Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].Br[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]>C(=O)=O.CC(C)=O.O1CCCC1>[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][C@@H:33]([CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])[C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a flame dried round bottom flask under a nitrogen atmosphere was added tetrahydrofuran (40 mL) followed by 1,1,1,3,3,3-hexamethyldisilazane (8 mL, 37.8 mmol). The mixture was cooled to 0° C. and n-butyl lithium (14.5 mL of a 2.5 M solution in hexanes, 36.0 mmol) was added. The mixture was stirred for 15 minutes, then cooled to −78° C. in dry ice/acetone bath. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (5 g, 16.4 mmol) (prepared by the method of Fray, J. Org. Chem., (51) 4828 (1986)) dissolved in tetrahydrofuran (50 mL) was added dropwise via syringe and stirring continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (2.07 mL, 18.0 mmol) in 40 mL of THF was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to −60° C. The mixture was quenched by slow addition of saturated, aqueous ammonium chloride (25 mL). Upon warming to room temperature, the solution was diluted with ether (300 mL) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (NaHCO3)(2×100 mL), and 100 mL brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent removed under reduced pressure. Thin layer chromatography in 1:2 hexane/diethyl ether (Et2O) revealed product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2:1 hexanes/diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1:2 Hexanes/Et2O Rf: 0.8. 1H NMR (400 MHz, CDCl3): δ7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J=9.3 Hz), Hz), 3.98 (1H, dt, J=8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1H, b), 2.68 (1H, m), 2.41 (1H, m), 1.92 (1H, m), 1.65 (3H, s), 1.58 (3H, s), 1.37 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH3:31])[CH2:19][C:20]([F:21])([F:23])[F:22])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCC(F)(F)F)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC(F)(F)F)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.67 h
Yield: 20.2 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylate (400 mg, 1.05 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (101 mg, 4.21 mmol) at 0° C. with stirring for 40 minutes and then iodomethane (899 mg, 6.33 mmol) was added to the reaction mixture, and the resulting mixture was allowed to react with stirring overnight at room temperature. The reaction mixture was adjusted pH to 4 with HCl to give the solid, which was collected by filtration to afford 2-(4-fluorophenyl)-3-[methyl(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylic acid as a yellow solid (80.6 mg, 20%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:26]=2)[C:13](OCCN2CCOCC2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:36]1([N:41]2[C:45]([NH2:46])=[C:44]([C:47]([NH2:49])=[O:48])[C:43]([CH2:50][CH3:51])=[N:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.O(C)[Na].C([O-])(=O)C1C=CC=CC=1>C(O)(=O)C.O.C(O)C>[CH:36]1([N:41]2[C:45]3=[N:46][C:13]([C:12]4[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:26]=[C:25]([O:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:24]=4)=[N:49][C:47](=[O:48])[C:44]3=[C:43]([CH2:50][CH3:51])[NH:42]2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=C(OCCN1CCOCC1)c1cc(OCCN2CCOCC2)cc(OCCN2CCOCC2)c1
Agent: CO[Na]
Agent: O=C([O-])c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(OCCN4CCOCC4)cc(OCCN4CCOCC4)c3)nc(=O)c1-2
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A mixture of 4-morpholinylethyl 3,5-di-[2-(4-morpholinyl)ethoxy]benzoate (2.0 g, 4 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.45 g, 2 mmol), NaOCH3 (0.23 g, 4 mmol) and ethanol (50 ml) was refluxed for 96 hours. The reaction was incomplete so an additional equivalent of the benzoate and NaOCH3 were added and the mixture was reluxed for 48 hours. The reaction mixture was stripped to dryness, and the residue was treated with water and acidified with acetic acid. The mixture was cooled and the product was isolated by filtration and dried at 90° C. to afford 0.61 g (54%) of 1-cyclopentyl-3-ethyl-6-[3,5-di[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 182-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([NH2:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7][NH:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Clc1ccc(OCCBr)cc1Cl
Reactant: CCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCNCCOc1ccc(Cl)c(Cl)c1

Procedure:
In 20 ml of ethanol was dissolved 2.06 g (7.63 millimoles) of 2-(3,4-dichlorophenoxy)ethyl bromide, and 1.06 g (10.0 millimoles) of anhydrous sodium carbonate and 3.48 g (27.0 millimoles) of n-octylamine were added to the solution. The mixture was heated and refluxed on an oil bath for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water and extracted with 20 ml of chloroform three times.
