 10.0 mmol) and 2-aminothiophenol was added (2.14 g, 20.0 mmol) and the solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was partitioned between ethyl acetate (EA, 200 ml) and saturated aqueous sodium bicarbonate (SASB, 200 ml). The organic layer was dried (Na2SO4) and concentrated on the rotary evaporator. The crude product was purified by flash chromatography on silica gel [1-5% 2-propanol/dichloromethane (DCM)] to deliver the product 1H NMR (CDCl3) δ2.10 (s, 3H), 2.15 (m, 1H, 2.17 (s, 3H 2.77 (ddd, 1H, J=2.2, 5.2,15.1 Hz), 4.14 (bs, 1H), 4.35 (m, 3H), 5.20 (m, 1H), 6.13 (t, 1H, J=6.5 Hz), 6.78 (m, 2H), 7.30 (m, 2H), 8.05 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:4][CH2:1][CH2:2][CH3:3])=[O:17]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)c1cccc(Br)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of N-propyl amine (0.33 mL, 4.1 mmol) and triethylamine (0.83 mL, 5.8 mmol) in methylene chloride was cooled to −5° C., treated with 3-bromobenzoyl chloride (1 g, 4.5 mmol), warmed to room temperature, stirred at room temperature for 1 h, poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by flash chromatography on silica gel, 2:1 hexane/ethyl acetate as eluent, to give 3-bromo-N-propyl-benzamide as a white solid, 0.74 g (67% yield); 1H NMR (DMSO-d6) δ 0.8 (t, 3H); 1.5 (m, 2H); 3.2 (t, 2H); 7.4 (t, 1H); 7.6 (d, 1H), 7.8 (d, 1H); 7.9 (s, 1H); 8.5 (b, 1H); MS [(+)ESI] m/z 242[M−H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(N([CH2:43][CH3:44])CC)C.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)(Cl)Cl>[CH2:49]([O:48][C:46]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[N:13]([C:46]([O:48][CH2:49][CH2:50][CH2:43][CH3:44])=[O:47])[CH:12]=[CH:11][N:10]=1)=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCN(CC)CC
Reactant: CCCCOC(=O)Cl
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)n1ccnc1CN(Cc1ccc(C(=O)Nc2ccc(CN(CCC)CCC)cc2)cc1)Cc1nccn1C(=O)OCCCC
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
The compound obtained in Example 19-3 was treated with an anion-exchange resin and then dissolved in anhydrous chloroform (2.8 ml). Subsequently, the solution was added with triethylamine (0.059 ml) and n-butyl chloroformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.044 ml), followed by stirring at room temperature for 17.5 hours. After completion of the reaction, the solution was added with chloroform (3.0 ml), washed with water, and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (66.9 mg) as a brown viscous substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][NH:25][CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[C:42]([F:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][N:25]([CH2:31][C:32]([N:34]5[CH2:39][CH2:38][N:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[C:42]([F:52])[CH:41]=6)[CH2:36][CH2:35]5)=[O:33])[CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCNC1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid [3-(4-isopropoxy-phenyl)-1H-indazol-5-yl]-amide (8AB) (40 mg, 0.086 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (35 mg, 0.103 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (22 mg, 30 uL, 0.172 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2.[CH2:16](I)[CH:17]=[CH2:18].O>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[C:11]1=[O:15])[CH:17]=[CH2:16]
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1CCc2cc(OC)ccc2C1=O
Reaction time: 4 h
Yield: 99 %

Procedure:
To a suspension of 95% NaH (1.2 equiv) in anhydrous DMF (2 mL) was slowly added a solution of amide 42 (198 mg, 1.12 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h after which time allyl iodide (1.2 equiv) was added. The resulting mixture was stirred for 4 hours at this temperature. After addition of water and extraction with EtOAc (3×), the resulting combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography on SiO2 (Petroleum ether/EtOAc=1:1) to afford the title compound 43 as a white solid (Yield 242.3 mg, 99%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.O>C1COCC1>[NH2:22][C:23]1[CH:28]=[C:27]([C:2]2[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]3[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:22][C:23]2[CH:28]=[C:27]([C:2]3[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]4[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:4][CH:3]=3)[CH:26]=[CH:25][CH:24]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2cccc(N)c2)s1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2cccc(NC(=O)Nc3ccc(F)cc3)c2)s1
