Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][NH2:22])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].C(O[C:26](OCC)(OCC)[CH2:27][CH3:28])C>C1(C)C(C)=CC=CC=1>[CH2:27]([C:28]1[N:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:10][CH2:11][CH:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][CH2:14]3)=[C:3]([C:1]#[N:2])[C:4]2=[N:21][N:22]=1)[CH3:26]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Solvent: Cc1ccccc1C
Product: CCc1nnc2c(C#N)c(N3CCC(c4ccccc4)CC3)ccn12

Procedure:
A solution of D7 (0.05 g, 0.17 mmol) and triethylorthopropionate (0.462 ml, 2.556 mmol) in xylene (1 ml) was heated in a sealed tube at 180° C. for 2 h. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield final compound E10 (0.042 g, 74%).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].C(OCC)(=O)C>C(O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([C:2](=[O:3])[CH3:1])[C:15]#[N:16]
Reactant: CC[O-]
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)C(C#N)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) was added 2,3,5-trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43 ml). The mixture was heated under reflux, under nitrogen for 2.5 hours. The mixture was left standing at room temperature overnight. The mixture was then concentrated and the residue was dissolved in water. The aqueous phase was washed with ether, acidified with concentrated H2SO4 and extracted with ether. The extracts were bulked, dried (MgSO4) and evaporated, 2.59 g, mp. 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt]>[CH3:12][CH:11]1[C:6]2[C:7](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: C=CCCCc1ccccc1C
Agent: [Pt]
Product: Cc1cccc2c1CCCC2C

Procedure:
The cyclization reaction of 5-OTP was carried out under the same reaction conditions as in Example 1-2, using the platinum and copper ion-exchanged zeolite beta catalyst prepared in the above 1.
Reaction SMILES: [C:1]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[C:2]1[C:3](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:4](OCCCC)=O>C(O)C>[C:1]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH2:2][CH2:4][CH2:3][CH2:11][CH2:12][CH2:13][CH2:14][CH2:2][C:1]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Solvent: CCO
Product: CCCCOC(=O)CCCCCCCCC(=O)OCCCC

Procedure:
Mixture of dibutyl phthalate (n=16: molecular weight 278.35) and 15% by weight of ethanol (Standard)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH:15]=2)=[CH:6][C:5]=1[O:19][CH:20]([CH3:22])[CH3:21])([O-])=O.C([O-])=O.[NH4+]>C(O)C.ClCCl.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Oc1cc(C2=CCN(CCO)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)Oc1cc(C2CCN(CCO)CC2)ccc1N
Temperature: 80 °C
Yield: 90.8 %

