Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([O:23][CH3:24])[N:10]=1.[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]1[O:28][CH2:27]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([O:23][CH3:24])[N:10]=1
Reactant: CCCCOCC1CO1
Reactant: COc1nc(-c2ccc(O)cc2O)nc(-c2ccc(O)cc2O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCCCOCC(O)COc1ccc(-c2nc(OC)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1
Temperature: 80 °C

Procedure:
10 g of 2,4-di(2,4-dihydroxyphenyl)-6-methoxy-1,3,5-triazine are stirred for 3 hours at 130° C. with 100 ml of butyl glycidyl ether and 0.20 g of tetrabutylammonium bromide. The mixture is subsequently allowed to cool to 80° C., 100 ml of ethyl acetate and 2.0 g of Prolith Rapid are added, the mixture is filtered through kieselguhr, and the solvent is removed under reduced pressure. The excess butyl glycidyl ether is then removed by vacuum distillation, giving 2,4-di[2-hydroxy-4-(3-butoxy-2-hydroxypropoxy)phenyl]-6-methoxy-1,3,5-triazine, which, after recrystallisation from ethanol, has a melting point of 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:5]([C:7]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][O:17]C(=O)C)[CH:13]=[CH:12][CH:11]=2)=[O:8])[N:6]=1.[OH-].[Na+].O.Cl>CO>[OH:17][CH2:16][C:14]1[N:15]=[C:10]([NH:9][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Nc2cccnc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)Nc2cccc(CO)n2)c(Nc2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of acetic acid 6-{[2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carbonyl]-amino}-pyridin-2-ylmethyl ester (0.046 g, 0.12 mmol) in methanol (20.00 ml) was treated with a 2N solution of NaOH in water (1.00 ml, 2.00 mmol). After 15 min stirring at room temperature, the mixture was acidified with HCl 2N, and the solvents removed. The residue was purified by flash chromatography (dichloromethane/methanol) to yield the title compound (0.035 g, 85%) as a light yellow solid, MS (ISP): m/e=342.1 (M+H+).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1.[H][H]>CO.[C].[Pd]>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1ccc2c(c1)OCO2

Procedure:
In 5 ml of absolute methanol was dissolved 500 mg of 3,4-methylenedioxy-cinnamic acid, followed by adding thereto 50 mg of 10% palladium-carbon, and the reaction was carried out with stirring in a hydrogen stream at room temperature for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][C:24]([SH:25])=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnc(S)o2)cc2[nH]cnc2c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in 3 mL absolute EtOH and cooled to 0° C. under N2. CS2 is added (26 mg, 0.346 mmol) followed by powdered KOH (8 mg, 0.150 mmol). After stirring at 0° C. for 30 minutes, the reaction mixture is heated to reflux. After 3.5 hours, the reaction mixture is quenched by the addition of water, followed by the addition of ethyl acetate and 1N HCl. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give the desired product as a yellow solid: LC/MS ESI (+) m/z 376, 378 (M+Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.29 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11]([CH2:13][C:14](=O)[CH3:15])=[O:12]>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[CH3:15][C:14]1[N:1]=[C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]2[C:13]=1[C:11](=[O:12])[CH3:10]
Reactant: CC(=O)CC(=O)CCl
Reactant: Cc1cccnc1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1c(C)nc2c(C)cccn12
Temperature: 25 °C

Procedure:
2 g of 2-amino-3-picoline was dissolved in a mixture solvent of 10 mL of tetrahydrofuran and 5 mL of diethyl ether, 4.4 mL of 3-chloroacetyl acetone was added, and heated overnight under reflux. The reaction mixture was cooled back to room temperature, diluted with ethyl acetate, and then washed with water and with saturated brine in the subsequent order. After drying the organic layer over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of chloroform and solidified by adding hexane, to obtain 664 mg of 1-(2,8-dimethylimidazo[1,2-a]pyridin-3-yl)ethanone [38-1] as a light grey solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:36])[CH3:6])C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)CCC.ClCC1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1>>[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:36])([CH3:37])[C:4]([OH:38])=[O:3]
Reactant: CCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CCCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCCC(Oc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
A] The title compound was prepared in analogy to example 34, via [rac]-2-methyl-2-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-propionic acid ethyl ester, but using in step A] [rac]-3-(1-chloro-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 21B]) instead of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as colorless foam.
Reaction SMILES: [CH:1](OC=C)=[CH2:2].[N+:6]([C:9]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:10][OH:11])([O-:8])=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([O:11][CH2:10][C:9]([N+:12]([O-:14])=[O:13])([N+:15]([O-:17])=[O:16])[N+:6]([O-:8])=[O:7])=[CH2:2]
Reactant: O=[N+]([O-])C(CO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=COC=C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=COCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Yield: 25.9 %

