Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH2:13]O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC(/N=N\C(OC(C)C)=O)=O)(C)C.P([N:67]=[N+:68]=[N-:69])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>O1CCCC1>[N:67]([CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])=[N+:68]=[N-:69]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CC(C)OCC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
In a 2.5 mL seal vial equipped with a stir bar was added (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (150.00 mg; 0.60 mmol; 1.00 eq.) in tetrahydrofuran (2.00 ml) followed by triphenylphosphine (316.90 mg; 1.21 mmol; 2.00 eq.), isopropyl(Z)-(isopropoxyacetyl)diazenecarboxylate (0.25 ml; 1.21 mmol; 2.00 eq.). Diphenyl azidophosphate (0.26 ml; 1.21 mmol; 2.00 eq.) was then added dropwise in 15 min. During the addition, the former obtained green-yellow clear solution slowly turned to turbid and finally became clear again. The mixture was stirred at room temperature for 48 h. The mixture was purified via Yamazen channel 2 and lyophilized to provide 134.6 mg (81%) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[NH:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 3-bromotoluene 0.10 mL, cesium carbonate 0.22 g, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.5 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg were added, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(3-methylanilino)-4-phenethylbenzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Nc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (520 mg, 1.2 mmol) and 6-aminopyridin-3-ylboronic acid (280 mg, 1.44 mmol), Pd(Ph3P)2Cl2 (100 mg), and aq Cs2CO3 solution (3 mL, 2M) in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxy propyl)-1,3-oxazinan-2-one. (400 mg, 74%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:19](=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:19][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=1[CH3:6]
Reactant: O=C([O-])O
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C

Procedure:
300 μl of concentrated sulfuric acid is added to a suspension of 2 g of 2-methyl-5-nitrobenzoic acid in 7 ml of methanol. It is refluxed for 6 hours. Then, the reaction mixture is diluted with ethyl acetate and poured into saturated sodium bicarbonate solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is incorporated without purification into the next step.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[O:17][CH3:18]>CO.[Ni](Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH3:18]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1cccc(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)ccc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
Nickel chloride 6H2O (3.19 g, 13.4 mmol) was dissolved in methanol (20 mL) and celite (200 mg) was added and 1.5 eq (1.52 g, 40.18 mmol) of sodium tetrahydridoborate was added slowly portion wise. The slurry was stirred for 30 minutes at room temperature. The compound (7.5 g, 26.8 mmol) prepared in Example 6 dissolved in methanol was added slowly to the slurry. After addition, sodium tetrahydridoborate (3.55 g, 93.84 mmol) was slowly added portion wise. The reaction was then stirred for an hour at room temperature. The reaction was filtered through celite and the pad was washed with methanol (50 mL). The solvent was removed and the residue was taken up in hydrochloric acid (1N) and the aqueous layer was extracted with ethyl acetate. The combine organic layers were dried over anhydrous sodium sulfate, filtered and solvent was removed to leave a reddish solid. The solid was triturate with hexane to obtain the title compound (6.03 g) having the following physical data.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31](I)[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21].[CH3:47][N:48](C=O)C>CCOC(C)=O.C1(C)C=CC=CC=1.[C-]#N.[C-]#N.[Zn+2]>[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31]([C:47]#[N:48])[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To Pd2(dba)3CHCl3 (60.1 mg, 5 mol %) and PPh3 (60.9 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The resulting precipitate was stirred at room temperature for 30 minutes during which time the colour changed from red to yellow/orange. To this was added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (626.4 mg, 1.16 mmol) dissolved in anhydrous DMF (1.0 mL). To the resulting red solution was then added Zn(CN)2. The resulting precipitate was then heated to 60° C. (bath temperature) and stirring was continued at that temperature for 4 hours. The mixture was allowed to cool to room temperature and diluted with EtOAc:toluene (1:1, 10 mL). The mixture was washed with H2O (6 mL). The aqueous phase was then extracted with EtOAc:toluene (1:1, 5 mL×5). The organic phases were combined and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo. The orange solid obtained was then purified by flash chromatography (silica gel, eluting 1% to 2% to 3%MeOH in CHCl3) to give the title compound as a light brown/orange solid (462.6 mg, 91%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH:5]([N:6]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][S:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CCSC)N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A suspension of methionine methyl ester hydrochloride (3.8 g, 19 mmol) and freshly distilled benzaldehyde (2 g, 19 mmol) in dichloromethane (60 mL) was cooled to 0° C. and magnetically stirred. A solution of triethylamine (1.92 g, 19 mmol) in solution in dichloromethane (30 mL) was added slowly thereto. The resulting solution was allowed to stand overnight at room temperature, with stirring. After removal of the solvent, the residue was taken up in anhydrous diethyl ether, with the insoluble material being filtered off. The filtrate was washed with water (3×30 mL), brine (2×40 mL), dried over sodium sulfate, and concentrated, to provide a crude material which was purified by distillation (bp 144° C., 4 mm) providing methyl-2-(benzylideneamino)-4-(methylthio)butyrate (3.62 g) at a yield of 76%.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[N:15][C:14]([CH:35]=[O:36])=[N:13]1.O>O1CCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:35]([C:14]1[N:15]=[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)[N:12]([CH3:11])[N:13]=1)[OH:36]
Reactant: Cn1nc(C=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 18 h

