Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:45])[C:7]([S:18][C@@H:19]1[CH2:23][N:22](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:21]([CH2:37][N:38]3[C:42](=[O:43])[CH2:41][NH:40][C:39]3=[O:44])[CH2:20]1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+].P(=O)(O)(O)O.[H][H]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:45])[C:7]([S:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([CH2:37][N:38]3[C:42](=[O:43])[CH2:41][NH:40][C:39]3=[O:44])[CH2:20]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: [H][H]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CN3C(=O)CNC3=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CN4C(=O)CNC4=O)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Yield: 42.1 %

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.44 g) in tetrahydrofuran (30 ml) were added triphenylphosphine (0.29 g), sodium 2-ethylhexanoate (0.41 g) and tetrakis(triphenylphosphine)palladium(0) (0.13 g) successively with stirring at ambient temperature After stirring at the same temperature for 1 hour, the reaction mixture was evaporated in vacuo to give a residue. A mixture of the residue, 20% palladium hydroxide on carbon (0.5 g), 0.1M phosphoric acid buffer (pH 5.8,60 ml) and tetrahydrofuran (60 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin, "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries)(30 ml) eluting in turn with water (80 ml) and 5% aqueous acetone (90 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(2,5-dioxoimidazolidin-1-yl)methylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.40 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[CH2:15]([C:19]1[N:20]=[C:21]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:22]2[NH:27][N:26]=[C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32]Cl)[C:23]=2[N:24]=1)[CH2:16][CH2:17][CH3:18]>CN(C)C=O.ClCCl>[CH2:15]([C:19]1[N:20]=[C:21]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:22]2[NH:27][N:26]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]3[CH2:13][CH2:14][C@H:10]([F:9])[CH2:11]3)[C:23]=2[N:24]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCl)c2n1
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CC[C@H](F)C3)c2n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
Triethylamine (0.860 mL, 6.20 mmol) was added to a mixture of (S)-3-fluoropyrrolidine hydrochloride (390 mg, 3.10 mmol) and 5-butyl-3-(5-chloropent-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (457 mg, 1.034 mmol) in N,N-dimethylformamide (7 mL). The mixture was heated to 80° C. and stirred for 18 hours. An additional portion of (S)-3-fluoropyrrolidine hydrochloride (195 mg, 1.55 mmol) and triethylamine (0.430 mL, 3.10 mol) were added to the reaction mixture. The reaction was stirred at 80° C. for a further 6 hours. N,N-Dimethylformamide (3 mL) was added and the reaction mixture was stirred at 80° C. for a further 18 hours and then allowed to cool to room temperature. The mixture was evaporated in-vacuo to yield a brown oil. The resulting oil was partitioned between dichloromethane (50 mL) and water/brine (20 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 50 g aminopropyl functionalised silica cartridge and purified using a 0-10% methanol in dichloromethane gradient over 40 minutes. (detection wavelength=230 nm). Appropriate fractions were combined and evaporated in-vacuo to yield a brown oil (261 mg). A mixture of the oil and 10% palladium on carbon (50 mg) in ethanol (20 mL) was stirred under a hydrogen atmosphere for 3 hours. Additional 10% palladium on carbon (50 mg) was added to the reaction and the mixture was stirred under a hydrogen atmosphere for 18 hours. A further portion of 10% palladium on carbon (50 mg) was added to the reaction and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction was filtered through a celite cartridge (10 g) and evaporated in-vacuo to yield a brown oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 50 g aminopropyl functionalised silica cartridge and purified using a 0-10% methanol in dichloromethane gradient over 40 mins. (detection wavelength=230 nm). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a brown oil (175 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][OH:15])[C:10]([NH2:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[NH2:17][O:15][CH2:14][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([NH2:12])=[O:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCON)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
To a solution of (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) in CH2Cl2 (150 mL) was added 2-hydroxyisoindoline-1,3-dione (5.1 g, 31.2 mmol) and triphenylphosphine (8.2 g, 31.2 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (6.0 ml, 31.2 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (60% EtOAc—Hexane). The resultant pale yellow compound was dissolved in CH2Cl2 (60 ml). Hydrazine hydrate (670 μL, 8.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear yellow oil of (S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1.1 g, 4.4 mmol). [M+H] calc'd for C10H24N2O3Si, 249; found, 249.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.C(OC([N:33]1[CH:37]=[C:36]([CH:38](OCC)[O:39]CC)[N:35]=[C:34]1[NH2:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[CH:38]([C:36]1[N:35]=[C:34]([NH:45][C:23]([C:16]2[C:17]3[N:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:13]([C:3]3[C:4]([F:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[F:1])=[CH:14][CH:15]=2)=[O:24])[NH:33][CH:37]=1)=[O:39]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: CCOC(OCC)c1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (200 mg, 0.578 mmol) (Step 185.1), 2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester (198 mg, 0.693 mmol, 1.2 equiv) (Step 179.8), TBTU (223 mg, 0.693 mmol, 1.2 equiv), DIEA (74.7 mg, 0.578 mmol) in DMF (4 mL) was stirred for 18 h at rt. The reaction mixture was diluted in EtOAc/H2O and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The resulting yellow foam (405 mg) was dissolved in acetone (5 mL) and H2O (3 mL) and treated with PPTS (30 mg). The reaction mixture was heated to 50° C., stirred for 2 h, allowed to cool to rt and diluted with EtOAc/H2O. The resulting yellow precipitate was collected by vacuum filtration and dried to provide 174 mg of the title compound: ES-MS: 440 [M+H]+; tR=3.89 min (System 1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17]>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1OC
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3 g of 3-fluoro-4-nitrophenol and 8.8 g of 3,4-dimethoxyaniline were mixed and stirred for 2 hours at 150° C. After cooling, it was dissolved in dichloromethane and extracted twice with 1N aqueous hydrochloric acid. The aqueous phase was extracted twice with chloroform, and the combined chloroform extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][N:48]=[C:49]=[O:50]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:49]([NH:48][CH3:47])=[O:50])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CN=C=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methyl isocyanate (0.023 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature and for 2 hours at ambient temperature. Methyl isocyanate (0.03 ml) was further added thereto, and the mixture was stirred overnight at ambient temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[3-methyl-4-(N'-methylureido)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (150 mg) as an amorphous powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:18])[C:5]([F:17])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cu][C:20]#[N:21]>CN(C=O)C>[C:20]([C:2]1[CH:3]=[C:4]([F:18])[C:5]([F:17])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: N#C[Cu]
Reactant: CCOC(=O)CCCOc1cc(Br)cc(F)c1F
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(C#N)cc(F)c1F
Temperature: 120 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 4-(5-bromo-2,3-difluorophenoxy)butanoate (2.9 g, 9.0 mmol) in anhydrous DMF (30 mL) was added copper(I) cyanide (1.6 g, 18.0 mmol) under nitrogen atmosphere. The resulting mixture was heated to 120° C. for 16 hours. Additional amount of copper(I) cyanide (0.8 g, 9.0 mmol) was added and the reaction mixture was stirred at 120° C. for 24 hours. A second additional amount of copper(I) cyanide (0.8 g, 9.0 mmol) was added. After 24 additional hours at 120° C., the reaction mixture was cooled down and filtered through a pad of Celite, which was rinsed with EtOAc. The organic layer was washed many times with an aqueous solution of NH4OH and brine, dried (MgSO4) and concentrated under vacuum affording the title compound as a beige solid (2.29 g, 95%). HPLC (Method A) Rt 4.73 min (Purity: 84.4%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][O:14]C(=O)C)[C:8]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[C:8]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCOc1ccnc(CO)c1C
Yield: 60.8 %

