Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:35][C:36](=[O:38])[CH3:37])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:35]/[C:36](=[O:38])[CH3:37])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmole) of 1-triphenylphosphoranylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.6 δ (1H); doublet 7.5 δ (2H); doublet 7.4 δ (2H); doublet 6.95 δ (1H); doublet 6.6 δ (1H); multiplet 4.5 δ (1H); doublet of doublets 4.0 δ (1H); multiplet 4.2 δ (3H); singlet 2.45 δ (3H); singlet 2.4 δ (3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[Br:13]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:13][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1Cc2cc(Br)ccc2O1
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-2-carboxylic acid (510 mg, 3.11 mmol) in glacial acetic acid (4 mL) is added bromine (497 mg, 3.11 mmol) dropwise. After 16 hours, the reaction is quenched with water (100 mL) and sodium bisulfite (1 g, 9.6 mmol) and extracted twice with EtOAc (100 mL). The extracts are concentrated in vacuo and dried under high vacuum to afford 5-bromo-2,3-dihydro-benzofuran-2-carboxylic acid (811 mg) as a solid. MS: 241 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 13.05 (1H, s); 7.4 (1H, s); 7.25 (1H, d); 6.8 (1H, m); 5.25 (1H, q), 3.55 (1H, dd); 3.25 (1H, m).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]([CH2:7][Br:8])=[CH2:6])=[CH2:4].[CH2:9](NC(OCC)=O)[NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClC(Cl)C.B(F)(F)F.CCOCC>[C:11]([N:10]1[CH2:4][C:3]([CH2:2][Br:1])=[C:5]([CH2:7][Br:8])[CH2:6][CH2:9]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)NCNC(=O)OCC
Reactant: C=C(CBr)C(=C)CBr
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)N1CCC(CBr)=C(CBr)C1
Yield: 90 %

Procedure:
To a solution of 2,3-bis (bromomethyl)-1,3-butadiene (4.8 g) and methylenediurethane (3.9 g) in dichloroethane (40 ml), borontrifluoride etherate (0.3 ml) was added. The reaction mixture was refluxed for 10 hours and washed with 10% sodium bicarbonate solution (30 ml×3). The organic phase was filtered though silicagel and evaporation of the solvent to give 1-carboethoxy-4,5-bis(bromomethyl)-1,2,3,6-tetrahydropyridine (6.14 g, yield 90%) which was cyclized with 40% methylamine (1.8 ml) and potassium carbonate (15 g) in acetonitrile (50 ml) for 2 hours at room temperature. The solid was filtered off and the filtrate was purified by silicagel column chromatography to give 3-carboethoxy-8-methyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene (2.57 g, yield 68%). This amine was refluxed in 20% hydrochloric acid (50 ml) and evaporation gave the title compound (1.35 g, yield 80%).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][S:12][C:7]=2[CH:6]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1.O>CN(C=O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=[C:11]2[C:10](=[O:13])[NH:9][C:8]3[CH:14]=[CH:15][C:5]([CH3:4])=[CH:6][C:7]=3[S:12]2)=[CH:17]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)SCC(=O)N2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Temperature: 140 °C

Procedure:
Sodium methoxide (0.28 g, 5.2 mmol) was added in one portion to a solution of 7-methyl-2H-1,4-benzothiazin-3(4H)-one (0.72 g, 4.0 mmol) and indole-3-carboxaldehyde (0.88 g, 6.0 mmol) in dry DMF (4 mL). The mixture was heated for 48 h at 140° C., allowed to cool, then poured into water (60 ml). The precipitate was collected by filtration and washed with water. The precipitate was then refluxed with toluene (100 ml) and filtered hot to give a yellow solid which was purified by silica gel chromatography using a gradient of (100:1) to (100:20) toluene:ethanol as the mobile phase.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[O:19][CH3:20].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCCC(CC(=O)OCC)Cc1ccc(F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(CC(=O)O)Cc1ccc(F)c(OC)c1
Yield: 99.6 %

Procedure:
Ethyl ester (131) (2.14 g, 7.58 mmol) was saponified with 1 N NaOH in THF and EtOH to give 1.92 g (˜100%) of the title compound (132) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J=7.0 Hz, 3H), 1.25-1.45 (m, 4H), 2.05-2.20 (m, 1H), 2.20-2.35 (m, 2H), 2.45-2.55 (m, 1H), 2.60-2.70 (m, 1H), 3.87 (s, 3H), 6.64-6.70 (m, 1H), 6.76 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 6.96 (dd, J1=11.3 Hz, J2=8.2 Hz, 1H). LCMS (ESI): m/z 253 (M−H)−.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:9]1(=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCCc2ccncc21
Temperature: 0 °C

