Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=O.C(#N)C=C.CCCCCC.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>O1CCOCC1>[O:11]=[C:10]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:4][CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C=CC#N
Solvent: CCCCCC
Product: CCOC(=O)CCC1CCCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Namely, to a solution of 50 ml (0.35 mol) of ethyl cyclopentanone-2-carboxylate in 130 ml of dioxane was added 3.8 ml of Triton B. Then, to the solution was added 27.1 ml (0.242 mol) of acrylonitrile in 50 ml of dioxane. The solution was stirred at room temperature for 12 hours, and extracted with ether after 100 ml of 10% hydrochloric acid was added thereto. An organic layer was dried over anhydrous magnesium silfate. After removinq the solvent, 300 ml of conc. hydrochloric acid was added to the residue and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ether and 5% aqueous solution of sodium hydroxide was added to the ether layer and the mixture was stirred. An aqueous layer was made acidic with addition of 10% hydrochloric acid, and then the mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, the residue was dissolved in 150 ml of ethanol and 10 ml of conc. sulfuric acid was added thereto. The mixture was heated under reflux for 14 hours, and then ethanol was removed therefrom after cooling, and ethyl acetate was added thereto. The mixture was washed with 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 45 g (yield 70%) of ethyl 2-oxocyclopentanepropionate from hexane-ethyl acetate (4:1) eluate. In 150 ml of 80% ethanol was dissolved 5.5 g (30 mmol) of this compound. To the solution were added 4.17 g (60 mmol) of hydroxylamine hydrochloride and 2.7 g (33 mmol) of sodium acetate and the mixture was stirred at room temperature over night. After removing ethanol, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 5 g (yield 84% ) of ethyl 2-hydroxyiminocyclopentanepropionate from hexane-ethyl acetate (6:1) eluate. In 15 ml of anhydrous ethanol was dissolved 4.4 g of this compound and the solution was stirred at 50° C. for 4 hours under a hydrogen pressure of 120 atm. with use of Raney nickel (W2) as a catalyst. After removing Raney nickel by filtration and removing the solvent, the resulting residue was chromatographed over silica gel to obtain 0.95 g (yield 31%) of 2-azabicyclo[4.3.0]nonane-3-one from ethyl acetate eluate.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CC(C)(CN)CO
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)(CO)CNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (191 mg, 0.458 mmol) obtained in Example 54 and 3-amino-2,2-dimethylpropan-1-ol (515 mg, 5.00 mmol) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (199 mg, 0.412 mmol, 90%) as an amorphous substance.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]2=[O:23])[CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A suspension of 4-methoxypiperidine (286) (4.1 g, 35.3 mmol), N-(3-bromopropyl)phthalimide (9.0 g, 33.6 mmol) and K2CO3 (7.0 g, 50.4 mmol) in DMF (80 mL) was stirred at 50° C. for 16 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (150 mL) and EtOAc (150 mL). The organic fraction was washed with water (2×50 mL) and brine (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give phthalimide 305 (6.0 g, 59%) as a white solid: 1H NMR δ 7.81-7.86 (m, 2H, Harom), 7.67-7.73 (m, 2H, Harom), 3.75-3.79 (t, J=7.0 Hz, 2H, CH2N), 3.28 (s, 3H, OCH3), 3.09-3.17 (m, 1H, CHO), 2.63-2.70 (m, 2H, CH2N), 2.39 (t, J=7.0 Hz, 2H, CH2N), 2.01-2.08 (m, 2H, CH2N), 1.85 (p, J=7.0 Hz, 2H, CH2), 1.74-1.81 (m, 2H, CH2), 1.37-1.46 (m, 2H, CH2). Anal. calcd for C17H22N2O3: C, 67.5; H, 7.3; N, 9.3. Found: C, 67.3; H, 7.4; N, 9.3%.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][CH:8](Cl)[CH2:9]Cl>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:7][CH:8]([S:2][CH2:3][CH2:4][OH:5])[CH2:9][S:2][CH2:3][CH2:4][OH:5]
Reactant: OCCS
Reactant: ClCC(Cl)CCl
Agent: [Na]
Solvent: CCO
Product: OCCSCC(CSCCO)SCCO

