Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](c2ncc3c(C)nccn32)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Temperature: 25 °C

Procedure:
To (trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (5.49 mmol, 1.5 g) in N,N-dimethylformamide (15 ml) was added N-bromosuccinimide (5.49 mmol, 0.977 g) and the mixture was stirred at room temperature. After one hour saturated aqueous sodium hydrogencarbonate solution was added and extracted with dichloromethane three times. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified using column chromatography (silica gel; dichloromethane/methanol (gradient 0 to 5% methanol)) to give the title compound (1.8 g).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=O)[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[C:6]1=O)(=O)C.[ClH:37]>C1COCC1>[ClH:37].[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[N:7]2[CH2:8][CH2:9][C@@H:5]([OH:4])[CH2:6]2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of (1R,2R)-1-{2-[2-(3-Benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate (42.0 g, 84.8 mmol) in anhydrous THF (300 mL) at 0° C. was added borane-THF complex solution (1.0 M, 297 mL, 3.5 mol equivalents) under N2 via an addition funnel over a period of 60 minutes. The reaction mixture was heated to reflux for 60 minutes. The reaction mixture was cooled to 0° C. and quenched slowly by addition of methanol (˜15 mL). The reaction mixture was concentrated under reduced pressure to remove the THF and to the residue was added methanolic-HCl solution (˜1.25 M in methanol, 297 mL, 3.5 equivalents). The solution was then heated at 70-80° C. for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give (3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol hydrochloride as a colorless syrup (35.0 g, 89% yield). The sample was used directly without further purification in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17](O)=[O:18])[CH:12]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:29]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17]([NH2:29])=[O:18])[CH:12]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)O)c(Br)o2)c(C)cn1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(N)=O)c(Br)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoic acid (10.0 g, 29.6 mmol) in THF (950 mL) at −20° C. was added TEA (4.55 mL, 32.5 mmol) over 20 min. The reaction mixture was allowed to stir for 10 min after addition was complete and then isobutyl carbonochloridate (10.7 g, 88.8 mmol) was added over 10 min. The reaction mixture was allowed to stir for 20 min at −20° C. and was then allowed to warm to rt. A solution of NH3 in THF was added and the reaction mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was diluted with water and filtered to give 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furamide (8.5 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@@H:13]3[CH2:14][C@@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15](OC)=[O:16])=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[N:32]=3)=[C:15]([OH:16])[C@H:9]3[C@@H:8]2[C@@H:13]2[CH2:14][C@H:10]3[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@@H]4CC[C@@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 48 %

Procedure:
Methyl (1R,2R,3S,4S)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.087 g, 0 3 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.315 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.126 mL, 0.9 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in methanol (4 mL) and the product was precipitated by the addition of 1.0 M aqueous hydrochloric acid solution (4 mL) while stirring. The solid was collected by vacuum filtration and further dried in vacuo to afford the desired product, N-{3-[(1S,2S,7R,8R)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0805 g, 0.144 mmol, 48%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.48 (6H, m), 2.67-2.68 (2H, m), 3.06 (3H, s), 3.24 (1H, d, J=15.0 Hz), 3.72 (1H, d, J=11.9 Hz), 4.07 (1H, d, J=15.6 Hz), 5.12 (1H, d, J=15.7 Hz), 7.14 (2H, t, J=8.4 Hz), 7.39 (2H, dd, J1=8.2 Hz, J2=5.8 Hz), 7.51 (1H, dd, J1=8.4 Hz, J2=2.3 Hz), 7.57-7.60 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.3 [M+H+]. ee=99% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.8 mL/min, 310 nm, t1=7.58 min (major), t2=10.08 min].
Reaction SMILES: [Cl-].[Na+].[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]([NH2:8])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCCl>[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]#[N:8]
Reactant: COC(C(N)=O)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml. of dry 1,2-dichloroethane containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2-pyridyl)-acetamide. After stirring at room temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride is added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10% aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2-pyridyl)acetonitrile, b.p. 72°-76° C./0.2 mm.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])=[N+]=[N-].[S:15](=[O:19])(=[O:18])([OH:17])[OH:16]>CC(O)C.[Pt]>[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13]
Reactant: CC1(CCCN=[N+]=[N-])NC(=O)NC1=O
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC1(CCCN)NC(=O)NC1=O
Reaction time: 7 h