Reaction SMILES: [C:1]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2N=N1>C(#N)C.[Cl-].[Na+].O>[CH2:4]([O:3][C:1]([C@@H:6]([NH:10][C@@H:11]([CH3:12])[C:13]([O:15][C:1]([CH:6]1[CH2:7][CH:26]2[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[NH:23]1)=[O:2])=[O:14])[CH2:7][CH2:8][CH3:9])=[O:2])[CH3:5]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC[C@H](N[C@@H](C)C(=O)OC(=O)C1CC2CCCCC2N1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.54 g of (2S,3aS,7aS)-2-carboxyperhydroindole benzyl ester, 7.26 g of N-((S)-1-carbetoxybutyl)-(S)-alanine and 12.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 225 ml of acetonitrile is stirred at room temperature for 30 min, then 560 ml of brine is added. The product is extracted twice with 400 ml of ethyl acetate, combined extracts are washed first with 800 ml of water, acidified with concentrated hydrochloric acid and then with 1.5 l of water. Organic phase is dried over anhydrous sodium sulphate and evaporated at 40° C. in vacuo to yield 13.5 g (88%) of benzyl (2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahydroindole-2-carboxylate (benzyl ester of perindopril).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C:6]1[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.O.C(Cl)Cl>[CH3:21][O:22][C:23](=[O:32])[CH:24]([N:9]1[C:8](=[O:12])[CH:7]=[C:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[C:2]([F:1])([F:17])[F:18])[CH:11]=[N:10]1)[CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(Cc2ccccc2C(F)(F)F)cn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
A solution of 5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (219.6 mg, 0.86 mmol) in tetrahydrofuran (4.32 mL, 0.2M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (41 mg, 1.03 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 223 mg, 0.95 mmol). The reaction was then warmed to 50° C., where it stirred overnight. After this time, the reaction was diluted with water (150 mL) and methylene chloride (30 mL) and the resulting bilayer was extracted with methylene chloride (3×75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 25-40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid methyl ester (155.9 mg, 44%) as a yellow oil; ES+-HRMS m/e calcd for C21H23N2O3F3 [M+H+] 409.1734, found 409.1733.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH2:16][N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][C:18](C)=O.[BH4-].[Na+].Cl[CH2:24]CCl>C(O)(=O)C.C(Cl)Cl>[CH:16]([N:7]1[CH2:6][CH:12]2[CH2:11][CH2:10][CH:9]([C:17]3[CH:18]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][C:13]=32)[CH2:8]1)([CH3:15])[CH3:24]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCC2CC1
Reactant: ClCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
4-Nitro-1-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (80 mg, 0.367 mmol) was placed in 1,2-dichloroethane (2 mL) and acetic acid (0.1 mL). Acetone (31.9 mg, 0.550 mmol, 40.4 μL, 1.5 eq) was added and the reaction was stirred for 5 minutes. Sodium borohydride (16.3 mg, 0.440 mmol, 1.2 eq) was added and the reaction was heated at 80° C. for 2 hours. The reaction was then diluted with CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain 10-isopropyl-4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene as pale orange oil (62 mg, 65%). LCMS (m/e) 261 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.02 (dd, 1H, J=2.2 and 8.1 Hz), 7.93 (d, 1H, J=2.2 Hz), 7.19 (d, 1H, J=8.1 Hz), 3.15-3.08 (m, 2H), 2.90-2.75 (m, 3H), 2.35 (t, 2H, J=9.5 Hz), 2.21 (d, 2H, J=8.8 Hz), 1.60-1.55 (m, 2H), 0.93 (d, 6H, J=6.6 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine -4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (57.8 mg, 83% yield). 1HNMR (500 MHz, CDCl3) δ: 11.95 (1H, s), 7.97 (1H, t, J=5.50 Hz), 7.41–7.38 (3H, m), 7.16 (1H, dd, J=8.24, 2.14 Hz), 6.63 (2H, d, J=8.24 Hz), 6.50 (2H, d, J=6.40 Hz), 3.76 (6H, s), 3.29 (3H, s). HRMS (ESI) calcd for C21H20Cl2N3O5 (M+H): 464.0780; found: 464.0775.