Procedure:
Following the procedure described in Examples I and II, divinyl ether and 2,2,2-trinitroethanol (X) were reacted for 60.25 hours in methylene chloride in the presence of red mercuric oxide and trifluoroacetic acid. A 25.9% yield of 2,2,2-trinitroethyl vinyl ether was obtained after elution with carbon tetrachloride through the neutral alumina (pH 7.3) column, followed by column chromatographic removal of 2,2,2-trinitroethanol in hexane through 60/200 mesh SiO2.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][OH:17])[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)NCc1cc(C(C)=NO)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(C(C)=NOCc2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 75.4 %

Procedure:
0.70 g of methyl N-[2-chloro-5-(1-hydroxyiminoethyl)benzyl]carbamate was dissolved in 10 ml of N,N-dimethylformamide, and 0.13 g of 60% sodium hydride was added thereto under cooling with ice, followed by stirring for 1 hour. 0.57 g of 4-fluorobenzyl bromide was dissolved in 2 ml of N,N-dimethylformamide, which was dropwise added to the reaction mixture under cooling with ice. After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=5/1) to obtain 0.75 g of methyl N-{2-chloro-5-[1-(4-fluorobenzyloxyimino)ethyl]benzyl}carbamate (m.p. 101-103° C.) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:25])[C:18]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CC(CCO)c1ccc(F)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
3,4-Difluoro-β-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (4.3 g) in EtOAc (100 mL) was treated with carbonyldiimidazole (3.24 g) and N,N-dimethylaminopyridine (195 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (3.02 g) in H2O (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (1×100 mL), sat. NaHCO3 (1×100 mL) and water (1×100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (3.64 g). Mass spectrum (CI): 320.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].OP([O-])(O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.[NH2:50][C@H:51]([C:56]([OH:58])=[O:57])[C@H:52](CC)[CH3:53].[C:59]([O-:62])([O-:61])=O.[Ca+2]>>[NH2:50][C@H:51]([C:56]([OH:58])=[O:57])[CH2:52][CH2:53][C:59]([OH:62])=[O:61]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 21 h

Procedure:
Both strains, VL334thrC+ and VL334thrC+-ΔgeneX, can be grown for 18-24 hours at 37° C. on L-agar plates. Then, one loop of the cells can be transferred into test tubes containing 2 ml of fermentation medium. The fermentation medium contains glucose (60 g/l), ammonium sulfate (25 g/l), KH2PO4 (2 g/l), MgSO4 (1 g/l), thiamine (0.1 mg/ml), L-isoleucine (70 μg/ml), and CaCO3 (25 g/l). The pH is adjusted to 7.2. Glucose and CaCO3 are sterilized separately. Cultivation can be carried out at 30° C. for 3 days with shaking. After the cultivation, the amount of L-glutamic acid which is produced can be determined by paper chromatography (liquid phase composition of butanol-acetic acid-water=4:1:1) with subsequent staining by ninhydrin (1% solution in acetone) and further elution of the compounds in 50% ethanol with 0.5% CdCl2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 102 %

Procedure:
A mixture of 1-(o-methoxyphenyl)piperazine (0.19 mol), N-(3-bromopropyl)phthalimide (0.186 mol) and micropulverized potassium carbonate (0.465 mol) in acetonitrile (375 ml) was heated at reflux for 16 hours. The cooled mixture was evaporated in vacuo and the residue diluted with water (800 ml) and extracted with chloroform (4×350 ml). After drying (MgSO4), the combined extracts were evaporated in vacuo. The residue was dried under high vacuum (<0.05 mm of Hg) at room temperature for 16 hours resulting in 72.0 g of a yellow solid ~100% yield); mp 85°-93° C. Spectral data were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[C:19]3[NH:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[C:13]2[N:12]=[C:11]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[CH2:1]([S:8]([C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[C:19]3[NH:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[C:13]2[N:12]=[C:11]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[CH:10]=1)=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(SCc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cnn3c(S(=O)Cc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the reaction flask, 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (4.1 g, 8.6 mmol) was added to dichloromethane (86 mL) along with m-chloroperbenzoic acid (5.9 g, 34.4 mmol). The mixture was allowed to stir at room temperature for 12 hours. The solid was collected by filtration, washed with dichloromethane then dried under vacuum overnight. The product, 5-((7-(benzylsulfinyl)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a bright yellow solid in quantitative yield. LCMS (M+1=493)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.CO.Cl.[NH2:17][OH:18]>O>[CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[N:17][OH:18]
Reactant: CNC(=O)C(=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NO)c1ccccc1C