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 14.7 parts of 1,2,3-trichloropropane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,2,3-tris(2-hydroxyethylthio)propane. This compound was added to 80 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,2,3-tris(2-chloroethylthio)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit 1,2,3-tris(2-chloroethylsulfonyl)propane. The deposited compound was recovered by filtration and dissolved in 100 parts of dimethyl sulfoxide, and the resulting solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and then the dimethyl sulfoxide was removed by distillation to deposit solids. The deposited solids were recrystallized from ethanol to obtain 1,2,3-tris(vinylsulfonyl)propane.
Reaction SMILES: Cl[CH:2]([CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)[CH2:3][OH:4].[OH-].[K+]>CCOCC>[CH3:10][C:7]1([CH3:11])[O:6][CH:5]([CH:2]2[O:4][CH2:3]2)[CH2:9][O:8]1
Reactant: CC1(C)OCC(C(Cl)CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(C)OCC(C2CO2)O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
340 g of 2-chloro-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol is dissolved in 1.5 l of absolute ether. At 5° C., a total of 130 g of pulverized potassium hydroxide is added under intensive agitation within 30 minutes, while the temperature is maintained between 5° and 15° C. by cooling. The suspension is then heated at 40° C. for 2 hours under gentle refluxing. After heater and agitator have been turned off, the phases begin to separate. After allowing the mixture to stand overnight, it is vacuum-filtered over kieselguhr. The residue is extracted with ether. The combined ether extracts are concentrated over a 60 cm Vigreux column. The residue (260 g) is distilled under vacuum, during which step 180 g of a colorless liquid passes over; this liquid is fractionated, yielding 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide at 65° C./13 mm.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]CC=C)[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:18])[CH:2]=[CH2:3].Br>C(O)(=O)C>[CH2:1]([N:4]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][C:5]1=[O:18])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2ccc(=O)n(CC=C)c2n1
Agent: Br
Solvent: CC(=O)O
Product: C=CCn1c(=O)ccc2ccc(=O)[nH]c21
Temperature: 80 °C

Procedure:
A solution of 1-(2-propen-1-yl)-7-(2-propen-1-yloxy)-1,8-naphthyridin-2(1H)-one (440 mg, 1.8 mmol) in acetic acid (1 ml) was treated with 33% hydrogen bromide in acetic acid (1 ml) and heated for 1 hour at 50° C. and 10 hours at 80° C. The mixture was evaporated to dryness and taken to pH4 with saturated aqueous sodium bicarbonate (˜5 ml). The mixture was extracted with ethyl acetate, dried and evaporated. The residue was chromatographed eluting with 0-100% ethyl acetate in hexane affording the product as a yellow oil (123 mg, 34%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10](B(O)O)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38].Br[C:40]1[S:41][CH:42]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:44]=1.C(=O)([O-])O.[Na+]>C(OCCCC)(=O)C.O.C(Cl)Cl>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([C:40]3[S:41][CH:42]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:44]=3)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
(1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)boronic acid (Intermediate F) (1001 mg, 1.906 mmol), ethyl 2-bromothiazole-4-carboxylate (409 mg, 1.732 mmol), sodium hydrogen carbonate (291 mg, 3.46 mmol) and Pd-118 (113 mg, 0.173 mmol) were suspended in n-butyl acetate (12.3 ml) and heated to 80° C. Water (3.08 ml) was then added and the mixture heated at 80° C. for 21 hours. The mixture was then cooled to room temperature and diluted with water (100 ml) and DCM (100 ml). The mixture was extracted with DCM (3×100 ml) and the combined organic extracts were washed with water (50 ml) and brine (50 ml). Silica-TMT (30 g) was added and the mixture stirred at room temperature for 5 mins, then filtered. The residue was rinsed with DCM (20 ml) and the filtrates evaporated under vacuum. The resultant residue was rinsed with diethyl ether and filtered to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:13](O)(=O)CCCCCCCCCCCCCCCCC.C(NCCCC)CCC>O>[CH2:7]([C:8](=[CH2:13])[CH:9]=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: C=O
Solvent: CCCCNCCCC
Solvent: O
Product: C=C(C=O)Cc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 3762.3 %

