Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10](CC4C=CC(OC)=CC=4OC)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][C:29]=4[F:42])[C:9](=[O:24])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (1.8 g), potassium carbonate (1.5 g) and acetonitrile (200 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (50 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (50 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (50 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.5 g, 64%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].Cl>>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([C:26]([CH2:25][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:27])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(CC(=O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
Powdered anhydrous aluminum chloride (0.78 g) was slowly added to a stirred mixture of 1,2-dimethoxybenzene (0.64 g, 4.66 mmol) and 3,4-dimethoxyphenylacetyl chloride (1.0 g, 4.66 mmol) in 10 mL freshly distilled dry dichloromethane. An exothermic reaction occurred. The orange solution became brown as the mixture refluxed. The reaction mixture was heated to reflux for an additional 2 h and then allowed to cool to room temperature. The cooled solution was poured into a mixture containing of 5 g crushed ice and 5.5 mL 7.5 N HCl. The organic phase was separated and the aqueous phase was extracted three times with 10 mL dichloromethane. The combined dichloromethane extract was dried (Na2SO4), filtered, and evaporated to give a white solid, which was crystallized from ethanol to give pure white needles of 11a in 98% yield; mp 105-107° C. (lit.30 mp 104-106° C.); 1H NMR δ 3.85 (s, 6H), 3.91 (s, 3H), 3.94 (s, 3H), 4.18 (s, 2H), 6.81 (m, 2H), 6.91 (m, 2H), 7.56 (d, 1H, J=2.0), 7.66 (dd, 1H, J=8.4,2.0); 13C NMR δ 45.2, 56.3, 56.4, 56.5, 110.4, 111.1, 111.8, 112.8, 121.3, 121.9, 123.9, 127.9, 130.2, 148.4, 149.5, 153.8, 197.0.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([F:19])[CH:8]=1.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1>C1COCC1>[F:19][C:9]1[CH:8]=[C:7]([C:21]2([OH:20])[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH:18]=[CH:17][C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: Fc1cc(Br)ccc1CN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5M/hexanes, 78 ml, 0.195 mol) was added down the reaction flask walls over 5 min to a −78° C. solution of 1-(4-bromo-2-fluorobenzyl)pyrrolidine (50.0 g, 0.194 mol) in THF (500 mL). After stirring at −78° C. for 1 h, a −78° C. solution of 3-oxocyclobutanecarboxylic acid (11.0 g, 96.4 mmol) in THF (150 mL) was cannulated over 10 min into the reaction mixture. The resulting dark orange solution was slowly warmed to room temperature over 16 h. LC/MS of the mixture showed the title compound 294.2 (M+H). This material was used as a crude solution without work-up, assuming ˜0.12 M concentration of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([OH:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]=[N:6][C:5]=2[N:4]([CH3:18])[N:3]=1.[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:18][N:4]1[C:5]2[N:6]=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([OH:11])[C:10]=2[C:2]([N:19]2[CH2:26][CH2:25][CH2:24][CH2:20]2)=[N:3]1
Reactant: Cn1nc(I)c2c(O)c(-c3ccccc3)nnc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(N2CCCC2)c2c(O)c(-c3ccccc3)nnc21
Temperature: 110 °C