Procedure:
2-(4-methoxy-benzyl)-3,4-dihydro-2H-[2,7]naphtyridine-1-on (1.63 g, 6.075 mmol) was suspended in 30 mL of anhydrous toluene, added with p-toluene sulfonic acid monohydrate (4.62 g, 24.30 mmol) and heated to reflux for about 6 hours under the nitrogen atmosphere. The mixture, while being stirred at 0° C., neutralized by adding a saturated solution of sodium carbonate and extracted seven times with 150 mL of 15% MeOH/MC. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. A silica gel column chromatography (7% MeOH/MC) was performed on the resulting residue an dobtained 550 mg (61%) of 3,4-dihydro-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]1([NH:65][CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:63][CH2:62]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:65]([CH2:66][CH2:67][C:68]#[N:69])[CH:61]2[CH2:64][CH2:63][CH2:62]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: N#CCCNC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 3-(cyclobutylamino)propionitrile (0.038 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [F:1][C:2]1C=CC=CC=1[C@]12COC[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1.O>CN(C)C=O>[F:1][CH2:2][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1
Reactant: COC(=O)c1cnc(O)cn1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)COC[C@H]2CS1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCF)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in N,N-dimethylformamide (2.0 mL). The reaction solution was stirred at 70° C. for five hours and 30 minutes and then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:31][NH2:32]>C(O)C.C(OCC)(=O)C>[CH:19]1([NH:18][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:8][N:7]4[C:2]([NH:31][NH2:32])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(NN)cccc23)nc(NC2CCCC2)n1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) in ethanol (1 mL) was added hydrazine (500 uL, 15.9 mmol). The reaction mixture was heated in a sealed tube at 90° C. for 72 hours. The mixture was cooled and diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (38:2 dichloromethane-methanol) provided N-cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-α]pyridin-3-yl]-6-methyl-2-pyrimidinamine (45 mg, 46%) as a yellow solid. Rf 0.43 (38:2 CH2Cl2-MeOH); 1H NMR (CDCl3) δ 7.78 (1H), 7.62 (2H), 7.35 (1H), 7.20 (1H), 7.12 (2H), 6.45 (1H), 6.24 (1H), 5.03 (1H), 4.35 (1H), 3.85 (2H), 2.18 (3H), 2.02 (2H), 1.62 (6H); MS m/z 418 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:35][OH:36]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:35][OH:36])=[NH:28])=[CH:25][CH:26]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
4-Chloro-N-(4-cyano-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (2.09 g, 5.00 mmol), sodium bicarbonate (0.52 g, 6.15 mmol) and hydroxylamine hydrochloride (0.43 g, 6.15 mmol) in a mixture of 20 ml ethanol and 4 ml water were refluxed for 11 hours. The solvents were removed by distillation and the residue was recrystalized from water. The solid was then suspended in dichloromethane, refluxed, cooled to room temperature and filtered to yield 1.74 g (77%) 4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine as white solid, MS: m/e (%)=451.0 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:42])=[O:41]
Reactant: COc1cc(C(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
30.0 g (63.8 mmole) of 2-[(2 R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 500 ml of methylene chloride. 11.5 ml (83.0 mmole) of triethylamine and 5.93 ml (76.6 mmole) of methanesulfonyl chloride were then added, in that order, to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was then diluted with methylene chloride and washed with 1 N aqueous hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 1:9 by volume as the eluent, to give 34.8 g of the title compound.
Reaction SMILES: [H][H].Br[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][S:12]([C:15]2[N:19]=[C:18]([NH:20]C=O)[NH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([Cl:23])[C:5]=1[CH3:24]>C(O)C>[Cl:23][C:6]1[C:5]([CH3:24])=[CH:4][CH:9]=[C:8]([Cl:10])[C:7]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]([NH2:20])[NH:17][N:16]=1)(=[O:14])=[O:13]
Reactant: Cc1c(Br)cc(Cl)c(NS(=O)(=O)c2n[nH]c(NC=O)n2)c1Cl
Reactant: [H][H]
Solvent: CCO
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl

Procedure:
A 3-necked flask equipped with a thermometer, reflux condenser with a nitrogen outlet, a sparge tube to introduce hydrogen and a spinbar was charged with the product of Example 11 (2 g, 4.66 mmol) and 100 mL of 95% ethanol. The mixture was stirred rapidly and purged with nitrogen and 150 mg of 10% Pd/C was added. Hydrogen gas was bubbled through the mixture while heating to reflux. After three hr of reflux the reaction was essentially complete. The mixture was purged with nitrogen and filtered. The filtrate was concentrated to yield the title compound as an off white solid, 1.5 g (98%) m.p. 198°-200° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH:19]=[C:20]=[CH2:21]>>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:6][CH:5]([CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:10])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH:19]=[C:20]=[CH2:21]
Reactant: COC(=O)C(N)C(C)C
Reactant: C=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.6 %