Procedure:
A four-necked 500-ml flask equipped with a thermometer and condenser was charged with 134 g (1.0 mol) of 3-phenylpropionaldehyde, 85 g (1.05 mol) of a 37% aqueous formalin solution and 6 g (0.02 mol) of stearic acid, followed by the dropwise addition of 9 g (0.07 mol) of dibutylamine at room temperature under a nitrogen atmosphere over 10 minutes. After the temperature was increased to 90° C., stirring was conducted at the same temperature for 30 minutes. After cooling, 200 ml of water were added to the reaction mixture. The resulting mixture was then extracted with 200 ml of hexane, followed by washing with 200 ml of water. The organic layer was dried and concentrated, whereby 161 g of a crude product were obtained. The crude product was distilled (3.5 mmHg, 80° C.), whereby 110 g (yield: 75%) of 2-benzylacrylaldehyde were obtained.
Reaction SMILES: C[O-].[Na+].CO.[NH2:6][C:7]([NH2:9])=[S:8].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)C>[OH:15][C:14]1[CH:13]=[C:12]([C:11]([F:21])([F:20])[F:10])[N:9]=[C:7]([SH:8])[N:6]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(S)n1
Temperature: 22 °C

Procedure:
To a solution of 25% NaOMe/MeOH (23 ml, 0.10 mol) and ethanol (27 ml) are added thiourea (5.33 g, 0.70 mol) and ethyl 4,4,4-trifluoroacetoacetate (7.3 ml, 50 mmol), then the reaction is heated to reflux for 16 hrs. The mixture is cooled to 22° C., concentrated in vacuo, and the residue dissolved in water (50 ml), acidified with HCl (7 ml), and filtered. The solid is collected, washed with water, and dried: 6.58 g (32.5 mmol, 65%).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:8]2[C:13](=O)[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][NH2:36]>>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[C@H:13]([NH:36][CH2:35][C:34]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:33]=3[O:32][CH3:31])[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(OC)c(CN)c1
Reactant: O=C1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Product: COc1ccc(OC)c(CN[C@@H]2[C@@H]3CCN([C@H](CCc4ccccc4)C3)[C@@H]2C(c2ccccc2)c2ccccc2)c1

Procedure:
A compound of Example 4 were prepared from compound 7 and 2,5-dimethoxybenzylamine by the same procedure for Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH2:15][CH3:16])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=1.[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:2]2[C:7]([CH2:8][N:9]([C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[CH2:15][CH3:16])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=2)[CH:24]=1)[CH3:19]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(C)cnc1Cl)C(=O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarboxylic acid (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amide (0.120 g, 0.48 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.183 g, 0.57 mmol), and potassium carbonate (0.198 g, 1.43 mmol) were combined in DME and H2O. The mixture was purged with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol) was added, and the reaction was stirred at 80° C. for 2 hours. Once no starting material was seen by analytical tlc, the mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:3][CH2:2]1.S(C)C.[ClH:16]>C1COCC1>[ClH:16].[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][NH2:8])[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SC1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1ccccc1SC1CC1
Temperature: 25 °C
Yield: 79 %

