Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]3[O:14][C@@H:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][N:17]1[N:21]=[N:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][C:19]3[N:20]=[N:21][N:17]([CH3:16])[N:18]=3)[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccccc2)n1
Product: Cn1nnc(CN(c2ccccc2)[C@H]2c3cc(C#N)ccc3OC(C)(C)[C@@H]2O)n1
Yield: 77.4 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (3R,4R)-6-cyano-2,2-dimethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (200 mg, 0.99 mmol) and N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (188 mg, 0.99 mmol). The crude product was purified, to give desired compound (299 mg, yield: 77%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH2:10]Br)=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CC(C)=O.O>[C:1]([C:5]1[O:9][C:8]([CH2:10][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C(C)(C)C)oc1CBr
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)(C)C)oc1CN1CCCCC1
Yield: 14.7 %

Procedure:
A solution of methyl 5-tert-butyl-2-(bromomethyl)furan-3-carboxylate (0.28 g, 1.0 mmol) and piperidine (99 μL, 1 mmol) in acetone (5 mL) was stirred at room temperature 3 days. The mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-50% EtOAc-hexanes) to obtain methyl 5-tert-butyl-2-((piperidin-1-yl)methyl)furan-3-carboxylate (41 mg, 15% yield). LC/MS: m/z 280.3 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C>O1CCCC1>[CH:20]1[C:27]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:9]=[CH:8][C:25]=3[CH2:24][N:23]([C:16]([C:15]3[CH:19]=[CH:20][C:12]([N:2]([CH3:1])[C:3](=[O:11])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[CH3:10])=[CH:13][CH:14]=3)=[O:17])[C:26]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.4 %

Procedure:
A mixture of 0.291 g of 6,11-dihydro-5-dibenz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.182 g of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1N HCl water, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170° C.
Reaction SMILES: C([Li])CCC.[C:6]([CH:8]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]1)#[N:7].[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CCCCCC.O1CCCC1>[C:6]([C:8]1([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]1)#[N:7]
Reactant: O=C1CCCCC1
Reactant: N#CC1Cc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: N#CC1(C2(O)CCCCC2)Cc2ccccc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Whilst maintaining the temperature at -78° C., 69 ml of 1.6M butyllithium in n-hexane are added to a solution of 12.9 g of 1-cyanobenzocyclobutane in 200 ml of tetrahydrofuran. After stirring for half an hour at that temperature, 15.5 ml of cyclohexanone are added and the reaction mixture is brought back to room temperature. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at -10° C. with water. After extraction with diethyl ether, the organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The crystalline residue is recrystallised from isopropyl ether to yield 12.32 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#N)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH2:22].[OH-:23].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:23])=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: N#CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
9-(4-Chlorobenzenesulphonamido)nonanenitrile (0.7 g) was dissolved in ethanol (50 ml) and water (10 ml) containing sodium hydroxide (1.5 g). The mixture was refluxed for 20 hours then the solvent was removed. The residue was dissolved in water and treated with hydrochloric acid to give a white precipitate. This was collected by filtration and recrystallised from ethanol-water to give the title compound (0.56 g) m.p. 121°-123° C.
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[CH:13][C:12]=2[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=2[C:27]([OH:29])=[O:28])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of LiOH (6.12 g, 146 mmol) in water (100 ml) was added to a stirred solution of bis(phenylmethyl) 4-[(phenylmethyl)oxy]-1,3-benzenedicarboxylate (may be prepared as described in Description 47; 6.6 g, 14.59 mmol) in tetrahydrofuran (25 ml) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was acidified with concentrated HCl. The white precipitate was collected by filtration, and dried to yield the title compound as a white solid. 3.8 g.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(C)C=O>[CH2:10]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: BrCCCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(CCOCCCCCCCCCOC2CCCCO2)cc1
Reaction time: 16 h
Yield: 39 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 264 mg, 6.6 mmol) was added at 0° C. to a solution of 2-phenylethanol (807 mg, 6.61 mmol) in tetrahydrofuran (8.6 mL) and N,N-dimethylformamide (3.4 mL), then after 1 h a solution of 2-(9-bromo-nonyloxy)-tetrahydro-pyran (2.44 g, 7.93 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The solution was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 2-(9-phenethyloxy-nonyloxy)-tetrahydro-pyran (898 mg, 39%). Colorless oil, m/e=366.2 ([M+NH4]+).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:25]([OH:27])=[O:26])=[CH:13][N:14]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[CH:9][C:8]=1[F:29].[N+:30]([O-])([O-:32])=[O:31].[K+]>>[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:25]([OH:27])=[O:26])=[CH:13][N:14]2[C:17]2[CH:22]=[C:21]([N+:30]([O-:32])=[O:31])[C:20]([F:23])=[CH:19][C:18]=2[F:24])=[CH:9][C:8]=1[F:29]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To 25 ml of conc. sulfuric acid was added 6.0 grams of 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid. With ice cooling and stirring, to the solution was added 5.0 g of potassium nitrate in portions. The temperature was slowly elevated to 80° C. at which stirring was continued for 2 hours. The reaction solution was allowed to cool, poured into 200 g of ice water, and allowed to stand overnight. The precipitate was collected by filtration, washed with distilled water, ethanol and diisopropyl ether, and air dried, to give 6.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[C:19]#[CH:20].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:20][C:19]#[CH:18])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1ccccc1-n1cnc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 36.6 %

