Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O.Cl>[O:12]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: c1ccsc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(O)CCC(=O)c1cccs1
Temperature: 25 °C

Procedure:
Thiophene (5.0 gm, 0.059 moles) and succinic anhydride (7.13 gm, 0.0713 moles) were taken up in dichloroethane (50 ml). Aluminium chloride (17.43 gm, 0.131 moles) was added at room temperature and the resulting mixture heated under reflux for 1 hr with stirring. The reaction mixture was cooled to room temperature, diluted with 30 ml of 1:1 mixture of water and Conc. hydrochloric acid. After stirring for 10 min the separated solid was filtered under suction, washed with water and dilute hydrochloric acid (50 ml). The solid was dried at room temp to give 9.8 gm (89%0 of the title compound, mp 103-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](O)(=[O:18])[C:16]#[CH:17]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[CH:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chlorobiphenyl-4-ylamine and propynoic acid. Yield: 0.4 g (29.2% of theory); C15H10ClNO (M=255.70); calc.: molecular ion peak (M+H)+: 256/258; found: molecular ion peak (M+H)+: 256/258; Rf value: 0.35 (silica gel, dichloromethane/ethanol 20:1).
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.Cl>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (26.0 g, 0.1 mol) and 3-amino-4-cyanopyrazole (10.8 g, 0.1 mol) were dissolved in the mixture of water (350 cm3) and methanol (200 cm3). Concentrated (37%) hydrochloric acid (12.5 cm3, 0.12 mol) was then added and the mixture was stirred at room temperature for about 2 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product formed was collected, washed with water and dried at about 60° C. to yield zaleplon (29.8 g, 97.7%) in 99.08% purity as determined by HPLC.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)CO.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCCCCCCCC>[Cu]I.C(OCC)(=O)C>[CH3:18][C:16]1[CH:17]=[C:12]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[C:14]([CH3:19])[CH:15]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCCCC
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
CuI (0.05 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to a screw-capped test tube with a Teflon-lined septum. The tube was evacuated and backfilled with argon (3 cycles). Solvent (1.0 mL), ethylene glycol (111 μL, 2.0 mmol; for entries 2, 4, 6, 8, 10), 5-iodo-m-xylene (144 μL, 1.0 mmol) and thiophenol (103 μL, 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80° C. and stirred for 20 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added. The aliquot was analyzed by GC or GC-MS. See FIG. 9.
Reaction SMILES: C(O)CCCCCCCCCCCCCCCCC.[C:20]1([C@@H:26]([OH:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@H:26]([OH:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCCO
Product: C[C@@H](O)c1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To the distillation residue were added 270 g of stearyl alcohol and 10 g of Lipase PL. The mixture was subjected to ultrasonication in the same manner as described above to regulate the particle size of the lipase in such a manner that 95% or more of the particles had a particle size of 20 to 50 μm. The water content of the reaction system was 0.04% by weight. The mixture was stirred at 90° C. and 350 rpm under reduced pressure of 3 mmHg for 12 hours to carry out interesterification while recovering the distillate to obtain highly pure (R)-(+)-1-phenylethanol (yield: 96%; chemical purity: 100%; optical purity: 100% ee).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:7]=1.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][N:13]=[C:8]2[CH2:9][CH3:10]
Reactant: CCC(=O)c1cc(Br)ccc1F
Reactant: NN
Product: CCc1n[nH]c2ccc(Br)cc12
Temperature: 72.5 °C
Yield: 40 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)propan-1-one (10 g, 43 mmol), anhydrous hydrazine (53 mL) was added and heated at reflux (70-75° C.) for 2 days. Excess hydrazine was distilled out under vacuum from the reaction mixture. To this was added xylene (60 mL) and the mixture heated to 145-150° C. for 3 days. Xylene was concentrated completely under vacuum to give a crude product, which was purified by column chromatography using 8% ethyl acetate/pet-ether as eluents to afford 5-bromo-3-ethyl-1H-indazole (4 g, 40%) as a solid. 1H NMR (CDCl3): δ 9.6-10.0 (br, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 3.0 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@H]1OC[C@H](O)CC1)(C1C=CC=CC=1)C1C=CC=CC=1>CCCCC>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Agent: O[C@@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CCCCC
Product: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 68.6 %