Reaction SMILES: [CH:1]1[C:6]2[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH:12]([OH:13])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[O:13][CH:12]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11]2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1Cc2ccccc2C#Cc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of 45 (0.22 g, 1 mmol) in CH2Cl2 (30 mL) was added 4-nitro-phenyl chloroformate (0.4 g, 2 mmol) and pyridine (0.4 ml, 5 mmol). After stirring 4 hours at ambient temperature, the reacting mixture was washed with brine (2×10 mL), and the organic layer was dried (MgSO4). The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 10/1, v/v) to afford 47 (0.34 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.23-8.18 (2H, aromatics), 7.56-7.54 (2H, aromatics), 7.46-7.18 (8H, aromatics), 5.52 (1H, dd, J=3.9, 15.3 Hz, CHOH), 3.26 (1H, dd, J=3.9, 15.3 Hz, CH2), 2.97 (1H, dd, J=3.9, 15.3 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.7, 149.1, 148.7, 129.0, 127.4, 127.3, 126.7, 126.5, 125.5, 125.2, 124.3, 124.0, 122.6, 122.4, 120.8, 120.6, 120.2, 112.2, 108.5, 80.6, 44.8. MALDI HRMS: m/z 408.0852 [M+Na+]. Calcd for C23H15NNaO5: 408.0848.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(NC2CCCCC2)CCCCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][CH2:33][C:34]([NH:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To 30 ml. of DMF were added 2.5 gms. (0.005 moles) of Nα -t-butyloxycarbonyl-O-benzyl-L-tyrosyl-D-alanyl-glycine (prepared as in Example 1) and 1.08 gms. (0.005 moles) of the hydrochloride salt of L-phenylalanine, methyl ester. The mixture was stirred at 0° C., and 0.99 ml. (0.005 moles) of dicyclohexylamine was added. The mixture was stirred for 5 minutes at 0° C., and 670 mg. (0.005 mmoles) of HBT and 1.03 gms. (0.005 moles) of DCC were added. Stirring was continued at 0° C. for 2 hours and then at room temperature for 48 hours. The reaction mixture was cooled to 0° C., and the resulting precipitate was collected. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was extracted successively with 1 N sodium bicarbonate, water, 0.75 N citric acid, and water. The ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was crystallized from ether and recrystallized from ethyl acetate to give 2.7 grams (82%) of the title compound, m.p. 149°-152° C. [α]D25 +22° (C=0.5, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1OS(C)(=O)=O)=[O:4].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CCCC2(CCCC2)C1OS(C)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)C1=CC2(CCCC2)CCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
To a solution of the crude 6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22 g) obtained in Step 4 in tetrahydrofuran (135 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (13.8 mL), followed by stirring the reaction mixture at 60° C. for 1.5 hours. After ice-cooling and adding 1N aqueous hydrochloric acid solution (102 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=3:97 to 25:75) to give spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (5.485 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8](C)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12]CN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:34]([NH2:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:43][C:34]([CH3:36])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35])=[O:6]
Reactant: Cc1cnc(Cl)c(C(=O)O)c1
Reactant: CC(C)(N)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(C)(C)c2ccccc2)c(Cl)n1
Yield: 0.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 2-chloro-5-methylnicotinic acid (2.00 g, 11.7 mmol) was dissolved in DMF (40 mL), and the solution was treated with EDCI (3.35 g, 17.5 mmol), HOBT monohydrate (890 mg, 5.83 mmol) and cumylamine (3.40 mL, 23.3 mmol). The mixture was added with water. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 2-chloro-6-methyl-N-(1-methyl-1-phenylethyl)nicotinamide (2.09 mg, yield 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH2:25][CH:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C(N)CO
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC(C)C(CO)NCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 2-amino-3-methyl-butan-1-ol to give a yellow solid. MS m/z: 421.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1.[I:15][C:16]1[C:17]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])(C(O)=O)[NH:18][N:19]([CH3:21])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.[O:44]1CCOC[CH2:45]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:45]([C:20]2[N:19]([CH3:21])[N:18]=[C:17]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[C:16]=2[I:15])=[O:44])=[CH:4][C:3]=1[C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Reactant: CN1C=C(I)C(C(=O)O)(C(F)(F)C(F)(F)F)N1
Reactant: C1COCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.49 g (2.34 mmol) of 4-chloro-3-(cyclopropylcarbamoyl)aniline dissolved in 0.5 ml of dioxane are added dropwise to a solution of 1.28 g (2.34 mmol) of 4-iodo-1-methyl-3-pentafluoroethyl-1H-pyrazolecarboxylic acid and 0.54 g (2.81 mmol) of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride in 20 ml of dioxane and the reaction mixture is stirred for three days at room temperature. The majority of the dioxane is distilled off at reduced pressure on a rotary evaporator and the residue is admixed with 20 ml of water. The aqueous phase is extracted three times with ethyl acetate and the organic phase is then washed three times with saturated sodium chloride solution. After drying over sodium sulphate, the solvent is distilled off at reduced pressure on a rotary evaporator and the residue is purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate). This gives 0.70 g of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-iodo-1H-pyrazole-5-carboxamide (53%) as an oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:31][C:28]([F:30])([F:29])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:44][CH2:43][N:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH3:34])[CH2:47][CH2:46]2)=[O:22])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2cccc(Cl)c2)CC1
Yield: 8 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (53.6 mg) in 8% yield as colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN(C)C=O>[CH2:7]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[F:16])[CH2:27][CH2:28]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 579.2 %

Procedure:
Potassium carbonate (0.526 g, 3.80 mmol) and benzyl bromide (0.155 ml, 0.130 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)-[1,4]diazepane hydrochloride (compound of Reference Example 55; 0.300 g, 1.08 mmol) in anhydrous N,N-dimethylformamide (6 ml), and the mixture was stirred at 80° C. for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (methanol ethyl acetate=1:1) to give the title compound (0.248 g, 69%) as a brown liquid.