Procedure:
A suspension of 5-amino-1-(2-hydroxyphenyl)benzimidazole (4) (499 mg, 2.21 mmol), 80% propargyl bromide (2.43 mmol) in toluene (271 μL), K2CO3 (398 mg, 2.88 mmol), and acetone (15 mL) is stirred at 70° C. under argon for 18.5 h and then cooled to room temperature. The mixture is concentrated, diluted with H2O (35 mL), and extracted with ethyl acetate (100 mL and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (2% to 7% methanol/ethyl acetate) to give 213 mg (39%) of 5 as a light-brown solid, mp 40-42° C. IR 3379, 2966, 1512, 1239 cm−1; 1H NMR (CDCl3) δ 2.51 (t, J=2.4 Hz, 1H, C≡CH), 3.09 (bs, 2H, NH2), 4.68 (d, J=2.4 Hz, 2H, CH2C≡CH), 6.74 (dd, J=8.4 Hz, 2.1 Hz, 1H, 6-BenzimidH), 7.14 (d, J=8.4 Hz, 1H, 7-BenzimidH), 7.16 (d, J=2.1 Hz, 1H, 4-BenzimidH), 7.19 (m, 1H, 3-PhH), 7.29 (m, 1H, 5-PhH), 7.42-7.49 (m, 2H, 4,6-PhH), 8.01 ppm (s, 1H, 2-BenzimidH). HRMS calcd C16H13N3O [M+H]+ 264.1137. found 264.1129.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:21][CH2:20]3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:27]([N:29]1CCN2C(C3CC3)=C(C#N)C=C2C1)=O)(C)(C)C.ClS(N=C=O)(=O)=O.CN(C)C=O>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:20][CH2:21]3)=[C:15]([C:27]#[N:29])[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2C2CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C3CC3)cc(C#N)c2C1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(c(C#N)c(C#N)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of a mixture of 8-cyano-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 7-cyano-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (6.67 g, Reference Example 9) in dry acetonitrile (370 mL) under a blanket of nitrogen at 0° C. was treated with chlorosulfonyl isocyanate (2.75 mL) dropwise whilst maintaining the temperature below 5° C. After stirring below 5° C. for a further 2.5 hours the reaction mixture was treated with dimethylformamide (18.5 mL), allowed to warm to room temperature and then stirred for a further 1 hour. The reaction mixture was then treated with triethylamine (21.7 mL), stirred for a further 1 hour and then left to stand overnight. The reaction mixture was evaporated and the residue treated with dichloromethane (200 mL) and water (80 mL). The organic phase was separated, further washed with water (80 mL), then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:3, v/v) to give the title compound (4.97 g) as a yellow oil, Rf 0.29 (ethyl acetate:pentane, 2:3). 1H NMR [(CDCl3]: δ 4.70 (s, 2H), 4.03 (t, 2H), 3.87 (t, 2H) 1.73–1.65 (m, 1H), 1.51 (s, 9H), 1.14–1.07 (m, 2H) and 0.99–0.93 (m, 2H).
Reaction SMILES: [CH2:1]1[S:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][C:9](=[O:12])[CH2:10][CH3:11]>CC(C)=O>[Br-:7].[O:12]=[C:9]([CH2:10][CH3:11])[CH2:8][S+:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: C1CCSCC1
Reactant: CCC(=O)CBr
Solvent: CC(C)=O
Product: CCC(=O)C[S+]1CCCCC1
Product: [Br-]
Reaction time: 24 h
Yield: 72.7 %

