Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:2]1([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:14][CH2:13]1)(=[O:4])[CH3:5]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 56111.1 %

Procedure:
A mixture of tert-butyl acetoacetate (497 mL, 3.00 mol), 1,2-dibromoethane (310 mL, 3.60 mmol), potassium carbonate (1.106 k g, 8.00 mmol), and dimethylformamide (2.0 L) was stirred in a water bath at 30° C. for 1.5 hours, in a water bath at 60° C. for 3.5 hours, and in a water bath at 30° C. for 4 days. The reaction mixture was separated by filtration through celite, and the residue on the celite was washed with diethylether (3.5 L). The filtrate and the diethylether used for the washing were combined and added to water (2 L), and the organic layer was separated. The aqueous layer was extracted with diethylether (2 L), and water (1 L) was added to the resulting aqueous layer, and further extraction was conducted by adding diethylether (2 L). All organic layers were combined, and washed with 10% aqueous solution of citric acid (2 L), water (2 L×3), and saturated aqueous solution of sodium chloride (2 L×3), and dried by adding anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 371.8 g of the target compound (10 mmHg, distillation fraction of 72 to 78° C., 2.02 mol, 67%) as a colorless transparent oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1cc(I)nc1C
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 4-iodo-2-methyl-1H-imidazole (162 mg, 0.78 mmol) in THF (2.6 mL, 0.3M) containing DIEA (0.33 mL, 1.95 mmol) and DMAP (47 mg, 0.039 mmol), cooled in a ice bath at 0° C., was added a solution of Ethyl chloroformate (211 mg, 1.95 mmol) in THF (2 mL, 1M). The reaction mixture was heated at 50° C. for 48 h and then concentrated. The residue was dissolved in DCM and the organic layer was washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (Prepacked column 10 g, DCM/MeOH: 97/3 as eluent) to afford 208 mg of ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (95%) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]O>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@@H](CCC(=O)O)[C@@H]2O
Reactant: CO
Product: COC(=O)CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1O

Procedure:
Compound 33 was prepared by esterification of crude 32 (436 mg) with MeOH as described for the preparation of 9. Purification of the residue by flash chromatography on a 3×21 cm column of silica gel using hexanes/EtOAc (2:1) as eluent gave 268 mg (52%, three steps) 33 as a white solid. Data for 33: TLC, T-5, Rf0.76. 1H NMR (500 MHz, CDCl3) δ 0.81 (s, 3H, H-1 8), 2.84 (m, 2H, H-6), 3.31 (d, 1H, J=7.3 Hz, H-17α), 3.69 (s, 3H, OCH3), 5.04 (s, 2H, benzylic), 6.72 (d, 1H, J=2.8 Hz, H-4), 6.79 (dd, 1H, J=8.6, 2.8 Hz, H-2), 7.21 (d, 1H, J=8.6 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C29H36O4Na (M+Na+) m/e 471.2511, found m/e 471.2513.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:29]\[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)C)n1
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate (1.16 g) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 0.24 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.57 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:2, v/v) to give 2-isopropyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 1.2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[N:26]=[C:24]([NH:23][C:12]2[C:13]3[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[N:10][CH:11]=2)[S:25][CH:29]=1)=[O:32])[CH3:35]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (62 mg, 0.158 mmol) and ethyl bromopyruvate (37.7 mg, 0.174 mmol) in acetone (1.6 mL) was added MgSO4 (9.5 mg, 0.079 mmol). The resulting suspension was stirred at 60° C. for 3 h. The reaction was cooled to RT and concentrated. The residue was purified by passing through a 5 g silica cartridge eluting with 2% MeOH in DCM to give 2-[1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester as a pale yellow solid (32.5 mg, 42%). 1H-NMR (CDCl3): δ, 8.53 (s, 1H), 7.47 (s, 1H), 6.82 (s, 1H), 6.61 (s, 1H), 5.07 (d, 2H, J=4.2 Hz), 4.41 (q, 2H, J=7.2 Hz), 4.00 (s, 3H), 3.89 (s, 3H), 1.52 (s, 9H), 1.41 (t, 3H, J=7.3 Hz); MS: calculated for C23H28N4O6S+H 489.0; found: 489.0.
Reaction SMILES: BrBr.O=C1C2C=CC=CC=2N(C([C:17]2[CH:35]=[CH:34][C:20]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[CH:19][CH:18]=2)=O)CCC1.O>C(Cl)(Cl)Cl>[CH:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:20]1[CH:19]=[CH:18][CH:17]=[CH:35][CH:34]=1)=[O:33])([CH3:32])[CH3:31]
Reactant: CC(C)Oc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)Oc1ccccc1C(=O)Nc1ccccc1
Reaction time: 20 h