Procedure:
A mixture of 150 mg of 10% palladium-on-carbon and 400 mg of 2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanol in 15 ml of ethanol is heated at 80° C. with stirring. 1.25 g of ammonium formate are then added in two portions. After stirring at 80° C. for 1 h, the mixture is allowed to return to ambient temperature and is filtered on Clarcel. The Clarcel is rinsed with 200 ml of ethanol and the filtrate is concentrated under vacuum, so as to obtain a residue which is solubilised in 150 ml of dichloromethane. The organic phase is washed three times with 70 ml of a saturated potassium carbonate solution, and the aqueous phase is extracted twice with 100 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 330 mg of 2-{4-[4-amino-3-(propan-2-yloxy)phenyl]piperidin-1-yl}ethanol used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([Br:18])=[C:13]([CH3:19])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Br:18][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][C:15]=1[CH3:17]
Reactant: Cc1cc(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(C)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCNC(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N,N-di-tert.-butoxycarbonyl-2-(4-bromo-3,5-dimethylphenyl)ethanamine (1.19 g) in dichloromethane (25 mL) is added trifluoroacetic acid (320 μL). The mixture is stirred for 12 hours at room temperature. Then the mixture is partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is dried (MgSO4), the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 550 mg; LC (method 8): tR=0.68 min; Mass spectrum (ESI+): m/z=328 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH3:22])[C:8]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:23]([O-])([OH:25])=[O:24].N>S(=O)(=O)(O)O>[CH:1]1([N:7]([CH3:22])[C:8]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][C:18]([N+:23]([O-:25])=[O:24])=[CH:17][C:16]=4[N:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)c1cn2c(nc3ccccc32)s1)C1CCCCC1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CN(C(=O)c1cn2c(nc3ccc([N+](=O)[O-])cc32)s1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 3 (12.3 g) was dissolved in concentrated sulfuric acid, and this was mixed with fuming nitric acid (1.95 ml) under ice-cooling and then stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and neutralized by adding saturated NH3 aqueous solution, and then the thus formed precipitate was collected by filtration. The thus collected crude crystals were washed with hot MeOH to obtain the title compound (12.7 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[CH3:7][C:4]1[S:3][C:2]2=[N:1][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[CH:9][N:6]2[CH:5]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cnc(N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2cc(-c3ccc([N+](=O)[O-])cc3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A mixture of 2-amino-5-methylthiazole (0.24 g, 2.11 mmol) and 2-bromo-4′-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (20 ml) was heated under reflux for 16 h. The reaction mixture was allowed to cool and sodium bicarbonate (200 mg, 2.38 mmol) was added and heating was continued for 1 h. On cooling to room temperature, the solvent was removed under reduced pressure and the residue dissolved in DCM (75 ml) and washed with water (30 ml), brine (30 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography (50:1 DCM/MeOH) to give the title compound (0.143 g, 26%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1ccccc1N
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
A mixture of 0.5 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.36 g of o-toluidine in 60 ml of N,N-dimethylformamide is refluxed for 16 hours. The mixture is poured into 200 ml of ice-water and extracted with three 100 ml portions of chloroform. The extract is washed with water, dried (Na2SO4) and the solvent removed. The residue is purified by chromatography on silica gel prep-plates with hexane-ethyl acetate (5:1) as solvent to give 0.56 g of yellow solid: mass spectrum (CI) 395.2 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:15][NH2:16]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:16][CH3:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCCCOc1ccc2c(c1)OCO2
Reactant: CN
Solvent: CO
Product: CNCCCOc1ccc2c(c1)OCO2
Temperature: 100 °C

