Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1>[I-].[K+].C(O)(C)C>[CH3:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:33][CH:32]=1)([CH3:35])[CH3:37]
Reactant: CC(C)(C)c1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, α,α-bis (p-fluorophenyl)-4-piperidinemethanol and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give with white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126°-127° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:38](=[O:39])[CH2:37][CH2:36][N:35]([CH2:41][CH2:42][OH:43])[C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.000175 mol), N,N-diisopropylethylamine (0.034 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous dichldromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.3 min. MS: MH+ 574.
Reaction SMILES: S(Br)(C)(=O)=O.[Li]C(C)(C)C.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31](N(OC)C)=[O:32])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.C(Cl)Cl>[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31]([C:22]1[C:13]([O:12][CH3:11])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:32])([CH3:26])([CH3:24])[CH3:25]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2n1
Agent: CS(=O)(=O)Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of mesyl bromide (17.23 mmol) in 10 mL of THF cooled to −78° C. was added a 1.7 M THF solution of tBuLi (34.5 mmol) dropwise. The mixture was left stirring at −78° C. for 1 h. The mixture was then allowed to reach 0° C. and a solution of 2-methoxyquinoline (12.9 mmol) in THF (40 mL) was added dropwise over 10 min. The resulting mixture was aged at 0° C. for 1 h, cooled to −78° C. and added dropwise with a solution of tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (4.31 mmol) in 20 mL of THF. The mixture was stirred at −78° C. for 30 min then left at room temperature over night. The mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (Na2SO4), concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 5% to 40% EtOAc). Pooled fractions were concentrated under vacuum to title product (1.01 g). MS (ES) C17H20N2O4 requires: 316.35, found: 317.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([N:21]2[C:29](=[O:30])[C:28]3[C@@H:27]4[C:31]([CH3:33])([CH3:32])[C@@:24]([CH3:34])([CH2:25][CH2:26]4)[C:23]=3[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O.CO>[CH2:1]([N:22]1[C:23]2[C@@:24]3([CH3:34])[C:31]([CH3:33])([CH3:32])[C@H:27]([CH2:26][CH2:25]3)[C:28]=2[C:29](=[O:30])[N:21]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1Cc1ccccc1
Temperature: 25 °C
Yield: 4 %

Procedure:
A mixture of benzyl bromide (1.54 mL, 13.0 mmol), potassium carbonate (3.58 g, 25.9 mmol), and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.74 g, 6.5 mmol) in acetone (20 mL) and methanol (3 mL) was heated at reflux overnight, then a further portion of benzyl bromide (0.75 mL, 6.3 mmol) was added and the reaction mixture was allowed to stir at room temperature over the weekend. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was evaporated and the residue was chromatographed (0-50% ethyl acetate/hexanes), and recrystallized from ethyl acetate/hexanes to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (94 mg, 3%) as a white solid. APCI-MS (M+H) 359.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH2:20][OH:21])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
N-(tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 mL) and the solution was cooled to −5° C. N-Methylmorpholine (10.32 mL) was added followed by a slow addition of isobutyl chloroformate (12.66 mL) such that the reaction temperature was kept below −10° C. The mixture was aged for 0.5 hour. The solids were quickly filtered and washed with dimethoxyethane (90 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C. Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The suspension was filtered, the solid washed with water (400 mL) and dried to yield benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:2]([NH:3][N:4]1[CH2:8][C:9]([CH3:10])=[N:14][NH:13][C:5]1=[O:7])(=[O:6])[CH3:1]
Reactant: CC(=O)Cn1nc(C)oc1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(=O)NN1CC(C)=NNC1=O

Procedure:
312 g of 2,3-dihydro-5-methyl-2-oxo-l,3,4-oxadiazol-3-ylacetone in 4 l of ethanol are stirred together with 200 g of hydrazine hydrate for 16 hours at 35° C. The solvent and the excess of hydrazine hydrate are evaporated in vacuo, and the residue is recrystallised from isopropanol to give 148 g (87% of the theoretical amount) of the title compound having a melting point of 197°-199° C.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O>>[S:3]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:4][CH2:1][CH2:2]1
Reactant: SCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Yield: 22.3 %