Yield: 55 %

Procedure:
(±)-(4R*,5R*)-5-{(1S*) [5-(3-aminophenyl) (2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one was prepared from (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (Example 5, step 2) and 3-aminophenylboronic acid, using a procedure analogous to that described for Examples 5, step 3. A mixture of the resulting compound (0.2 g, 0.53 mmol) and 4-fluorophenylisocyanate (0.073 g, 0.53 mmol) in THF (5 mL) were heated at the reflux temperature for 4 h. The resulting mixture was treated with water and extracted with CH2Cl2. The organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-{1(1S*)[5-(3-{[(4-fluorophenyl)amino]carbonylamino}phenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (0.15 g, 55%) as an off-white solid: mp: 181° C.; TLC (EtOAc) Rf 0.26.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:10]([O:14][C:15](=[O:18])[CH2:16][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: NCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
A mixture of 4-iodobenzylamine (5.0 g, 21.5 mmol), tert-butylbromoacetate (4.19 g, 21.5 mmol), potassium carbonate (3.55 g, 21.5 mmol) in 40 mL of 1:1 toluene/water was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (100 mL×3) and the combined organic phase was washed with brine, dried over sodium sulfate, and evaporated to give an oil. Chromatography on silica gel gave 2.3 g (31%) of N-(4-iodobenzyl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.C(N(CC)CC)C.[C:48](=[O:51])([OH:50])[O-].[Na+]>C(Cl)(Cl)Cl>[C:7]([OH:9])(=[O:8])/[CH:6]=[CH:5]/[C:48]([OH:50])=[O:51].[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:35]2[CH2:36][CH2:37][N:38]([C:7](=[O:9])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:3]=3[O:2][CH3:1])[CH2:39][CH2:40]2)=[CH:33][CH:32]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([N:35]2[CH2:36][CH2:37][N:38]([C:7](=[O:9])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:3]=3[O:2][CH3:1])[CH2:39][CH2:40]2)[C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C([O-])O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
In 100 ml of chloroform was suspended 25 g (120 millimoles) of 2,4-dimethoxycinnamic acid, and at room temperature, 44 ml (about 600 millimoles) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for 2 hours, and the excess of thionyl chloride and chloroform were distilled off under reduced pressure. The residue was diluted with 200 ml of chloroform, and added dropwise at room temperature to 300 ml of a chloroform solution of 34.6 g (120 millimoles) of bis(4-fluorophenyl)methylpiperazine and 24.3 g (240 millimoles) of triethylamine. The mixture was stirred at room temperature for 2 hours, and then a 10% aqueous solution of sodium bicarbonate was added. The mixture was shaken, and the organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. To the resulting oily product was added 200 ml of an ethanol solution of 14 g of fumaric acid. The crystals that precipitated were collected by filtratiion. Recrystallization from chloroform/methanol (1/1, v/v) gave 18.8 g (yield 29.2%) of 1-[bis(4-fluorophenyl)methyl]-4-(2,4-dimethoxycinnamoyl)piperazine hemifumarate as colorless crystals.
Reaction SMILES: [CH:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][C:23]([O:25]C)=[O:24]>CO>[CH3:15][N:8]([CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: NC(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CO
Product: CN(CC(=O)O)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
111 Parts of α-cyclohexylcyclohexanemethanamine and 60 parts of sodium carbonate were dispersed in 320 parts of methanol. 54 Parts of methyl bromoacetate were added dropwise to this dispersion. The mixture was stirred at room temperature for 72 hours. The precicitate was separated and the solution was concentrated to dryness, yielding methyl N-[(dicyclohexyl)methyl]glycine quantitatively (int. 1).