Procedure:
Crude 1-benzo[3,4-d]1,3-dioxolan-5-yloxy-3-chloropropane (1.95 g, 9.1 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation, and saturated NaCl solution (50 mL) was added. The mixture was acidified to pH 1 with 10% HCl solution, and extracted with CHCl3 (4×25 mL) to remove impurities. The pH of the aqueous phase was adjusted to 7 with 10% NaOH solution, and the mixture was extracted with ether (4×30 mL) to remove impurities. The aqueous phase was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give a residue. The residue was briefly dried under high vacuum producing a light-brown oil (0.286 g). The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH—Et3N (50:50:2, v/v/v) to collect the product (Rf 0.14). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 and the CHCl3 solution was dried (MgSO4), filtered and concentrated by rotary evaporation to a residue. The residue was dried under vacuum at 40° C. to give 0.274 g (14.4%) of a brown oil.
Reaction SMILES: [C:1]1([P:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([Br:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[OH:30])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[SiH](Cl)Cl>O1CCOCC1>[C:31]1([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([Br:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[OH:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1-c1c(O)ccc2cc(Br)ccc12
Agent: Cl[SiH](Cl)Cl
Solvent: C1COCCO1
Product: Oc1ccc2cc(Br)ccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
An optically active binaphthol (VII) as a starting material is reacted by a method described in the literature (M. Vondenhof and J. Mattay, Tetrahedron Lett., 1990, Vol. 31, pp. 985-988; L. Kurz, G. Lee, D. Morgans, Jr., M. J. Waldyke, and T. Ward, Tetrahedron Lett., 1990, Vol. 31, pp. 6321-6324) and by a method described in the literature (Y. Uozumi, A. Tanahashi, S.-Y. Lee, and T. Hayashi, J. Org. Chem., 1993, Vol. 58, pp. 1945-1948). That is, the binaphthol (VII) is reacted with trifluoromethanesulfonic anhydride (Tf2O) using pyridine in methylene chloride to convert compound (VII) to 2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (VIII), which is reacted with diphenylphosphine oxide (Ph2PHO) in the presence of a catalytic amount of a palladium-phosphine complex, whereby 2'-diphenylphosphinyl-2-trifluoromethanesulfonyloxy-1,1'-binaphthyl (IX) can be synthesized. Compound (IX) is hydrolyzed with lithium hydroxide (LiOH) to obtain 2'-diphenylphosphinyl-2-hydroxy-1,1'-binaphthyl (X), which is brominated in dioxane to obtain 2'-diphenylphosphinyl-2-hydroxy-6-bromo-1,1'-binaphthyl (XI). Compound (XI) is reduced with trichlorosilane (HSiCl3) to obtain 2'-diphenylphosphino-2-hydroxy-6-bromo-1,1'-binaphthyl (XII), which is reacted with 2-vinyl-5,5-dimethyl-1,3-dioxa-2-borinane using a palladium catalyst by a method described in the literature (Y. Miyaura and A. Suzuki, J. C. S. Chem. Commun., 1979, p. 866) to obtain 2'-diphenylphosphino-2-hydroxy-6-vinyl-1,1'-binaphthyl (XIII).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11]1([N:17]2[CH2:21][CH2:20][C:19](N)=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([N:17]2[CH2:21][CH2:20][C:19]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[C:3]([OH:10])=[C:4]([CH3:9])[CH:5]=3)=[N:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC1=NN(c2ccccc2)CC1
Reactant: Cc1cc(N)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1cc(NC2=NN(c3ccccc3)CC2)cc(C)c1O
Yield: 46.2 %

Procedure:
2,6-dimethyl-4-aminophenol (15 g) and 4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (17.6 g) were heated with p-toluene sulfonic acid (0.2 g) at 160° for 1 hour under nitrogen. The mix was cooled, taken up in dichloromethane and washed with dilute HCl, and water. Evaporation, and chromatography of the residue (silica, dichloromethane/ethyl acetate [9:1]) gave 4-(4,5-dihydro-1-phenyl-1H-pyrazol-3-yl)amino-2,6-dimethylphenol (14.2 g), mp 154°-158°. This was refluxed in toluene (40 ml) with 10% palladium on charcoal (10 g) for 3 hours. The mixture was filtered and evaporated to give, after crystallisation from cyclohexane/ethyl acetate, the title compound (8 g), mp 154°-155°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11]C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(I)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(I)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0° C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of α, α-dichloromethyl methyl ether was added and the reaction maintained at 0° C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:17])([O-:9])=[O:7]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccccc1[N+](=O)[O-]