Procedure:
A 1.32 g portion of bromine dissolved in 6.6 ml of chloroform was dropwise added gradually (spending about 60 minutes) to 36 ml of chloroform solution containing 3.55 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-isopropoxybenzanilide at room temperature. When disappearance of the color of bromine was confirmed, the reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The resulting organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then evaporated to dryness using a vacuum pump. The thus obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 5.0 g of cyclopropylcarbamidine hydrochloride and 8.02 g of potassium carbonate and subjected to 20 hours of heating under reflux in a stream of argon. The resulting reaction solution was mixed with water to effect phase separation, and the separated organic layer was dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was crystallized from toluene to obtain 2.96 g of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazol4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide. A 1.08 g portion of this compound was dissolved in 20 ml of ethyl alcohol, mixed with 0.8 ml of 4N hydrochloric acid-ethyl acetate and recrystallized to obtain 916 mg of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([N+:19]([O-])=O)[C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[Pd]>[NH2:19][C:11]1[C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reaction time: 48 h

Procedure:
A mixture of methyl 5-[(4-fluorophenyl)methyl]-3-nitro-2-pyridinecarboxylate (200 g, 0.66 mol) and Degussa 10% Pd on carbon (50% by weight water, 20 g) in THF (1.5 L) was stirred under an atmosphere of H2 for 2 d. The mixture was filtered through celite and the filtrate was re-subjected to similar hydrogenation conditions with 10% Pd on carbon (30 g) at 45° C. for 7 d. During this time, conc. HCl (14 mL, 0.17 mol) in MeOH (75 mL) and 10% Pd on carbon (18 g) were added in approximately three portions each. The mixture was filtered through celite, concentrated at reduced pressure, reconstituted in CH2Cl2 and washed with saturated NaHCO3 solution. The organic phase was concentrated and the resulting material was triturated with EtOAc to provide the product as an off-white solid: 1H NMR (CDCl3) δ 7.94 (1H, d, J=1.5 Hz), 7.11 (2H, m), 6.98 (2H, m), 6.72 (1H, 1.5 Hz), 5.67 (2H, br s), 3.95 (3H, s), 3.89 (2H, s); ES+ MS: 261 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CC#N>N1C=CC=CC=1>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[NH:21][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: Nc1nccs1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(N1CCc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (8.4 g, 0.03 mol) was dissolved in pyridine (10 mL) and heated to 60° C. 2-Aminothiazole (2.5 g, 0.03 mol) was added slowly and the reaction mixture was stirred at 60° C. for 1 hour. Complete conversion to product was observed by LC/MS (10-99% CH3CN). The crude reaction mixture was then purified via column chromatography using 5% MeOH/CH2Cl2 to obtain the sulfonamide (7.0 g, 0.018 mmol, 70% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=392.0; tR=2.65 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][OH:10].Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:9][OH:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(C=NO)s1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
1.20 kg (9.51 moles) of 5-methyl-2-thiophenecarboxaldehyde and 727 g (10.46 moles) of NH2OH.HCl were placed in a reaction vessel and cooled to 10° C. Then, 0.85 L (10.46 moles) of pyridine was dropwise added thereto for 1 hour (an exothermic reaction: 10° C.→43° C). After 10 minutes, 7 L of benzene was added thereto and heated to remove the obtained water by Dean-Stark apparatus (initial internal temperature: 80° C.). After 165 mL of water was collected for 8 hours, (theoretical quantity: 171 mL), the product was cooled to obtain 5-methyl-2-thiophenecarboxaldehyde oxime. At this time, if stirring was stopped, two-phases were formed. After 0.85 L (10.46 moles) of pyridine was completely added at 15° C., 1.26 kg (12.36 moles) of Ac2O was dropwise added thereto for 25 minutes, with maintaining a temperature less than 15° C. The reaction mixture was stirred for 1 hour at room temperature, and completion of the acetylation reaction was confirmed by HPLC (2 phases).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[F:21][C:22]([F:28])([CH:25]([F:27])[F:26])CI>O>[N+:11]([C:3]1[CH:4]=[C:5]([S:8][CH2:9][C:25]([F:27])([F:26])[CH:22]([F:28])[F:21])[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: FC(F)C(F)(F)CI
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(SCC(F)(F)C(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is treated under nitrogen with 0.97 g. of sodium borohydride in 10 ml. of dimethylformamide at 20°-30° C. After 1 hour at 20°-25° C, 6 g. of 2,2,3,3-tetrafluoro-1-iodopropane is added and the mixture is heated at 100° C for 4 hours. The mixture is cooled, diluted with water and extracted with chloroform. Evaporation of the dried chloroform solution yields 2-nitro-4-(2,2,3,3-tetrafluoropropylthio)aniline as an oil. Acetylation of the latter compound in acetic anhydride with sulfuric acid catalysis according to the first paragraph of Example XXI yields 1-acetamido-2-nitro-4-(2,2,3,3-tetrafluoropropylthio)benzene which can be isolated by extraction into chloroform. Alternatively, this may be prepared by substituting 1-acetamido-2-nitro-4-thiocyanatobenzene in the above alkylation reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25]#[N:26])[C:9]2=[O:27])=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:29][OH:30])[NH2:26])[C:9]2=[O:27])=[CH:4][CH:3]=1
Reactant: N#CCCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NO

