Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[F:18])=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:12]([F:18])[CH:13]=1
Reactant: Fc1cc(Cl)ccc1-c1cnc2ccc(Br)cn12
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: Fc1cc(Cl)ccc1-c1cnc2ccc(-c3ccnn3-c3ccc(Cl)cc3)cn12

Procedure:
The title compound, white solid (46 mg, 46%), MS (ISP) m/z=423.5 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-2-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate I) (0.1 g, 0.31 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.11 g, 0.37 mmol).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:14].[C:15](Cl)(=[O:17])[CH3:16]>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To 9H-carbazol-2-ol (915 mg, 5 mmol) in 10 mL DMF and 20 mL DCM was added TEA (1.0 g, 10 mmol), followed by acetyl chloride (589 mg, 7.5 mmol) at 0° C. The reaction mixture was then stirred at rt for 1 h and poured onto ice (50 g). The mixture was extracted with EtOAc (2×60 mL) and combined organic phase was dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 9H-carbazol-2-yl acetate (WZ02013) as an off-white solid (800 mg, 71%). MS (ESI) m/z 348 (M+H+).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:18][NH2:19]>C(O)C>[C:10]1([C:9]2[NH:19][N:18]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 67 %

Procedure:
To a solution of ethyl 2,4-dioxo-4-phenylbutanoate (16.0 g) in ethanol (150 mL) was added hydrazine monohydrate (4.0 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give the title compound as a pale-brown solid (yield 12.0 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
A solution of 6-methoxy-3,4-dihydro-1H-naphthalen-2-one (1) (5.64 g, 32 mmol) in methanol (60 mL) was treated with pyrrolidine (3.5 mL, 41.6 mmol) and the resultant mixture was stirred at ambient temperature for 1.5 h. The product precipitated from solution within minutes of the addition of pyrrolidine. The resultant suspension was cooled in an ice bath and the enamine product (2) was collected by filtration as a white solid (5.6 g, 76%). NMR (CDCl3):δ 1.86-1.94 (m, 4 H), 2.46 (t, 2H), 2.80 (t, 2 H), 3.19-3.25 (m, 4 H), 3.77 (s, 3 H), 5.10 (s, 1 H), 6.59-6.65 (m, 2 H) and 6.78 (d, 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH2:13])=[O:12])[CH2:8]1.[CH2:19]=[O:20]>>[OH:20][CH2:19][NH:13][C:11]([N:9]1[CH2:8][CH:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10]1)=[O:12]
Reactant: C=O
Reactant: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Product: O=C(NCO)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 65 °C
Reaction time: 60 h
Yield: 30.5 %