Procedure:
The toluene derivative (1) is charged with concentrated sulfuric acid and potassium nitrate (reaction 11) to obtain the 2-nitro toluene (m), which subsequently is reduced (reaction 12) with hydrogen on palladium/charcoal to the amine (n). The methyl group of the amine (n) is brominated with bromine under illumination (reaction 13). The brominated aniline (o) is charged (reaction 14) with triphenylphosphine in dimethylformamide to give the phosphonium salt (p), which undergoes a Wittig reaction (reaction 15) with n-butyl-lithium and the aldehyde R7 --C(O)H. The ethylene-substituted aniline (q) is reduced with hydrogen over palladiurn-charcoal to the ethyl-substituted aniline (r) (reaction 16), which is further allowed to react with NaNO2 and H2SO4, followed by copper cyanide, and is then heated with formic acid over Raney-nickel to obtain the aldehyde (a) (reaction 18). The ethylene-substituted aniline (q) can also be charged with NaNO2 and H2SO4, followed by copper cyanide (reaction 17), which is then heated with formic acid over Raney-nickel (reaction 19) to give the ethylene-substituted aldehyde (a).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)=[C:14]([CH:27]=[O:28])[CH:13]=2)=[CH:7][C:6]=1[O:29][CH3:30])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]3)=[C:14]([CH2:27][OH:28])[CH:13]=2)=[CH:7][C:6]=1[O:29][CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(CO)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 8 (3.22 g, 7.55 mmol) in methanol (40 mL) was added sodium borohydride (0.373 g, 9.82 mmol) at 0° C. The resulting mixture was stirred at rt for 30 min. The solvent was removed under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product and used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.91 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.01 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.60 (s, 1H), 6.67 (d, J=8.6 Hz, 1H), 4.65 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.42 (s, 12H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(C)C>CC(N(C)C)=O>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(=O)N(C)C
Solvent: CC(C)O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 110 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
10 g (35.6 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 5 mL of DMA (dimethyl acetamide) and 8.3 mL (75 mmole) of N-methyl piperazine. The reaction mixture was heated to 110° C. until the complete conversion of the starting material, about 1.5 h. The reaction mixture was then cooled to 80° C. and 60 ml of isopropyl alcohol was added. The reaction mixture was then slurried for 3 hours at ambient temperature filtered under vacuum, washed with 40 ml IPA and dried in vacuum oven overnight to obtain 11.48 g (89.3%) of levofloxacin.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([OH:12])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12.Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28]CC)=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:32][CH2:31][CH2:25][C:26]([OH:28])=[O:27])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12
Reactant: CCOC(=O)C(Br)CC
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 1.0 g (3.18 mmol) of (6aR,10aR)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol and 2.32 ml of ethyl bromobutyrate in 10 ml of dimethylsulfoxide was degassed, 1.39 g of potassium carbonate was added, the mixture was degassed and then stirred at room temperature under argon overnight. The reaction was diluted with 250 ml of water and extracted with ether. The extracts were concentrated under vacuum, and the residue was dissolved in benzene and chromatographed over silica gel. The fractions containing the intermediate ester were combined and concentrated under vacuum. The residue was mixed with 60 ml of methanol, 12 ml of water and 1.30 g of sodium carbonate, and the mixture was heated under reflux for 3 hrs. The methanol was evaporated under vacuum, and the residue was acidified with hydrochloric acid and extracted with dichloromethane. The extracts were dried and concentrated, and the residue was dissolved in hexane and chromatographed over silica gel. Elution with from 5 through 20% ethyl acetate in benzene gave fractions containing product which were combined and concentrated to give 1.12 g (88%) of (6aR-trans)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid as a colorless oil: ir (CHCl3) 1740 and 1715 cm-1 ; uv max (C2H5OH) 225 nm (infl) (ε13,000), 275 (2600), and 281 (2700); nmr (CDCl3) δ9.7 (br, CO2H), 6.28 and 6.22 [d, (H-2 and H-4) which includes m~6.25, H-10], 4.02 (t, OCH2C), 3.16 (m, H-10a), 2.63 (t, ArCH2C), 2.47 (t, COCH2C), 1.63 (s, 9-CH3), 1.37 and 1.04 (two s, 6,6-diCH3), and 0.86 (t, ω-CH3); mass mol wt 400; [α]C25° -122.6° (c 1.003, CHCl3).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.C(=O)(OC(C)(C)C)[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:10][CH2:9]2)[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc(Br)nc1N1CCNCC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)nc1N1CCN(C(=O)OC(C)(C)C)CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A mixture of 1-(6-bromo-3-methoxy-2-pyridyl)-1,4-diazepan-6-ol (0.9968 mmol; 301.2 mg), tert-butoxycarbonyl tert-butyl carbonate (1.495 mmol; 326.3 mg), and sodium bicarbonate (9.968 mmol; 837.4 mg) in dichloromethane (20 Ml) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified on silica eluted with 0 to 40% EtOAc in DCM to afford tert-butyl 4-(6-bromo-3-methoxy-2-pyridyl)-6-hydroxy-1,4-diazepane-1-carboxylate (262.5 mg, 65%).