Procedure:
To 1A (1.50 g, 7.25 mmol) in refluxing THF (72 mL) was added a 2M THF solution of BH3.SMe2 (10.8 mL, 21.7 mmol). After heating at reflux for 2 h, the reaction was cooled to rt and 6M HCl (4.32 mL) was slowly added. The reaction was heated to reflux for 30 min, then cooled to rt, concentrated and azeotroped (3×) with THF/MeOH on a rotary evaporator. The resulting residue was taken up in THF and filtered to provide 1B (1.40 g, 79%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.15 (m, 2H) 1.29 (m, 2H) 2.91 (m, 1H) 4.52 (s, 2H) 7.72 (m, J=7.69, 7.69 Hz, 2H) 7.80 (t, J=6.81 Hz, 1H) 8.04 (d, J=7.91 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO.O1CCCC1>[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
Conc.hydrochloric acid (0.9 g) was added at ambient temperature to a solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.4 g) in a mixture of methanol (16.8 ml) and tetrahydrofuran (4.8 ml) and the mixture was stirred for 3 hours at 30° C. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.72 g).
Reaction SMILES: [CH2:1]([N:3]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:4]([CH3:24])[CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[O:10][CH:11]([CH2:13][NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:12][C:8]=2[CH:7]=1)[CH3:2].O[N:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38].C(N=C=NCCCN(C)C)C>ClCCl>[O:38]=[C:33]1[CH2:34][CH2:35][C:36](=[O:37])[N:32]1[O:19][C:18](=[O:20])[CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH:11]1[O:10][C:9]2[CH:22]=[CH:23][C:6]([CH2:5][CH:4]([N:3]([CH2:1][CH3:2])[C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH3:24])=[CH:7][C:8]=2[O:12]1)=[O:21]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
To 150 mg (0.34 mmol) of 2K was added 15 mL of dichloromethane (distilled over CaH2) followed by 99 mg (0.86 mmol) of N-hydroxysuccinimide and 166 mg (0.86 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The reaction mixture was allowed to stir at room temperature under argon atmosphere for 18 hours. The reaction mixture was diluted with an additional 40 mL of dichloromethane and washed with 2×25 mL of water, 3×25 mL of saturated sodium bicarbonate, and 2×25 mL of water. The organic layer was dried (Na2SO4) and concentrated to dryness to give 154 mg (0.29 mmol, 84%) of 2L as a white solid (M+Na, 552).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.CS(O[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH3:19])(=O)=O.[CH3:20]N(C=O)C>>[N:1]([CH2:20][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH3:19])=[N+:2]=[N-:3]
Reactant: Cc1cc(C#N)ccc1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)ccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.0 g (0.015 mol) of sodium azide and 10 mL of water were added to a solution of 2.1 g (9.3 mmol) of 4-methanesulfonyloxy-3-methylbenzonitrile (from step (iii) above) in 20 mL of DMF. The reaction mixture was stirred for 1.5 h at room temperature, poured into 200 mL of water and extracted three times with ether. The combined organic phase was washed several times with water, dried (Na2SO4) and evaporated. Yield: 1.4 g (87%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][C:25]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=1[F:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: Nc1ccc(F)cc1F
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(F)c(F)c1C
Yield: 87.1 %

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and 2,4-difluoroaniline (0.5 g), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate (1.1 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC(Cl)(Cl)Cl.BrBr.C(O)C>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CNC(=S)Nc2ccccc2)CC1
Agent: BrBr
Solvent: CCO
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1

Procedure:
To a stirred mixture of 5.8 parts of N-[(1-acetyl-4-piperidinyl)methyl]-N'-phenylthiourea and 160 parts of tetrachloromethane were added 3.7 parts of bromine. The whole was stirred and refluxed for 15 minutes. After the additions of 16 parts of ethanol and 16 parts of acetonitrile, the reaction mixture was cooled. The precipitated product was filtered off, washed with acetonitrile and dried. The hydrobromide salt was dissolved in methanol and water. This solution was alkalized with ammonium hydroxide. The precipitated product was filtered off, washed with water and dried, yielding 2.7 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine; m.p. 138.1° C. (intermediate 29).