Procedure:
(1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane (0.05 g, 0.19 mmol) was treated with LiAlH4 (0.036 g, 0.94 mmol) (Procedure I) in dry pentane to yield trans-(3S, 6R)-6-benzhydryl-tetrahydro-pyran-3-ol 33b 0.035 g (70%, [α]D=(+)61.7, c=1, MeOH).
Reaction SMILES: [S-2].[Na+].[Na+].[Se].[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([O:16]C)=[CH:14][CH:15]=1)[CH3:7].C(OC(=O)C)C>CN1CCCC1=O.O>[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH3:7]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [Na+]
Agent: [S-2]
Agent: [Se]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 145 °C
Yield: 60.2 %

Procedure:
A mixture of 1.90 g of anhydrous sodium sulfide, 2.0 g of selenium and 6 mL of 1-methylpyrrolidone was heated to 145° C. under nitrogen, and then 3.5 g of venlafaxine dissolved in 10 mL of 1-methylpyrrolidone was added. The mixture was stirred and heated at 145° C. under nitrogen. Reaction mixture was heated at 145° C. for 16 hours, then it was cooled and mixed with 70 mL of ethylacetate and 50 mL of water. The mixture was placed into a refrigerator and crystals were filtered. After being recrystallized from 45 mL of ethanol, 2.0 g of desvenlafaxine was obtained with the yield 60%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].OC1C=C2C(NC=C2CCN)=CC=1.C1C([C@@H](O)CN)=CC(O)=C(O)C=1>>[CH3:3][N:2]([CH3:1])[CH2:4][CH:5]([C:14]1([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: NCCc1c[nH]c2ccc(O)cc12
Agent: NC[C@H](O)c1ccc(O)c(O)c1
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1

Procedure:
It is reported that venlafaxine of formula (II), 1-[2-dimethylamino-1-(4-methoxylphenyl)ethyl]cyclohexanol, is a reuptake inhibitor of 5-hydroxytryptamine (5-HT) and norepinephrine (NA), and is widely used for inhibiting reuptake of 5-hydroxytryptamine (5-HT) and norepinephrine (NA) and treating or adjuvantly treating central nervous system diseases such as depression. Venlafaxine is metabolized in liver to form a strongly active metabolite of formula (III), 1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, a weakly active metabolite of formula (IV), 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol, and a metabolite of formula (V), 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, in which the metabolite (III) and venlafaxine have the same therapeutic effects (see U.S. Pat. No. 4535186A, US20040176468A1, US20040147601A1, US20030191347A1). Moreover, the direct uptake of the metabolite (III) for treating central nervous system diseases, especially, depression, has the advantages of using a single active compound, facilitates the adjustment of dosage and therapeutic effects, alleviates side-effects, and reduces the risk of interaction with other drugs (see U.S. Pat. No. 6673838B2). However, because of the presence of more hydroxyl groups, the metabolite (III) has increased hydrophilicity, thus decreasing absorption rate via oral or transdermal routes of administration and possibly increasing pre-system side effects of unabsorbed drugs. In order to overcome the above defects of the metabolite (III), a series of derivatives represented by formula (VI) were synthesized. These compounds of formula (VI), which are prodrugs of the metabolite (III), were shown to have metabolized in vivo to produce the metabolite (III), thereby exhibiting therapeutic effects (see Chinese Patent No. CN1955159A, CN1706813A). Chinese Patent No. CN1955159A discloses a compound of formula (I), 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, and a method for preparing the same. The compound of formula (I), as described in CN1955159A, is a white crystalline solid with a melting point of 203.2° C.-206.5° C.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10 but in the presence of (S)-phenylethylamine (2.29 mmol) instead of NaOH as a base, 5 g (11.48 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in 37 ml methanol/dichloromethane (3:2) in the presence of 0.93 mg of [Ru(OAc)2((S)-TMBTP)] (S/C molar ratio 10'000) under 30 bar of hydrogen for 4 h at 40°, then 2h at 60° h to reach 99.9% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 91.8% ee with 99.4% purity (HPLC area). In analogy to example 13, the experiments described in table 1 have been carried out with different substrate-to-catalyst ratios.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH3:5][CH:6]([CH2:9][CH2:10][CH3:11])[CH:7]=O.[OH-].[Na+].O>>[CH3:3][C:2](=[CH:5][CH:6]([CH3:7])[CH2:9][CH2:10][CH3:11])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CCCC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C)C=C(C)C=O