Procedure:
22.0 g (0.088 mol, 1.0 eq.) of 4-pentyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react for one hour at room temperature. Subsequently, the reaction liquid was diluted with toluene, and then the toluene phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 11.2 g of 4-pentyloxy-2-hydroxymethyl-3-methylpyridine as an oily matter (yield 60.8%).
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][N+](C)(C)C.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(O)C>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:21][C:20]1[N:11]2[CH:12]=[CH:13][C:14]3[C:19]([C:10]2=[N:9][C:8]=1[CH3:7])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C
Reactant: c1c[nH]cn1
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cc1nc2c3ccccc3ccn2c1Cc1ncc[nH]1
Reaction time: 7 h
Yield: 71.2 %

Procedure:
A mixture of 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (4.5 g) and imidazole (2.02 g) in ethanol (45 ml) was refluxed with stirring for 7 hours and evaporated in vacuo. To the residue was added water and the resulting precipitates were collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(1-imidazolylmethyl)-2methylimidazo[2,1-a]isoquinoline (2.3 g).
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[O:3][C:4]3[CH:14]=[C:13]4[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:7][C:5]=3[N:6]=2)[CH2:24][CH2:23]1
Reactant: Sc1nc2cc3ccccc3cc2o1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3cc4ccccc4cc3o2)CC1
Reaction time: 2.5 h