Procedure:
A mixture of (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)-phenyl)imidazolidin-1-yl)propanenitrile (97 mg, 0.25 mmol), hydroxylamine hydrogen chloride (85.5 mg, 1.23 mmol), K2CO3 (187 mg, 1.35 mmol) and anhydrous ethanol (4 mL) are refluxed for 2 days. The solvent is removed under vacuum. The residue is taken into ethyl acetate, washed with sat. NaHCO3 and brine. The organic phase is dried by Mg2SO4. The solvent is removed under vacuum to afford crude (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-hydroxy-propanimidamide which is used directly in the next step without further purification. HPLC-MS calculated for C19H19ClF3N4O2 (M+H+) 427.1, found 427.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH:52]([N:55]=[C:56]=[O:57])([CH3:54])[CH3:53]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:56]([NH:55][CH:52]([CH3:54])[CH3:53])=[O:57])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CC(C)N=C=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)NC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and isopropyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.06 (d, 6.5 Hz, 6H), 1.39 (s, 6H), 1.82 (m, 1H), 2.19-2.58 (m, 3H), 3.74 (m, 1H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated for C40H45N5 O5 675; found 676(M+H, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>ClCCl>[C:6]([N:8]([CH3:20])[C@H:9]([C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CN(C)CCCN
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)CCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
N-t-Butyloxycarbonyl-N-methylphenylalanine (2.79 g) and NMM (1.01 g) were dissolved in dichloromethane (20 ml) and the stirred solution cooled to -20° IBCF (1.37 g) was then added and the mixture stirred for 5 minutes before the addition of NH2CH2CH2CH2NMe2 (1.02 g). The solution was stirred for 1 hour at -20° and then at room temperature for 12 hours. The mixture was evaporated, and the residue dissolved in ethyl acetate (50 ml) and an aqueous solution of sodium bicarbonate (saturated, 50 ml). The ethyl acetate layer was washed with aqueous sodium bicarbonate (saturated, 50 ml), water (2×50 ml) and 10% aqueous citric acid (2×50 ml). The citric acid extracts were combined, made basic with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated to yield the title compound as an oil Rf1E 0.24, Rf3A 0.37.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][C:14]=1[NH2:25]>>[CH2:9]([O:8][C:1](=[O:7])[C:2]([NH:25][C:14]1[CH:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[O:4])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(N2CCOCC2)cc1N
Product: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Temperature: 180 °C
Yield: 76.9 %

Procedure:
139 ml (1015 mmol) Diethyl oxalate was heated to 120° C. 30.3 g (145 mmol) 2-methoxy-5-morpholin-4-yl-phenylamine was added very cautiously in small quantities and the mixture was heated for 90 minutes at 180° C. After cooling to room temperature and filtration 1.5 n-hexane were added. The resulting precipitate was collected by filtration. After washing with hexane and drying, 34.4 g (77%) N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester was obtained as greenish crystals, M.p.: 95–97° C., MS m/e (%): 309 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Cl)=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])[CH:36]=[CH2:37]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C=CCOc1ccc(CCl)cc1[N+](=O)[O-]
Product: C=CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1[N+](=O)[O-]

Procedure:
Analogously to Method D, 2.0 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.06 g of 1-allyloxy-4-chloromethyl-2-nitrobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.31 (1:1 EtOAc-heptane); Rt=6.99.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a dark brown solid (47 mg, 68%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.26 (dd, J=1.5, 4.5 Hz, 2H), 7.06 (s, 1H), 6.93 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.81 (dd, J=2.1, 8.1 Hz, 1H), 6.81 (s, 1H), 6.06 (s, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@:5]([CH:12]([CH3:14])[CH3:13])([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:12]([C@:5]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7][C@@H:3]([NH:2][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:4]1)([CH3:14])[CH3:13]
Reactant: O=C1CCOCC1
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@]1(C(C)C)CC[C@@H](NC2CCOCC2)C1
Reaction time: 0.17 h

Procedure:
Methyl (1S,3R)-3-amino-1-isopropylcyclopentanecarboxylate hydrochloride (prepared in the same way as the intermediate from Step F, Procedure A, INTERMEDIATE 2, except with the modification that the methyl ester was employed instead of the benzyl ester, 1.4 g, 6.1 mmol) was combined with tetrahydro-4H-pyran-4-one (730 mg, 7.3 mmol), and triethylamine (1 mL, 7 mmol) in 50 mL of DCM. After 10 min, 4 Å powdered molecular sieves (1 g), and sodium triacetoxyborohydride (5.1 g, 24 mmol) were added and the resulting mixture was permitted to stir overnight. The reaction mixture was filtered through celite, and the filtrate was washed with saturated NaHCO3 solution twice, then once with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford 1 g of methyl (1S,3R)-1-isopropyl-3-(tetrahydro-2H-pyran-4-ylamino)cyclopentanecarboxylate.