Procedure:
In a similar manner as Example 1, this example is a cross-aldol condensation reaction (Aldol II) of propanal and 2-methyl-pentanal in a sodium hydroxide/water medium to form the 2,4-dimethyl-2-heptenal product that shows the productivity and selectivity results in a conventional system. The 2-methyl-pentanal starting material (175 mmol, 17.5 g) and nonane (internal standard) (8.7 mmol, 1.12 g) were added to a water solution of sodium hydroxide (1 M) (8.8 mmol, 0.352 g). The resulting mixture was heated to 90° C. and treated with propanal starting material (44.8 mmol, 2.6 g). After the addition, the reaction mixture was refluxed for an additional 3 hours at 90° C. The resulting solution turned a light yellow color and was further investigated using GC and GC/MS techniques. Catalyst evaluation results are presented in the bottom row of Table 2.
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)[CH2:2][CH2:3][OH:4]>CC(C)=O>[OH:4][CH2:3][CH2:2][N:1]1[CH2:6][CH2:5][N:1]([CH2:2][CH2:3][OH:4])[CH2:6][CH2:5]1
Reactant: OCCNCCO
Solvent: CC(C)=O
Product: OCCN1CCN(CCO)CC1
Temperature: 210 °C
Yield: 40.2 %

Procedure:
N,N'-tetra-(2-hydroxyethyl)oxamide (2.64 g, 0.01 mol) and diethanolamine (2.10 g, 0.02 mol) are charged in a reaction flask equipped as described in Example 1 and the reaction mixture is heated to 210° C. for 20 hours. Acetone (15 ml) is then added and the precipitate is recovered by filtration and recrystallized from acetone. N,N'-bis-(2-hydroxyethyl)-piperazine (0.7 g) is thus obtained with a yield on N,N'-tetra(2-hydroxyethyl)oxamide of 40.2%, calculated on the starting diethanolamine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1