Procedure:
The synthesis was carried out under radiation from a yellow lamp. A 100-millilitter three-port flask was prepared. Using the flask, 4 grams of pentamethylenesulfide was dissolved in 40 milli-litter of acetone. 6 grams of 1-bromo-2-butanone was dropped into the solution over agitation. After 24 hours, white crystal was precipitated, and was filtrated. The white crystal was pulverized, and the pulverized white crystal was washed in ether. The resultant crystal was dried by using a low-pressure drier at 30 degrees in centigrade for six hours. Then, 7.2 grams of 2-oxobutyl-thiacyclohexanium bromide was obtained. The yield was 72.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.CS(Cl)(=O)=[O:25].[C-]#N.[K+].[CH2:31]([OH:33])C>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:31]([OH:33])=[O:25])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCO
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2ccccc2)c(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
(2-Fluoro-biphenyl-4-yl)-methanol (0.75 gm, 3.7 mmole) was dissolved in 20 ml DCM, cooled using ice/methanol, triethylamine (0.55 ml, 4.0 mmole) was added followed by methanesulfonylchloride (0.3 ml, 4.0 mmole) added drop wise over 5 minutes. The reaction was allowed to stir at room temperature till the TLC indicated consumption of the starting material (2 hrs), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated to produce yellow oil, the oil produced was dissolved in 25 ml of 70% ethanol, KCN (0.4 gm, 6 mmole) was then added and it was heated under reflux overnight. Ethanol was evaporated; solid was washed with 50 ml water and filtered. The solid was dissolved in 20 ml of ethanol, then 20 ml of conc. H2SO4 was added, and was refluxed overnight; the solution was allowed to cool to room temperature, poured to 200 ml of crushed ice, the solid was collected by vacuum filtration, suspended in 25 ml of NaOH 30%, heated at reflux temperature for 24 hrs, cooled to room temperature, washed with DCM and ethyl acetate. The aqueous layer was acidified with conc. HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give white solid (0.15 gm, 18% in 3 steps) H1-NMR INOVA-500 (DMSO d6) δ 3.672(s, 2H), 7.191-7.254(m, 2H), 7.389-7.560(m, 6H), 12.494 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]#[N:21]
Reactant: NO
Reactant: COCCOc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(C#N)cc1OC
Temperature: 130 °C
Yield: 91.3 %

Procedure:
To a solution of 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 3-methoxy-4-(2-methoxyethoxy)benzonitrile (9 g) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 7.26 (dd, J=8.4, 1.6, 1H), 7.08 (d, J=1.6, 1H), 6.93 (d, J=8.4, 1H), 4.23-4.20 (m, 2H), 3.88 (s, 3H), 3.82-3.80 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].FC1N=C2C(N=CN2C2CCCCO2)=C(N)N=1.C[C@H](N)CCC>>[CH3:1][C@H:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Agent: CCC[C@H](C)N
Agent: Nc1nc(F)nc2c1ncn2C1CCCCO1
Product: CCC[C@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 70 from 2-fluoro-9-(tetrahydro-2H -pyran-2-yl)-9H-purin-6-amine and (2S)-2-pentanamine.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])C.[C:8]([NH:11][C:12]1[N:16](CCO)[N:15]=[CH:14][CH:13]=1)(=[O:10])[NH2:9]>C(O)=O>[C:8]([NH:11][C:12]1[N:16]([CH2:6][CH2:5][O:4][CH:1]=[O:3])[N:15]=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)Nc1ccnn1CCO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: NC(=O)Nc1ccnn1CCOC=O
Reaction time: 0.5 h