Procedure:
A suspension of platinum (200 mg) in 2-propanol (50 ml.) and 1 N sulfuric acid (20 ml.) was briefly hydrogenated (3.4 atm) and 5-(3-azidopropyl)-5-methyl-2,4-imidazolidinedione (3.94 g., 0.020 mol) was added. Hydrogenation was continued for 7 hours at 3.4 atmospheres. The catalyst was removed by filtration and the filtrate concentrated to a small volume, addition of 2-propanol afforded 5-(3-aminopropyl)-5-methyl-2,4-imidazolidine dione hemisulfate as prisms, 4.40 g. (0.019 mol, 96%); m.p. 183°-185° C. after one crystallization from aqueous 2-propanol.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([CH3:9])=[O:8].[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:15])=[O:14])([CH3:12])[CH3:11]>O1CCCC1>[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25]([OH:32])([CH2:6][S:7]([CH3:9])=[O:8])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:14])=[O:15])([CH3:12])[CH3:11]
Reactant: CS(C)=O
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CS(C)=O)c3ccccc3)cc21
Temperature: 25 °C

Procedure:
Lithium methyl sulfinyl carbanion was prepared by reacting 37 ml. of a 1.6 M solution of n-butyl lithium in tetrahydrofuran with 5 ml. of dimethyl sulfoxide dissolved in 70 ml. of tetrahydrofuran. After stirring the reaction mixture under nitrogen for thirty minutes at 0°-5° C., a mixture of 4.0 g. of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 60 ml. of tetrahydrofuran was added in one portion. The reaction mixture was stirred for one hour at 0° C., and then was warmed to room temperature and stirred for an additional twelve hours at 24° C., followed by thirty-six hours of stirring at 50° C. The reaction mixture next was diluted with 100 ml. of water, and the organic solvent was removed by evaporation under reduced pressure. The aqueous mixture was acidified to pH 2 with 1 N hydrochloric acid, and then filtered. The filtrate was neutralized with sodium carbonate, and the product was extracted therefrom into ethyl acetate. The extracts were combined and the solvent was removed by evaporation under reduced pressure to provide 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-methylsulfinylmethylbenzyl)benzimidazole.
Reaction SMILES: [F:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:5]>CO.[Pd]>[NH2:21][C:20]1[C:2]([F:1])=[C:3]([CH:17]=[CH:18][CH:19]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])=[O:5]
Reactant: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc(N)c1F
Yield: 97 %

Procedure:
A solution of 2.12 g (6.55 mmol, 1.0 eq) of isopropyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate in 40 ml of methanol in the presence of 0.32 g (15% by weight) of palladium on carbon at 10% was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. The reaction medium was filtered through celite and concentrated to dryness. 1.87 g of isopropyl (S)-1-(3-amino-2-fluorobenzoyl)pyrrolidine-2-carboxylate were obtained in the form of a colorless oil. Yield=97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11]Cl)[CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:15]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloride (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) in ethanol (1000 ml) was heated at reflux for 8 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether. The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111 g, 99%) as an amorphous brown solid which was used in the next step without purification. MS m/e: 273 ([[M+H]]+).
Reaction SMILES: NC[CH2:3][N:4](CCN)[CH2:5]CN.[CH3:11][C:12]1([CH3:32])[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][N:20]([CH:26](N)[CH3:27])[CH2:19][CH2:18][N:17]([CH3:29])[CH2:16][C:15]([CH3:31])([CH3:30])[S:14][S:13]1>>[CH3:3][N:4]([CH2:27][CH2:26][N:20]1[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:12]([CH3:32])([CH3:11])[S:13][S:14][C:15]([CH3:31])([CH3:30])[CH2:16][N:17]([CH3:29])[CH2:18][CH2:19]1)[CH3:5]
Reactant: CC(N)N1CCN(C)CC(C)(C)SSC(C)(C)CN(C)CC1
Reactant: NCCN(CCN)CCN
Product: CN(C)CCN1CCN(C)CC(C)(C)SSC(C)(C)CN(C)CC1