Procedure:
Ethane-1,2-dithiol (20.6 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (41.4 g.) in a similar manner to that of Example A-(i) to give ethyl 2-(2,3-dihydro-1,4-dithiin-6yl)-2-methoxyiminoacetate (syn isomer, 11 g.), white crystals, mp. 65° to 67° C.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[NH:11](CCO)[CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(=O)OCC
Product: O=C1OCCN(CCO)C1=O
Reaction time: 2 h

Procedure:
In a flask similar to that used for example 9 was placed 146 g (1.0 mole) of diethyl oxalate, and to this flask was added dropwise 26 g (0.25 moles) of diethanolamine maintaining reaction temperature at 30° C. during 1 hour. After the dropping finished, the stirring was continued at 25° C. for further 2 hours and then crystals separated were taken by filtration to obtain N-hydroxyethylmorpholine-2,3-dione.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[CH:6]([NH2:28])[CH:7]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:8][O:9][CH3:10])([CH3:3])[CH3:2].[CH2:30]=O>C1(C)C(C)=CC=CC=1>[CH:1]([O:4][C:5]([CH:6]1[CH:7]([CH2:8][O:9][CH3:10])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[NH:13][C:12]=2[CH2:30][NH:28]1)=[O:29])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: COCC(c1c[nH]c2ccc(OCc3ccccc3)cc12)C(N)C(=O)OC(C)C
Solvent: Cc1ccccc1C
Product: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Yield: 61.2 %

Procedure:
A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 minutes to 100° C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80° C. for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3 -yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After 1/2 hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27% strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[F:15][C:16]([F:20])([F:19])[CH2:17]I.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:17][C:16]([F:20])([F:19])[F:15]
Reactant: COc1ccccc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 130 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To dry N,N-dimethylformamide (10 ml) were added 2-methoxyphenol (150 mg), 2,2,2-trifluoroethyl iodide (584 mg) and potassium carbonate (400 mg), and the mixture was stirred vigorously at 130° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and chloroform (5/2) as eluent to give 179 mg of 1-methoxy-2-(2,2,2-trifluoroethoxy) benzene as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[CH3:8][C:9](=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:4][CH2:8][C:9](=[O:12])[CH:10]=[CH:11]1)[CH3:2]
Reactant: CCC(C=O)CC
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCC1(CC)C=CC(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
In 75 ml of benzene was dissolved 15.0 g of 2-ethylbutanal, to which were added 10.5 g of 3-buten-2-one and 0.15 ml of concentrated sulfuric acid at ambient temperature. While heating the mixture under reflux, an azeotropic distillation treatment was carried out for 3 hours by means of Dean Stark apparatus. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 4.90 g of 4,4-diethyl-2-cyclohexen-1-one as a light yellow oily product.
Reaction SMILES: ClCC1C=CN=CN=1.Cl[CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[CH2:10][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cnccn1
Agent: ClCc1ccncn1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cnccn1
Yield: 46 %

Procedure:
Following the procedure as described in step A of Preparation 14, making variations as required to replace 4-(chloromethyl)pyrimidine with 2-(chloromethyl)pyrazine (prepared according to R. W. Carling, et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) to react with potassium phthalimide, 2-(pyrazin-2-ylmethyl)isoindoline-1,3-dione was obtained as a colorless solid in 46% yield: nip 141-143° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (5, 1 H), 8.47 (s, 2H), 7.90-7.87 (m, 2H), 7.76-7.73 (m, 2H), 5.05 (s, 2H): MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: CCOC(=O)C=CN1CCCCC1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Tributylamine (9.5 g, 51 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml) and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.7 g; purity according to GC: 82.15%; yield: 82.8%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>>[CH2:19]([O:18][C:14](=[O:17])[NH:15][N:16]=[CH:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]=1)[CH3:20]
Reactant: CCOC(=O)NN
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Product: CCOC(=O)NN=Cc1c[nH]c(-c2ccccc2)n1

Procedure:
A mixture of 8.16 gm. of 2-phenyl-4-imidazolecarboxaldehyde and 5.52 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 196°-200° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 150 °C
Yield: 37.4 %