Procedure:
A mixture of 0.639 g (0.0024 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide and 6 ml of 37% formaldehyde solution were heated on a water bath at 65° C. for 1 hr, at which time dissolution was complete. The solution was stirred at room temperature for approximately 60 hr. The reaction mixture was divided into two 15 ml centrifuge tubes each extracted three times with ether. The combined extracts were dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue weighing about 1.5 g was dissolved in ether, washed 5 times with 3 ml of water each time. The ether layer was again dried over magnesium sulfate and evaporated to dryness. The residue was triturated with hexane and ether to give 0.213 g (30.5%) of white powder, m.p. 113°-115° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1>[I:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: ICCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ICCCCCCn1c2ccccc2c2ccccc21
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of carbazole (0.5 g, 2.99 mmoles) in THF (6 mL), NaH (0.25 g, 6 mmoles) was slowly added. The mixture was stirred for 1 hour giving a solution. The resulting solution was introduced under nitrogen in a dropping funnel and slowly added in 10 minutes to a solution of 1,6-diiodo hexane (3 ml, 18 mmoles) in THF (2 mL). The reaction mixture stirred for 2 hours at room temperature, it was quenched with water and ice and THF was evaporated under reduced pressure. The mixture was extracted with ethyl ether (3×5 mL) and the organic phases were collected and combined, dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by chromatography (from n-hexane to n-hexane:CH2Cl2 10:1). Yield: 83%. Rf=0.55 (cyclohexane/dichloromethane 3/1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([O:21]C)=O)=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:21])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1
Reactant: COC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (25 mg, 0.077 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (24 mg, 0.23 mmol) in THF (2 mL) at 0° C. was added LiHMDS (0.54 mL, 0.54 mmol, 1 M in THF). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1.5% MeOH in CH2Cl2) to afford 30 mg (99%) of the desired product.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]1)=O)C1C=CC=CC=1.[NH3:17]>>[OH:16][C@H:14]1[CH2:13][NH:12][C@H:11]([C:9]([NH2:17])=[O:8])[CH2:15]1
Reactant: N
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Product: NC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
A solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid benzyl ester (1 g) in 880 ammonia (5 ml) was stirred for 18 h then evaporated and triturated with Et2O to give the title compound as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 9.15 (s, br, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 5.56 (s, 1H), 4.40 (s, 1H), 4.27-4.16 (m, 1H), 3.27 (d, 1H), 3.02 (d, 1H), 2.33 -2.19 (m, 1H), 1.89-1.76 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Br:21])[CH:23]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cccc(Br)c1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Sodium hydride (246 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (15 mL). Compound A3 (1.5 g, 5.85 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 3-Bromobenzyl bromide (1.48 g, 5.91 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-(3-bromobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A6) (2.33 g, 93% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: C(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)(=[O:3])C.C(#N)C.ON1C(=O)CCC1=O.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
N-Acetyl-L-tyrosine (1.68 g, 7.53 mmol) was taken up in 94 mL of ethyl acetate/26 mL of acetonitrile and stirred at room temperature. N-Hydroxysuccinimide (NHS, 0.87 g, 7.56 mmol) was added and the resulting solution cooled to 0° C. under N2 (g) in an ice-water bath. To the cold, stirring solution was then added dicyclohexylcarbodiimide (DCC, 1.55 g, 7.52 mmol) predissolved in 3 mL of ethyl acetate. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight with continued stirring. The insoluble dicyclohexylurea (DCU) was removed by filtration and the resulting filtrate concentrated to a solid residue under reduced pressure. Trituration of this residue with warm ethyl acetate and subsequent storage at 4° C. then afforded a white solid. This was isolated by vacuum filtration, washed with cold ethyl acetate and dried in vacuo to yield the product in greater than theoretical yield (due to contamination with residual DCU). 1H-NMR (300 MHz, CDCl3): δ 2.00 (s, 3H); 2.87 (s, 4H); 3.22 (m, 2H); 4.05 (m, 1H); 5.80 (d, 1H, J=7.2 Hz); 6.96 (AB quartet, 4H, J=8.4 Hz).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 60 °C
Reaction time: 96 h
Yield: 71.1 %

Procedure:
1-Cyano-4-fluoronaphthalene (273 mg, 1.60 mmol), tert-butyl (piperidin-3-ylmethyl)carbamate (411 mg, 1.92 mmol) and DBU (25 μl, 0.16 mmol) were dissolved in pyridine (4 mL) and stirred at 60° C. for 4 days. The reaction was worked up in the same way as for 198RL60 followed by purification using silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane, giving the desired compound (416 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nccnc2c1
Yield: 77.5 %

Procedure:
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL×5). The extracts were concentrated under vacuum. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J=2.1, 8.7 Hz, 1H), 4.70 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH:13]=[CH:21][N:22]([CH3:24])[CH3:23])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)=O)c1C
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C)c(C(=O)C=CN(C)C)c1C
Temperature: 50 °C
Reaction time: 20 h