Procedure:
To a solution of DL-valine methyl ester hydrochloride (527 mg, 3.15 mmol) was added triethylamine (579 mg, 5.72 mmol) followed by product from Example 5 (700 mg, 2.86 mmol) and the resulting mixture was stirred for 10 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 850 mg (87%) of the product as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC.[Cl-].[NH4+]>CCCCCC.CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[O:17])=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(CCOC2CCCCO2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 11.3 g of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene and 100 ml of tetrahydrofuran was cooled to −78° C., to which 25.9 ml of 1.56 M solution of n-butyl lithium in n-hexane was added dropwise over 15 minutes. After stirring at −78° C. for 1 hour, 4.2 ml of N,N-dimethylformamide was added dropwise at the same temperature over 15 minutes. After further stirring at −78° C. for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added, and the stirring was further continued until the reaction mixture came to room temperature. The reaction mixture was extracted twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined, washed three times with saturated aqueous ammonium chloride solution, and washed with saturated aqueous sodium chloride solution. The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. This residue was subjected to silica gel chromatography, which afforded 7.20 g (yield, 78%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-benzaldehyde, nD24.5 1.5311.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[NH4+].O.C.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Ammonium (Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33–35° C. This aqueous solution was treated with activated charcoal and EDTA at 35° C. for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml). This aqueous acetone solution was cooled to −30° C. and a (10%) solution of aqueous sulphuric acid was added rapidly, stirred for 30 minutes and warmed to 0–2° C. The product thus obtained was filtered at 0–2° C., washed with cold-water (100 ml) and dried at 40–45° C. under vacuum for 5–6 hours to get (Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 89.0%, water content 4–5%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reaction time: 0.33 h

Procedure:
To a solution of 16.3 g. of isatoic anhydride in 200 ml. of dimethylacetamide at room temperature is added sodium hydride obtained from 5.0 g. of 57% solution in mineral oil. The resulting mixture is stirred for 20 minutes and 16 g. of p-fluorobenzyl chloride is added followed by stirring at room temperature for about 15 hours. The resulting mixture is concentrated in vacuo to about one half its volume, a mixture of ice and water added and the resulting precipitate filtered off, washed with water, dried under suction and washed with pentane. The solid material is then dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and about twice the volume of diethyl ether added to crystallize N-(p-fluorobenzyl)isatoic anhydride, m.p. 142°-145°C.
Reaction SMILES: CC[O:3][C:4](=[O:11])[C@@H:5]([CH2:7][C:8](O)=[O:9])[NH2:6].Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[CH2:7]([C:8]([NH:13][OH:14])=[O:9])[CH:5]([NH2:6])[C:4]([OH:3])=[O:11]
Reactant: CCOC(=O)[C@H](N)CC(=O)O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(CC(=O)NO)C(=O)O
Reaction time: 48 h
Yield: 50 %

Procedure:
0.1 mole of D-aspartic acid β-ethyl ester is dissolved in 200 ml of methanol, 0.2 mole of hydroxylamine hydrochloride is then added and the mixture is stirred until complete dissolution occurs. 0.4 mole of triethylamine is added and stirring is continued at room temperature for about 48 hr. The precipitate formed is collected on a filter. This crude product is recrystallized by dissolution in water, then diluted in absolute ethanol. This solution is kept at +4° C. for 12 hr. The crystals are filtered, washed with absolute ethanol and air-dried. This reaction yields 50 to 70% of D-Aspartic acid β-Hydroxamate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])(=[O:25])=[O:26]
Reactant: OCC1CCCCN1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Piperidin-2-yl-methanol (17.39 mmol, 1 eq) was dissolved in methylene chloride (20 ml) and triethylamine (43.47 mmol, 2.5 eq) at 0° C. and a solution of 2-chloro-6-methyl-benzenesulfonyl chloride (17.39 mmol, 1 eq) in methylene chloride (65 ml) was added dropwise. The reaction solution was stirred at room temperature for 90 min. 0.5 M HCl (75 ml) was then added and the mixture was stirred for a further 15 min. The organic phase was washed with water (10 ml), dried over sodium sulfate and concentrated to dryness under reduced pressure. Yield: 90%