Procedure:
n-Butyllithium (1.55M in n-hexane, 5.96 ml) was added dropwise to a stirred solution of furan (0.16 ml) in anhydrous tetrahydrofuran (20 ml), under nitrogen at -40°. The stirred solution was allowed to warm slowly to 20°, heated under reflux for 3 h, added dropwise at 0° to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (1.0 g) in tetrahydrofuran (10 ml), and the resulting solution was stirred at 20° for 18 h. Water (20 ml) was added, the mixture concentrated, extracted with ethyl acetate and the extract was dried and evaporated. The residual oil (0.9 g) was chromatographed using System C to give the title compound (0.16 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[NH:12][C:11]1=[O:28].Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[N:12]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:11]1=[O:28]
Reactant: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3Cl)c(=O)c2c1C
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(-c2ccccc2Cl)c(=O)c2c(C)c(C(=O)OCC)c(C)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A portion (50 mg) of sodium hydride suspension (50%) in mineral oil was added to a stirred solution of 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4-(1H,3H)-quinazolinedione (373 mg) in dried dimethylformamide (20 ml). After addition of ethyl chloroacetate (123 mg), the mixture was stirred at 70° C. for one hour. The solvent was evaporated at reduced pressure, and the residue was extracted with CHCl3, and the CHCl3 extract was washed with water, dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethanol to give 3-(2-chlorophenyl)-1-ethoxycarbonylmethyl-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)-quinazolinedione (287 mg, 62.6%) melting at 158°-159° C. MS: m/e, 458(M+), 423. NMR: δ (ppm, CDCl3), 1.28 (3H, t), 1.39 (3H, t), 2.40 (3H, s), 2.74 (3H, s), 4.28 (2H, q), 4.42 (2H, q), 4.92 (2H, s), 6.74 (1H, s), 7.41 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O:19]C)=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)O
Yield: 85.7 %

Procedure:
A solution of methyl [2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetate (3.5 g) in ethanol (50 cc) is treated with normal sodium hydroxide solution (15 cc) at 80° C. for 4 hours. The reaction mixture is concentrated under reduced pressure (2.7 kPa). The residue is taken up with water (100 cc) and the solution, acidified to pH 1 with 4N hydrochloric acid, is extracted with ethyl acetate (2×100 cc). The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give [2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetic acid (2.85 g) in the form of a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]([O:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:22]([O:21][CH:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([OH:8])[CH:10]=1)[C:18]([OH:20])=[O:19])[CH3:23]
Reactant: CCOC(C(=O)O)c1ccc(OC)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(C(=O)O)c1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.6 %

Procedure:
To a stirred solution of (RS)-(3-benzyloxy-4-methoxy-phenyl)-ethoxy-acetic acid (0.801 g) at rt in ethanol was added 10% Pd/C (0.1 g). The mixture was then stirred at rt under a hydrogen atmosphere for 17 h. The catalyst was filtered off and washed with dichloromethane. The filtrate was concentrated (rotavapor). The residue was purified by chromatography to give (RS)-ethoxy-(3-hydroxy-4-methoxy-phenyl)-acetic acid (0.250 g) as a light yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([C:33](=[O:43])[CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([CH2:34][C:33]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:43])=[CH:36][CH:37]=1
Reactant: NCc1ccc(CC(=O)C2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Yield: 46.1 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (137 mg, 0.325 mmol) and 4-(2-cyclohexyl-2-oxo-ethyl)-benzylamine (150 mg, 0.65 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) to obtain 7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (76 mg, 46%). MS (ES+) m/z: 507 (M+H)+.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[C:14](OC(=O)C)(=[O:16])C.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.CO.O.C(O)=O>[CH:14]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[OH:1])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(CCCNO)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOP(=O)(CCCN(O)C=O)OCC
Yield: 91.1 %