Procedure:
A mixture of 3-iodo-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (100 mg, 0.28 mmol), copper iodide (11 mg, 0.056 mmol), L-proline (13 mg, 0.11 mmol), K2CO3 (193 mmol, 1.4 mmol) in anhydrous DMF (5.6 mL) was degassed by bubbling nitrogen through for 10 minutes, then heated to 110° C. for 20 h. The mixture was left to cool to room temperature, then partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried (MgSO4), filtered and evaporated. The residue (117 mg) was used as such in the next step.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([N:6]([CH2:27][CH2:28][CH3:29])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17](=O)[CH2:18][C:19](OC(C)(C)C)=[O:20])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)[CH2:4][CH3:5]>CO>[CH2:3]([N:6]([CH2:27][CH2:28][CH3:29])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17]3[CH:18]=[C:19]([OH:20])[NH:2][N:1]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)[CH2:4][CH3:5]
Reactant: NN
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC(=O)OC(C)(C)C)c2C1
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(-c3cc(O)[nH]n3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydrazine (1 ml, 32 mmole) was added to a solution of 500 mg (1.34 mmole) of 2-di-n-propylamino-8-t-butoxycarbonylacetyl-1,2,3,4-tetrahydronaphthalene in 25 ml methanol and stirred at room temperature for for 24 hours. The product was isolated by concentrating the reaction mixture followed by flash chromatography, eluting with 1:1 CH2Cl2 :MeOH, and finally crystallizing from MeOH/EtOAc, m.p. 214°-216° C. Analysis: Theory: C, 72.81, H, 8.68, N, 13.41; Found: C, 73.01, H, 8.81, N, 13.27.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[Na].C(OC(=S)[SH:33])C.[OH-].[Na+]>O.C(OCC)(=O)C>[SH:33][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=S)S
Reactant: Nc1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(Cc1ccc(S)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a suspension of 3-(4-amino-phenyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (4.0 g, 12.9 mmol) in water (50 ml) and hydrochloric acid (2.8 ml, 32.3 mmol) at 0-5° C. was added sodium nitrite (0.89 g, 12.9 mmol) in water (20 ml). The reaction mixture was warmed to room temperature and poured in a solution of the sodium salt of dithiocarbonic acid O-ethyl ester (4.14 g, 25.8 mmol) in water (20 ml). The reaction mixture was stirred at 60° C. for 2 hours and the precipitate (resin) was solved with ethyl acetate. The organic layer was washed with water, dried, and evaporated in vacuo. The resulting dark brown oil was solved in ethanol (50 ml). At refluxing temperature, sodium hydroxide (3.6 g, 64.5 mmol) was added. After three hours at that temperature, the ethanol was removed, the residue solved in water, and the aqueous layer washed with dichloromethane. To the aqueous layer, potassium hydrogensulfate (10 g) was added. The resulting oil was extracted with dichloromethane, dried, and evaporated in vacuo to give 3.05 g (72%) of the desired product. MS m/z: 327.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:28].O1CCOCC1.C(OCC)C>C(Cl)Cl>[ClH:28].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.4 g, 3.7 mmol) in DCM (3 mL) was added 4.0M HCl in dioxane (4.6 mL, 18.56 mmol) and stirred at rt for 3 h, Diethylether (200 mL) was then added and the mixture was stirred at rt for 30 min and then filtered and washed with diethylether and dried to give the title compound (1.3 grams).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(Br)ccc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Br)ccc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-bromoanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [Sn:1]([CH2:14][CH2:15][CH2:16]Br)([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:18]([CH3:20])[CH3:19]>>[CH3:19][N:18]([CH3:20])[CH2:16][CH2:15][CH2:14][Sn:1]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CNC
Reactant: CCCC[Sn](CCCC)(CCCC)CCCBr
Product: CCCC[Sn](CCCC)(CCCC)CCCN(C)C
Yield: 86 %

Procedure:
In a reaction vessel provided with a carbon dioxide condenser, a mixture of 6.18 g (0.015 mol) of Bu3Sn(CH2)3Br and 20 ml of Me2NH was refluxed for 7 h. The residue obtained after evaporation of the excess of Me2NH was taken up in 30 ml of diethyl ether and treated for 15 min with 50 ml of a 10% aqueous solution of NaHCO3. Distillation gave 4.95 g (86%) of (3-dimethylaminopropyl)tributyltin.
Reaction SMILES: [S:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][S:1][C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]=1
Reactant: CI
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
Dissolve benzyl N-[(3R)-2-thioxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (1.5 g, 4.60 mmol) in THF (40 mL), cool to 0° C., and add sodium hydride (NaH) (192.9 mg, 4.83 mmol, 60% in mineral oil) all at once. Remove the bath and stir the reaction for approximately 1 hour under nitrogen. Add methyl iodide (300 μL, 4.83 mmol) and stir for approximately 1 hour at ambient temperature. Concentrate the reaction under reduced pressure to remove most of the THF, dilute the residue with ethyl acetate, and wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layers under reduced pressure to give the title compound (1.5 g, 96%) as a white solid: MS (m/z): 341 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH3:20])([CH3:19])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:16]([O:15][CH2:14][CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C:11]1([CH3:20])[CH3:19])([CH3:18])[CH3:17]
Reactant: C1COCCN1
Reactant: CC(C)OCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Product: CC(C)OCCN1c2nc(N3CCOCC3)cc(=O)n2CCC1(C)C
Yield: 29 %

Procedure:
0.19 g of 2-chloro-9-(2-isopropoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 2.5 mL of morpholine are heated in the microwave oven to 80° C. for 2 h. The crude is purified by flash chromatography on silica gel SiO2 (100% CH2Cl2 to 92/8 CH2Cl2/MeOH). 0.06 g (yield=29%) of 9-(2-isopropoxyethyl)-8,8-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white solid including the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+](=[CH2:18])=[N-]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:18])=[O:13]
Reactant: O=C(O)CCCC(=O)c1ccccc1Br
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCC(=O)c1ccccc1Br
Yield: 97 %