Procedure:
A vial (20 ml) was charged with Raltegravir free hydroxy (0.5 g) and acetonitrile (7.5 mL) to obtain a solution. KOH 85% (75.6 mg) was added to the solution at room temperature. The solution was then sonicated for 40 minutes. The product was isolated by vacuum filtration to provide Raltegravir potassium Form X.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C([O-])(O)=O.[Na+]>ClCCl>[CH3:15][S:16]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCC1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirring solution of (3-oxolanyl)methan-1-ol (25 g, 245 mmol) and triethylamine (34.37 mL, 245 mmol) in dry dichloromethane (250 mL) at 0° C. under N2 atmosphere was added dropwise methanesulfonyl chloride (18.94 mL, 245 mmol). The reaction mixture was stirred overnight after warming to room temperature, then a saturated solution of NaHCO3 (100 mL) was added and the mixture stirred for another 30 min. The biphasic mixture was separated and the organic layer was discarded. The aqueous layer was extracted with dichloromethane (3×25 mL) and the combined dichloromethane extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 42.16 g of (3-oxolanyl)methyl methanesulfonate (99%) as a light brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][N:13]3C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8].O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(OCC)(=O)C>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:15][C@@H:14]3[C@@H:11]([CH2:12][NH:13]3)[CH2:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cnc(Cl)c(Cl)c3)C[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Example 3A (23.2 g) was dissolved in ethyl acetate (250 mL) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol) was added. The solution was warmed to reflux and stirred for 90 minutes, cooled to room temperature, and allowed to stand for 12 hours to complete precipitation. The solid was isolated by filtration and dried to provide the title compound. mp 174–178° C.; [α]D20=−20.0° (MeOH, 0.105); 1H NMR (MeOH-d4, 300 MHz) δ 2.36 (s, 3H), 3.06 (dd, J=10.5, 6.1 Hz, 1H), 3.17 (dd, J=12.2, 4.8 Hz, 1H), 3.50 (m, 1H), 3.72 (dd, J=11.2, 5.4 Hz, 1H), 3.90 (d, J=10.5 Hz, 1H), 4.10 (d, J=12.6 Hz, 1H), 4.25 (dd, J=11.2, 9.8 Hz, 1H), 5.05 (dd, J=6.7, 5.1 Hz, 1H) 7.22 (d, J=8.1 Hz, 2H), 7.52 (d, J=2.7 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.95 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 244/246/248 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13]C(CCC[C@@H](N)C(O)=O)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3].O=O>>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: O=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1

Procedure:
combining in a reaction vessel cephalosporin C, catalase, D-amino acid oxidase obtained from T. variabilis strain ATCC 20931, externally supplied oxygen, and deacylase obtained from Acinetobacter sp. strain ATCC 53891 under conditions sufficient to produce 7-amino cephalosporanic acid; and
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]#[N:20].C(Cl)Cl.CCOC(C)=O>C(#N)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:19]#[N:20])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: N#CCCl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCOa (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149°-151° C. ANALYSIS: Calculated for C14H15FN4 : 65.10%C 5.85%H 21.69%N Found: 64.84%C 5.90%H 21.74%N
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
9.15 g of Z-Pro-OtBu are hydrogenated in 100 ml of methanol and 1.0 g of Pd on charcoal (10 %) at room temperature. The hydrogen uptake has ended after 30 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30°C. The resulting oil is homogeneous in a thin layer chromatogram on silica gel. Rf = 0.55 in the system chloroform-methanol (1:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
A solution of 6 (1.85 g, 5.7 mmol) in a mixture of AcOH—H2O—H2SO4 (8:6:1 v/v, 75 mL) was heated at reflux for 2 h. The reaction mixture was poured into ice water and adjusted to pH 4 with 1M NaOH solution. A precipitate formed and was collected by filtration, washed successively with water and ethanol and then dried to give 7 (1.3 g, 77%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[Cl-].[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:35]>CC(C)=O.O1CCCC1>[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:23])=[CH:40][CH:39]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (1.0 g, 2.6 mmol) in acetone (130 mL) and tetrahydrofuran (30 mL) was treated with triethylamine (0.5 g, 0.68 mL, 1.9 equiv.) and stirred at room temperature overnight. A solution of cianuric chloride (596 mg, 3.2 mmol, 1.24 equiv.) in acetone (20 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 4 hours, 4-amino-benzoic acid ethyl ester (775 mg, 4.7 mmol, 1.8 equiv.) was then added. The reaction mixture was stirred at room temperature overnight, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-{[4-(5-chloro-2-methoxy-benzene-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester as a white solid, 0.91 g (66%). δH (300 MHz; CDCl3) 8.10 (1H, d), 8.03-8.07 (3H, m), 7.92 (1H, bs), 7.73 (2H, d), 7.70 (1H, d), 7.67 (1H, d), 7.53 (1H, d), 7.50 (1H, d), 4.37 (2H, q), 4.03 (2H, m), 3.88 (2H, m), 3.56 (3H, s), 1.40 (3H, t).