Procedure:
To a solution of diethyl 3-(N-hydroxyamino)propylphosphonate (2.80 g.) in chloroform (30 ml.) was added dropwise a mixture of acetic anhydride (2.04 g.) and formic acid (1.38 g.), which was prepared in the same manner as that of Example (31), under ice-cooling with stirring. The reaction mixture was stirred for half an hour at 0°-5° C. and for additional an hour at ambient temperature, and then evaporated to dryness under reduced pressure to give an oily residue, which was dissolved in a mixture of methanol (15 ml.) and water (5 ml.), adjusted to pH 8 with 1N aqueous sodium hydroxide solution and stirred for 1.5 hours at ambient temperature. The methanol was distilled off from this solution under reduced pressure to give an aqueous solution, which was adjusted to pH 5 with 10% hydrochloric acid and extracted with chloroform (once with 30 ml. portion and three times with 10 ml. portions). These combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude diethyl 3-(N-formyl-N-hydroxyamino)propylphosphonate (2.89 g.), which was passed through a column packed with silica gel (60 g.). The column was eluted with a mixture of chloroform and methanol (25:1 by volume), and the fractions containing an object compound were collected and evaporated to dryness under reduced pressure to give the same pure object compound (1.71 g.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH3:24])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Yield: 55.1 %

Procedure:
Using General Procedure B, to a solution of COMPOUND 249(0.1331 g, 0.43 mmol) in CH3CN (5 mL) was added Ac2O (0.05 mL, 0.51 mmol), Et3N (0.09 mL, 0.65 mmol), and KI (0.0116 g, 0.04 mmol). Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 83.5 mg (53%) of COMPOUND 251 as a white solid. 1H NMR (CDCl3) δ 1.53-1.69 (m, 2H), 1.78-1.85 (m, 2H), 2.08 (s, 9H), 2.35 (t, 1H, J=13.0 Hz), 2.72 (t, 1H, J=12.0 Hz), 2.91 (t, 1H, J=12.0 Hz), 3.73-3.90 (m, 5H), 4.69 (d, 1H, J=24.0 Hz), 7.06-7.11 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.35, 21.86, 27.09, 28.19, 42.05, 46.79, 54.99, 57.78, 122.82, 133.77, 138.43, 146.31, 157.49, 169.14. ES-MS m/z 353 (M+H). Anal. Calcd. for C21H28N4O.H2O: C, 69.43; H, 8.10; N, 15.42. Found: C, 69.52; H, 7.82; N, 15.28.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.N1CC(=O)NC1=O.C(O)(C(F)(F)F)=O>>[CH3:10][C:3]1([CH2:2][NH:1][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:25][CH:26]=2)[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7]1
Reactant: Cc1cc(COc2ccc(CC(=O)O)cc2)c2ccccc2n1
Reactant: CC1(CN)NC(=O)NC1=O
Agent: O=C1CNC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(CC(=O)NCC3(C)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 30.8 %

Procedure:
5-(aminomethyl)-5-methylhydantoin (109a) (30 mg, 0.17 mmol) was coupled with {4-[(2-methyl-4-quinolinyl)-methoxy]phenyl}acetic acid (46 mg, 0.15 mmol) using general coupling method B to give 20 mg (24%) of the product hydantoin as a TFA salt. MS found: (M+H)+=433.
Reaction SMILES: C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:17]1[C:21]([C:22]2[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[N:23]=2)=[CH:20][CH:19]=[N:18]1.I[C:40]1[CH:44]=[CH:43][S:42][CH:41]=1>CC#N.CCOC(C)=O.O.[Cu-]=O>[S:42]1[CH:43]=[CH:44][C:40]([N:17]2[C:21]([C:22]3[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=4)[N:23]=3)=[CH:20][CH:19]=[N:18]2)=[CH:41]1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Reactant: Ic1ccsc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccsc1
Temperature: 90 °C
Reaction time: 96 h
Yield: 1.8 %

Procedure:
To a mixture of copper (I) oxide (0.028 g, 0.20 mmol), salicylaldoxime (0.11 g, 0.78 mmol), Cs2CO3 (0.64 g, 2.0 mmol) and 3-(1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.30 g, 0.98 mmol) in MeCN (8 mL) was added 3-iodothiophene (0.15 mL, 1.5 mmol), and the mixture was stirred at 90° C. for 2 days and at room temperature for 4 days. The mixture was diluted with AcOEt and water, and filtered. The filtrate was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (20/80-100/0 AcOEt/hexane) to give yellow crystals. The crystals were purified by preparative HPLC and recrystallized from AcOEt/hexane to give the title compound (7 mg, 2% yield) as off-white crystals: 1H NMR (300 MHz, CDCl3): δ ppm 6.75 (1H, d, J=7.9 Hz), 7.12 (1H, dd, J=4.5, 1.9 Hz), 7.24 (1H, s), 7.30-7.34 (2H, m), 7.36 (1H, d, J=1.9 Hz), 7.41 (1H, s), 7.50-7.57 (1H, m), 7.59-7.64 (1H, m), 7.78 (1H, d, J=1.9 Hz), 8.23 (1H, d, J=7.9 Hz). LC-MS (ESI) m/z 389 [M+H]+.