Procedure:
To N-methyl-2-(2-methylphenyl)-2-oxoacetamide (5.31 g, 0.03 mol), added were methanol (30 ml) and hydroxylamine hydrochloride (4.17 g, 0.06 ml), and the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-hydroxyiminoacetamide in E-form (4.79 g; yield, 83.1%) and Z-form (0.50 g; yield, 8.7%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc[nH]c(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccnc(Cl)c2n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A suspension of 2-Methyl-7H-[1,7]naphthyridin-8-one (820 mg, 5.12 mmol) and phosphorus oxychloride (7 ml, 76.8 mmol) was stirred at 90° C. for 4 hours. The reaction mixture was evaporated to dryness, poured on ice and set alkaline with aqueous ammonia. A red solution resulted. The aqueous layer was extracted with dichloromethane (three times). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 0:100->20:80 gradient). The desired compound was obtained as a white solid (810 mg, 89%), MS: m/e=(M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]2[C@@H:9]1[CH2:10][N:11]([C:22]1[CH:23]=[CH:24][C:25]3[C:26]4[C:18](=[CH:17][C:16]([Br:15])=[CH:28][CH:27]=4)[C:19](=[O:30])[C:20]=3[CH:21]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H]2CN(c3ccc4c(c3)C(=O)c3cc(Br)ccc3-4)C[C@@H]21
Temperature: 85 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
A mixture of 3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (600 mg, 3.0 mmol; prepared according to patent WO2001081347), 2,7-dibromo-fluoren-9-one (1.3 g, 4 mmol; Aldrich), sodium tert-butoxide (400 mg, 4.2 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3; 160 mg, 0.17 mmol; Alfa) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 330 mg, 0.53 mmol; Strem) in dry toluene (30 mL) was warmed to 85° C. and stirred under nitrogen atmosphere for 3 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography (80 g silica gel, 40:60 hexanes-EtOAc) to afford the title compound (800 mg, 1.76 mmol; 55% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.56-7.61 (2H, m), 7.47 (1H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.06 (1H, d, J=3 Hz), 6.92 (1H, dd, J=8, 3 Hz), 4.60-4.67 (1H, m), 3.91-4.16 (2H, m), 3.73-3.86 (1H, m), 3.55-3.66 (1H, m), 3.41-3.51 (1H, m), 2.90-3.27 (3H, m), 1.36-1.55 (9H, s); MS (DCI/NH3): m/z 455 (M+1)+, 457 (M+3)+.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[Cl-:40].[NH4+]>O>[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[ClH:40]
Reactant: [Cl-]
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: [NH4+]
Solvent: O
Product: Cl

Procedure:
Crude deferoxamine B hydrochloride (7.88 kg) containing 5.30 kg deferoxamine B was dissolved in water (362 L). The aqueous solution was then passed through an equal volume of Diaion® SP 207 adsorption resin (Mitsubishi Chemical Corp.) in a 10 liter chromatographic column at a flow rate of 14 L h−1. The eluent contained 5.04 kg deferoxamine. Ammonium chloride was then added in an amount of 5 g L−1 to the eluent with stirring until the ammonium chloride completely dissolved. The solution was then loaded onto a column containing Amberlite® XAD 1180 adsorption resin (132 L) (Rohm & Haas) and driven into the bed with salt water. The column was eluted with 10% acetonitrile-water and then 20% acetonitrile-water at a flow rate of 14 L h−1. The eluent was collected in fractions. The main fraction yielded deferoxamine hydrochloride solution containing 4.53 kg of deferoxamine B. The main fraction was then decolorized over activated carbon (45 g) and Duolite® C 467 (Rohm and Haas) ion exchange resin in H+ form yielding deferoxamine hydrochloride solution containing 4.03 kg of deferoxamine B.
Reaction SMILES: [CH2:1]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCCCCCl
Reactant: CCCCCCCCC1CNCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC1CN(CCCCCO)CCO1

Procedure:
20.0 grams (0.1 mole) 2-octylmorpholine, 13 grams (0.1 mole) of 5-chloropentanol and 12 grams of triethylamine in 150 ml. toluene were kept at 140°-150° C. for 12 hours in an autoclave. After cooling, the organic phase was washed twice with water, dried, and the solvent was evaporated and the base distilled at 128° C./0.01 mm Hg.; yield: 22.0 grams (77%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH:7](Br)([CH3:9])[CH3:8]>>[CH:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:9])[CH3:8]
Reactant: OCCCCO
Reactant: CC(C)Br
Product: CC(C)OCCCCO

Procedure:
Using 1,4- butandiol and isopropylbromide, the above compound is produced.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[S:9][CH:10]=1)=[O:5])[CH3:2].C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(SCCCC(=O)OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCOC(=O)c1csc(SCCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (10.7 g) of (55-1) was dissolved in trifluoroacetic acid (30 mL), thioanisole (10.3 mL) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate as an eluent. The solvent was evaporated from the eluent to give the title compound (5.81 g) as a white solid.