Procedure:
Formic acid (2.09 ml) was added to acetic anhydride (4.17 ml) at room temperature and the mixture was stirred for 30 minutes at the same temperature. 5-Carbamoylamino-1-(2-hydroxyethyl)pyrazole (3.76 g) was added thereto under stirring and ice-cooling. The mixture was stirred for 2 hours at room temperature. The reaction mixture was evaporated in vacuo and diisopropyl ether was added thereto to give 5-carbamoylamino-1-(2-formyloxyethyl)pyrazole (4.15 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:20])([CH3:19])[CH2:11]CC1C=CC=CC=1)(=[O:8])[CH2:4][C:5]([O-:7])=[O:6].[CH3:21][O:22][CH2:23][CH2:24]Br.O.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.C(OCC)C>[CH3:21][O:22][CH2:23][CH2:24][CH:4]([C:3]([O:9][C:10]([CH3:20])([CH3:19])[CH3:11])=[O:8])[C:5]([O:7][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:6]
Reactant: CC(C)(CCc1ccccc1)OC(=O)CC(=O)[O-]
Reactant: COCCBr
Reactant: CCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred suspension of sodium hydride (14.4 g of a 60% dispersion in mineral oil, 360 mmol) in THF (300 ml) was cooled to 0° C. under nitrogen. To the resultant slurry was added, over a period of 45 minutes, a solution of benzyl-tert-butyl malonate (90.0 g, 360 mmol) in THF (500 ml). The reaction mixture was allowed to warm to room temperature and was then stirred for 1 hour. The reaction mixture was then cooled to 0° C. again, and a solution of 2-bromoethyl methyl ether (50.0 g, 360 mmol) in THF (100 ml) was then added over a period of 0.5 hours. The reaction was then allowed to warm to room temperature and left to stir for 19 hours. The reaction was then brought to reflux for 24 hours before cooling to room temperature. To the reaction mixture was added deionised water (500 ml) and the product was then extracted with ethyl acetate (3×500 ml). The organic phases were combined, dried over magnesium sulfate and were then concentrated by distillation under reduced pressure to give the product as a crude oil (100 g). The product was then purified by column chromatography on silica gel using 10% diethyl ether in heptane then 20% diethyl ether in heptane as the eluent, to give the title compound as an oil (37.1 g, 120 mmol, 33% yield); TLC (diethyl ether/heptane 3:7, visualised with Dragendorff's dip) Rf 0.25; 1H NMR (300 MHz, CDCl3) δ: 1.4 (s, 9H), 2.13 (dt, 2H), 3.30 (s, 3H), 3.43 (t, 2H), 3.51 (t, 1H), 5.20 (d, 2H), 7.29-7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15]Br.[C-:17]#[N:18].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][C:17]#[N:18]
Reactant: Clc1cccc(Oc2ccccc2)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Cl)cccc1Oc1ccccc1
Yield: 63 %

Procedure:
A solution of 21.0 g (70.57 mmol) of (2-chloro-6-phenoxy-phenyl)-bromomethane in 16.5 ml of ethanol is added dropwise at 80° C. to a solution of 4.5 g (91.74 mmol) of sodium cyanide in 9.2 ml of water and 2.3 ml of ethanol and the reaction mixture is boiled under reflux for 4 hours. After cooling, the mixture is concentrated using a rotary evaporator, the residue is taken up in ethyl acetate and the organic phase is washed 2× with water and 1× with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel with ethyl acetate to yield 10.82 g (44.40 mmol)=63% of (2-chloro-6-phenoxyphenyl)-acetonitrile in the form of a brown oil; TLC (silica gel; ethyl acetate; UV): Rf =0.42; 1H-NMR (CDCl3, 200 MHz): 3.96 (s, 2H); 6.74-7.46 (m, 8H)
Reaction SMILES: C([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(OC(C)C)(C)C>C(O)=O>[C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([OH:35])=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])([OH:16])=[O:14]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3 g) in formic acid (12 ml) was added 35% hydrochloric acid (1 ml) at 0° C. After stirring at ambient temperature for an hour, the reaction mixture was poured into diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and then dissolved in water (15 ml). The aqueous solution was adjusted to pH 3.5 with 5% aqueous sodium bicarbonate. The precipitates were collected by filtration and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32](C(OC(C)(C)C)=O)[C@@H:31]([CH3:40])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[NH:32][C@@H:31]([CH3:40])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.