Procedure:
In a dry flask containing THF (15 mL) was added 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 9.3 mmol) then Bredereck's reagent (5 mL). The reaction was stirred at 50° C. for 20 hours. The resulting precipitate formed during the reaction was removed by filtration and washed with hexanes. The enaminone was recovered as a yellow solid (2.2 g), HPLC Rt=4.0 minutes; FIA, ES+=265.1
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[N:4]=1.[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([NH:28][NH2:29])=O)[CH3:23]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]1[N:4]2[C:5]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][CH2:9][C:3]2=[N:29][N:28]=1)[CH3:23]
Reactant: CCOC(OCC)C(=O)NN
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(OCC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 15.9 g of 2-(methylthio)-5-(o-fluorophenyl)-7-chloro-3H-1,4-benzodiazepine and 9.7 g of diethoxyacetic acid hydrazide in 100 ml of hexamethylphosphoric acid triamide is heated for 10 hours at 140°; processing is then carried out analogously to the procedure described in Example 1, and the residue recrystallised from ethyl acetate/petroleum ether to obtain 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal, M.P. 120°-121°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of rac-cis-Allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound. ESI-MS (m/z): 358, [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][S:12](=[O:17])(=[O:16])[NH:13][CH2:14][CH3:15])[C:8]([CH3:18])=[CH:7][C:6]=1[S:19]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[OH:30][C:31]1[CH2:32][C:33]([CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([NH:58]C(=O)[O-])=[CH:54][CH:53]=2)([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46]C(=O)[O-])=[CH:42][CH:41]=2)[O:34][C:35](=[O:37])[CH:36]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[C:6]([S:19][C:36]2[C:35](=[O:37])[O:34][C:33]([CH2:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=3)([CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([NH2:58])=[CH:56][CH:57]=3)[CH2:32][C:31]=2[OH:30])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[NH:13][CH2:14][CH3:15])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])Nc1ccc(CCC2(CCc3ccc(NC(=O)[O-])cc3)CC(O)=CC(=O)O2)cc1
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(N)cc3)(CCc3ccc(N)cc3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 0.218 g, 0.470 mmol), (1,1-dimethylethyl)[(3,6-dihydro-4-hydroxy-6-oxo-2H-pyran-2,2-diyl)bis[2,1-ethanediyl-(4,1-phenylene)]-biscarbamate (prepared in Example OO; 0.200 g, 0.380 mmol), K2CO3 (0.260 g, 1.88 mmol), and DMF (8 mL), as described in General Method 9. The reaction was stirred at room temperature for 3 hours and then worked up in the usual fashion. The residue was submitted to flash chromatography (100% EtOAc). The product form chromatography was taken up in EtOAc, triturated with hexane, filtered, and then taken up in CH2Cl2 (20 mL). Gaseous HCl was bubbled into this solution for 30 minutes. The solids that formed were filtered, washed with Et2O and dried under high vacuum to yield the title compound, m.p. 194° C. 1H NMR (DMSO-d6) δ 1.14 (t, 3 H), 1.49 (s, 9 H), 1.88 (s, 3 H), 2.09 (br m, 4 H), 2.70 (br m, 4 H), 3.12 (s, 2 H) 3.13 (m, 2 H), 6.79 (s, 1 H), 7.11 (s, 1 H), 7.27 (d, 4 H), 7.33 (d, 4 H), 8.40 (t, 1 H).
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[CH2:22]([O:21][C:19]([CH:18]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1)[CH3:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc(-n2cnc(O)n2)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C)cc2)n1
Yield: 28.7 %

Procedure:
The process was carried out as described in Example 8, starting with 1.1 g of sodium, 20 ml of methanol, 150 ml of dimethylsulfoxide, 8.5 g of 3-hydroxy-1-(4-methylphenyl)-1,2,4-1H-triazole and 8.7 g of ethyl 2-bromopropionate. A yield of 3.8 g of the desired product, m.p. 69°-71°, was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:25]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 7 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.50 (s, 1H), 7.34–7.19 (m, 6H), 6.96 (d, 1H, J=7.8 Hz), 6.72–6.67 (m, 1H), 3.42 (q, 2H, J=7.1 Hz), 3.31 (q, 3H, J=5.4 Hz), 2.49–2.35 (m, 5H), 2.08–1.95 (m, 2H), 1.82–1.74 (m, 2H), 1.71–1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H, J=7.8 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[O:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25]>CCOC(C)=O>[Cl:29][C:28]([Cl:31])([Cl:30])[CH2:27][O:26][C:24](=[O:25])[NH:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:9]([O:10][CH2:11][CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCO)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A solution of Intermediate 186a (1.0 g, 3.63 mmol) in EtOAc (20 mL) was treated with aqueous NaOH (1M, 6.53 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.529 mL, 3.85 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with a further 20 mL EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in DCM. The combined fractions were evaporated under reduced pressure and the product was triturated with DCM. The solid was filtered and washed with Diethyl ether to afford the title compound as a white solid (0.930 g, 58%). LCMS (Method 3): Rt 4.01 min, m/z 450 [M].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:24])=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.[CH3:26][O:27][NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]([Cl:24])=[C:5]([C:7](=[N:28][O:27][CH3:26])[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=CCS[C@H]23)c(Cl)s1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl

Procedure:
In a similar procedure to that of Example 2-1, 7β-[2-(2-amino-5-chloro-4-thiazolyl)glyoxylylamino]-3-cephem-4-carboxylic acid (276 mg) is treated with methoxyamine hydrochloride (58 mg) in methanol (5 ml) in the presence of sodium carbonate (74 mg) to afford 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid. Similarly prepared are compounds of Table 1.