Procedure:
A 100 mg portion of 2-mercaptonaphtho[2,3-d]oxazole dissolved in 30 ml of anhydrous benzene was mixed with 130 mg of phosphorus pentachloride, and the mixture was refluxed under heating for 2 hours. To this was further added 90 mg of phosphorus pentachloride, followed by additional 2.5 hours of heating under reflux. Under cooling with ice, 995 mg of N-methylpiperazine was added to the resulting solution, and the reaction was carried out for 1 hour at the same temperature and then for 48 hours at room temperature. Precipitated materials in the reaction solution were removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue was dissolved in 300 ml of ethyl acetate, washed three times with water, dehydrated with sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol=50:1) to obtain 18 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O.C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
2-[6-([2-(4-nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (0.35 g) was dissolved in a mixture of ethanol (40 ml), water (5 ml) and acetic acid (5 ml) and the resulting solution degassed under reduced pressure. 10% Palladium on carbon (56% paste, 0.27 g) was added and the resulting mixture stirred vigorously under a hydrogen atmosphere (atmospheric pressure) for 12 h. The reaction mixture was filtered through Celite™ and washed with ethanol. The filtrate and washings were evaporated to dryness to give the title compound (0.313 g) which was used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:10]1([C:16]2[N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2ccnc2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A mixture of 4-fluorobenzonitrile (3.63 g, 30 mmol), 2-phenylimidazole (3.72 g, 30 mmol) and anhydrous K2CO3 (4.15 g, 30 mmol) in dry DMSO (30 ml) was heated at 100° C. for 20 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into an ice-cold saturated aqueous NH4Cl (100 ml) solution and the whole extracted with Et2O (150 ml×2). The combined extracts was washed with water (100 ml), brine (80 ml), dried over MgSO4 and solvent removed under reduced pressure. The resultant residue was purified by column chromatography (SiO2 ; dichloromethane:ethyl acetate:ethanol=20:1:1) to afford title compound (3.61 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:13])[C@H:10](O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:13])[O:48][CH2:47][C:46]([CH3:50])([CH3:49])[NH:45][C@H:10]2[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(N)CO
Reactant: COc1cccc(C(=O)[C@@H](C)O)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc([C@]2(O)OCC(C)(C)N[C@H]2C)c1
Yield: 72 %

Procedure:
Compound 4f was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-methoxyphenyl)-2-hydroxypropan-1-one (10f, 4.2 g, 0.023 mol), Proton sponge (5.9 g, 0.028 mol), triflic anhydride (4.2 mL, 257 mmol), and 2-amino-2-methyl-1-propanol (4.5 g, 0.051 mol) in CH2Cl2 (50 mL). After purification, 4.16 g (71%) of the free base 4f was isolated and converted to 1.24 g the hemi-D-tartrate salt, which had 91% ee: mp 99-100° C.; [α]20D +7.9° (c 1.1, CH3OH); 1H NMR (methanol-d4) δ 7.32 (t, 1H, J=7.8 Hz), 7.19-7.14 (m, 2H), 6.96-6.92 (m, 1H), 4.33 (s, 1H), 4.18 (d, 1H, J=12.3 Hz), 3.81 (s, 3H), 3.52 (d, 1H, J=12.3 Hz), 3.48-3.45 (m, 1H), 1.59 (s, 3H), 1.34 (s, 3H), 1.06 (d, 3H, J=6.6 Hz). 13C NMR (methanol-d4) δ 178.8, 161.4, 144.1, 130.7, 120.1, 115.4, 113.8, 97.1, 75.2, 67.6, 56.1, 55.2, 24.4, 21.5, 14.5; LCMS (ESI) m/z 252.3 [(M-tartrate)+, % M=C16H24NO6]; Anal. (C16H24NO6.0.5H2O) calcd: C, 57.30; H, 7.51; N, 4.18. found: C, 57.33; H, 7.55; N, 4.14.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CS(C)=O>[S:13]1[C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:15]=[CH:14]1
Reactant: O=C(Nc1ccccc1O)c1ccsc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2Oc2sccc21
Temperature: 155 °C
Reaction time: 0.42 h
Yield: 45.5 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (16 g) in dimethyl sulfoxide (160 ml) was added potassium carbonate (15 g) and the mixture was stirred at 150-160° C. for 25 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5.3 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH3:20])[C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:32]1([CH2:38][N:39]=[C:40]=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N-]=C=O>CCOC(C)=O.CO.C(Cl)Cl>[C:32]1([CH2:38][NH:39][C:40](=[O:41])[O:19][C:17]2[CH:16]=[CH:15][C:14]3[C:10]([N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH3:20])=[N:11][O:12][C:13]=3[CH:18]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Reactant: O=C=NCc1ccccc1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CN(CCN1CCOCC1)c1noc2cc(OC(=O)NCc3ccccc3)ccc12
Yield: 70.5 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2.3 g) and 1,8 diazabicyclo[5.4.0]undec-7-ene (0.2 g) in EtOAc (80 ml) was added phenylmethyl isocyanate (1.3 g). After 24 hours an additional equivalent of the isocyanate was added. TLC (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was concentrated in vacuo. Flash chromatography (silica gel) eluting with 1% MeOH/DCM provided the product (2.4 g), m.p. 106-107° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:15]1[N:16]=[C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[S:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnn(Cc2nc(CO)cs2)n1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1csc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazol-4-yl)methanol (672 mg, 2.79 mmol) in CH2Cl2 (15.0 mL) was added to a suspension of Ag2O (968 mg, 4.18 mmol) and MeI (0.52 mL, 8.36 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 07: tR=0.66 min, [M+H]+=226.27.