Procedure:
To 0.54g (2.0 mmol) of the product of Example 2 dissolved in ether was added an ethereal solution of excess diazomethane at 0°C. to produce a 97% yield of the ester as a yellow oil. The ester was used without further purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][OH:8])[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN([C@H](CO)c2ccccc2)CC1
Yield: 25.3 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer, 15 g (125 mmoles) of (R)-phenyloxirane, 19.75 g (125 mmoles, 18.3 ml) of ethyl-N-piperazine carboxylate, and 80 ml of ethyl alcohol were introduced. The mixture was heated at reflux for 3 hours. Volatile substances were removed under reduced pressure and the resulting mixture was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/aqueous ammonia 98.5/1.5/0.5 (v/v/v)), affording 8.8 g of (S)-4-(2-Hydroxy-1-phenyl-ethyl)-piperazine-1-carboxylic acid ethyl ester (compound 2) as a colorless oil. Yield: 25%.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([CH3:3])[CH3:2].[I-].[I:16]([O-])(=O)(=O)=O.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[I:16][C:11]1[C:12]([CH3:14])=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(C)cc1C(C)C
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C)cc1C(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask, was added a solution of methyl 2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol, 1.00 equiv) in acetic acid (60 mL). Iodide (9.50 g, 37.4 mmol, 1.10 equiv), sodium periodate (3.60 g, 16.8 mmol, 0.50 equiv), and sulfuric acid (0.500 g, 0.15 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at 100° C. After cooling to room temperature, the reaction was quenched with Na2S2O3 (aq., sat.). The mixture extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with 3×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 6.00 g (56%) of methyl 5-iodo-2-isopropyl-4-methylbenzoate as a yellow oil.
Reaction SMILES: O.NN.[CH3:4][CH:5]1[C:9]2[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6]1>C(O)C.[Pd]>[CH3:4][CH:5]1[C:9]2[C:10]([O:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6]1
Reactant: CC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1OCc2cccc(Oc3ccc(N)cn3)c21
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 93.9 %

Procedure:
In a 50 ml round-bottomed flask 2-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-5-nitropyridine (Intermediate 99, 38.3 mg) was dissolved in ethanol (10 ml) to give a pale yellow solution. Pd/C (14.22 mg, 0.013 mmol) and hydrazine hydrate (0.026 ml, 0.267 mmol) were added. The reaction mixture was stirred at 90° C. After 45 minutes, the reaction mixture was filtered and the organic phase was evaporated under vacuum to afford the title compound (32 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])([CH2:10]OS(C)(=O)=O)[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CN(C=O)C>O>[CH:1]1([O:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])([CH2:10][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(C#N)(COS(C)(=O)=O)OC1CCCC1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(C#N)(Cn1ccnc1)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.3 %

Procedure:
60.7 g (0.188 mol) 2-cyclopentyloxy-2-(2-methylphenyl)-3-methylsulfonyloxy-propanenitrile, 63.9 g (0.938 mol) imidazole and 3.88 ml DMF are stirred for six hours at 160° C. bath temperature. They are then poured into 200 ml water, extracted twice--each time with 200 ml methylene chloride--and the organic phase is then dried with MgSO4. It is then rotated in a vacuum after which the oil is dissolved in 100 ml isopropanol and then reacted dropwise with 10 ml 100% nitric acid, with cooling with ice. Next follows 20 minutes after-stirring with RT, addition of 200 ml acetic ester, and evacuation in a vacuum. In this manner 30.7 g of the title compound are obtained, MP: 160° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
A mixture of 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), N-[4-(2-methanesulphonyloxyethyl)phenyl]methanesulphonamide (0.3 g-see Preparation 18), sodium bicarbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.12 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:22]2[CH:23]=[CH:24][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 147 g (1.05 moles) of 4-nitrobenzoyl chloride in 250 ml of 1,2-dichloroethane and a solution of 154 g (1.0 mole) of biphenyl in 200 ml of 1,2-dichloroethane are added dropwise, in succession, to the suspension of 160 g (1.2 moles) of anhydrous aluminum chloride in 400 ml of 1,2-dichloroethane at 0° C. The mixture is allowed to reach room temperature, after which it is stirred for 2 hours at 50° C. and poured carefully onto ice water. The precipitate is filtered off under suction, washed thoroughly with water and recrystallized from ethanol to give 230 g (89% of theory) of brown crystals of melting point 174°-176° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][N:9]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.C(OCC)(=O)C>[CH3:1][C@H:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:4][CH2:5][N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:7]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2ccccc12
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
(R)-1-(2-methylpiperazin-1-yl)-4-phenylphthalazine (JK-10) (200 mg, 0.65 mmol) was dissolved in 5 mL of dichloromethane at room temperature. To this solution was added triethylamine (0.18 mL, 1.3 mmol, 2 eq) and benzoyl chloride (0.083 mL, 0.72 mmol, 1.1 eq). After 5 minutes, the reaction was diluted with 75 mL of ethyl acetate and washed with 5 mL of sat. NaHCO3, 5 mL of water, and 5 mL of brine. The organic phase was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (35% ethyl acetate in hexanes) afforded 200 mg (75% yield) of (R)-(3-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl)(phenyl)methanone (4). MS (M+H)+=409.1
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 54.8 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 8 g.), 10% palladium carbon (3.6 g.), methanol (36 ml.), tetrahydrofuran (90 ml.), acetic acid (0.63 g.) and water (6.3 ml.) were treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.4 g.).