Procedure:
1H NMR (300 MHz,in CDCl3): δ2.71 (t,J=6 Hz,4H,-N-CH2 -CH2 -N(CH3)-), 2.64 (s,4H,-N-CH2 -C(CH3)2-S-), 2.62 (t,J=6 Hz,4H,-N-CH2 -CH2 -N(CH3)-), 2.52 (m,2H,-CH2 -CH2 -N(CH3)2), 2.46 (m,2H,-CH2 -CH2 -N(CH3 (2), 2.37 (s,6H,-CH2 -N(CH3)-CH2 -), 2.25 (s,6H,-CH2 -CH2 -N(CH3)2) and 1.28 (s,12H,-S-C(CH3)2 -) ppm. 13C NMR (75 MHz, in CDCl3): δ74.8, 67.7, 57.6, 57.2, 53.9, 51.7, 51.3, 45.9, 45.1 and 26.9 ppm. MS (El; m/z): 376(4,M+), 377(2,M+ +1), 378(0.6,M+ +2), 318(1,M+ -((CH3)2N-CH2 ·)), 262 (3), 255 (1), 246(1), 187 (7), 156(9), 144(8), 133(9), 130(16), 113 (17), 101(27), 99(21), 98(12), 72(32), 71(28), 70(42), 58(100), 56(13), 55(13), 43(31), and 42(38).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:39])[F:38])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:4].[CH3:41]I>CN(C=O)C>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([N:17]([CH3:41])[CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)[C:14]([C:37]([F:40])([F:38])[F:39])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
Sodium hydride (0.02 g, 0.86 mmol) was added to a solution of ethyl [(1S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 318) (0.21 g, 0.39 mmol) in DMF (2 mL). After stirring at rt for 30 min, MeI (0.05 mL, 6.32 mmol) was added. The mixture was stirred at rt for 18 h, quenched with water (5 mL), and extracted with ether (3×). The combined ether extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.017 g, 8%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.15 (q, 2H), 4.00 (t, 2H), 3.73 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.32-1.26 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCCCC2)CC1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 0.30 g (0.81 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one in 0.3 ml of DMA was treated with 0.19 ml (1.22 mmol) of piperidine and 0.265 g (0.81 mmol) of cesium carbonate. The reaction was stirred over night at RT, CH2Cl2 was added, filtrated and evaporated. Crystallization (CH2Cl2/Et2O) gave 0.16 g (43%) of the title compound as pink crystalline solid. MS: 454.2 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[NH2:32])[O:17][N:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]([NH:32][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[NH:21][CH2:20][C:18]1[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[CH:19]=1)=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:6])[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.6 g, 13 mmol) was added over a period of ten minutes to a cooled (6° C.) solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (4.1 g, 12 mmol) and anhydrous triethylamine (2.6 mL, 18 mmol) in anhydrous dichloromethane (150 mL). After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.1 g) was added. The reaction was stirred for an additional 30 minutes and then was diluted with dichloromethane and washed with saturated aqueous potassium carbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-ethoxy-N-[4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)[1,5]naphthyridin-3-yl]acetamide as a black oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH:14]([Mg]Br)=C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:14])[CH:11]=[CH:12][CH:13]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)c1cccc(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A solution of 3-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) in THF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120 mmol) was added slowly. The mixture was stirred at −78° C. for 10 min, at rt for 3 h, and quenched by addition of 1 N aq HCl (100 mL) at 0° C. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to afford 1-(3-fluorophenyl)ethanone (9.7 g, yield: 75%) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1C(=O)NC(C(OC(C)(C)C)=O)CC(C)C)[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.F[C:48](F)(F)[C:49]([OH:51])=[O:50]>ClCCl.C1(OC)C=CC=CC=1>[C:49]([CH:48]([NH:12][C:13]([SH:22]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=1)[S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:5])=[O:46])=[O:45])=[O:45])[CH2:8][CH:9]([CH3:11])[CH3:10])([OH:51])=[O:50]
Reactant: Cc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1cccc([SH](Sc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)O)C(=O)NC(CC(C)C)C(=O)O)c1

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methyl-phenyldisulfanyl]-4-methyl-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.8 mmol) in 20 mL dichloromethane, anisole (2.0 mL), and 10 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to yield 1.1 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28]([O:30]CC)=O)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>CO>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:28](=[O:30])[CH2:27][S@:19](=[O:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1)[CH3:34]
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 30 °C
Yield: 60.3 %

Procedure:
(S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was added N,N-diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reaction mixture was heated at 30° C. for 4 hours. The reaction mixture was evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed once with brine, dried (anhydrous Na2SO4), concentrated. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH to 10:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a foamy solid (50 mg, 59%).
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[NH4+:27]>C1COCC1>[NH2:27][C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (120 mg, 0.31 mmol) in 3 mL THF, was added ammonium hydroxide (28% in water, 0.12 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The resulting crude title compound was used in the next step without further purification. HPLC/MS: retention time=3.60 min, [M+H]30 =372.