Procedure:
To a solution of 4-fluoronitrobenzene (0.70 g, 4.96 mmol) in THF (8 mL) was added piperadine-4-carboxylic acid methyl ester (0.71 g, 4.96 mmol) and diisopropylethylamine (0.66 g, 5.11 mmol). The mixture was heated in a microwave oven at 150° C. for 1.5 hr. The resulting mixture was extracted with ethyl acetate and hydrochloric acid (0.2 N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a Biotage flash column chromatography using ethyl acetate and hexanes (1:1 ratio) to give a yellow solid as 1-(4-nitrophenyl)-piperidine-4-carboxylic acid methyl ester (490 mg). 1H-NMR is consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10](OCC)OCC)[CH:3]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:9][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(COc1cccc(Br)c1)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2ccoc2c1
Yield: 72.9 %

Procedure:
To a solution of 1-bromo-3-(2,2-diethoxyethoxy)benzene (2.3 g, 8.35 mmol) in toluene (28 mL), PPA (5.0 mL) was added, and the resultant mixture was stirred overnight while heated to reflux. The reaction solution was added with water at room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane). 6-Bromobenzofuran (1.2 g, yield 68%, mixture with 7-bromobenzofuran) was obtained as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].[N-:27]=[C:28]=[O:29].C([O-])(O)=O.[Na+].CCOCC>O1CCOCC1>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:28]([NH2:27])=[O:29])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.12 h

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4carboxylic acid (3.8 g) in dioxan (35 ml) was added to the above isocyanate reagent in one portion and the resulting solution was stirred at ca 22° for 7 minutes. The reaction mixture was poured into 3% aqueous NaHCO3 solution (170 ml) and the pH was adjusted to 5 by the addition of more aqueous NaHCO3 solution. After heating to 40° for 2 hours and allowing to cool to 22° over 14 hours, the reaction mixture was washed (at pH 5.9) with ethyl acetate (2×200 ml), the aqueous layer was separated, layered with ethyl acetate (200 ml), and acidified with concentrated hydrochloric acid to pH 1.9. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (200 ml). The organic extracts were combined, washed with brine (2×400 ml), dried (MgSO4) and evaporated to give a white solid which, on trituration with ether (100 ml) afforded the title compound (3.18 g, 75% m.p. (MSO2) 175°; [α]D +42° (c 1.02, DMSO).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC>[O:19]=[C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.42 h

Procedure:
A solution of n-butyllithium (100 mL, 1.6 M, 160 mmol) in hexanes was added over 2 min. to a stirred solution of 2-bromopyridine (15.0 mL, 24.9 g, 157 mmol) in 500 mL of ether cooled in a dry ice/i-PrOH bath, causing a temporary rise in temperature to 47° C. After 25 min., the solution was transferred rapidly to a stirred 0° C. solution of diethyl oxalate (75 mL, 81 g, 550 mmol) in 1000 mL of ether. After 2 h at 0° C., the mixture was washed with saturated aq. NaHCO3 (900 ml), water (900 mL), and saturated aq. NaCl (450 mL). The organic layer was dried (MgSO4), filtered, and evaporated. Distillation gave the title compound as 11.68 g of yellow liquid, B.p. 96-108° C. (0.3 mm Hg pressure). For the title compound: 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=5, 1H), 8.13 (d, J=8, 1H), 7.93 (td, J=8, 2, 1H), 7.56 (ddd, J=8, 5, 1, 11H), 4.51 (q, J=7,22H), 1.44 (t, J=7, 3H).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C([O-])(=O)C.[Na+].O.[CH2:14]([O:18][CH2:19][CH:20]=O)[CH2:15][CH:16]=[CH2:17]>C(O)C>[CH2:14]([O:18][CH2:19][CH:20]=[N:6][OH:7])[CH2:15][CH:16]=[CH2:17]
Reactant: NO
Reactant: C=CCCOCC=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCCOCC=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Hydroxylamine sulfate (20.5 g), sodium acetate (12.8 g) and water (20 ml) were added to a solution of 3-butenyloxyacetaldehyde (17.8 g; J. Chem. Soc., Perkin Trans. 1, 1999, 3143-3155) in ethanol (200 ml). The mixture was stirred at room temperature overnight and then water was added. The excess of ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (6.20 g).