Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27](=[N:29][OH:30])[NH2:28])[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.[C:31](N1C=CN=C1)(N1C=CN=C1)=[S:32].N12CCCN=C1CCCCC2.Cl>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27]3[NH:28][C:31](=[S:32])[O:30][N:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(N)=NO)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(-c2noc(=S)[nH]2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To a suspension of 6-[2-(2,5-difluorophenyl)-5-methoxyindol-1-ylmethyl]pyridine-2-carboxamidoxime (63 mg) in acetonitrile (1.54 mL) were successively added 1,1′-thiocarbonyldiimidazole (41 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (70 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.41 (2H, s), 6.50-6.60 (1H, m), 6.67 (1H, s), 6.80 (1H, dd, J=2.4, 9.0 Hz), 7.15 (1H, d, J=2.4 Hz), 7.25-7.45 (3H, m), 7.50-7.60 (1H, m), 7.65-7.80 (2H, m). ESI-MS (m/z): 451 (M+H)+
Reaction SMILES: NC(N)=NC(=O)C1C=C(S(C)(=O)=O)C(S(C)(=O)=O)=CC=1C.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[CH3:30].[C:31](=[O:33])=[O:32]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:31]([OH:33])=[O:32])=[C:24]([CH3:30])[CH:25]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C=O
Agent: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
In a process for preparing N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, the step comprising reacting 2-bromo-5-chlorotoluene with a secondary or tertiary organolithium compound and CO2 to produce 4-chloro-2-methylbenzoic acid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:6]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of 2-bromobenzoic acid (20.12 g, 0.1 mol) in THF (200 mL) was treated dropwise with n-BuLi (2.5 M, 80 mL) at −78° C. The mixture was stirred at this temperature for 30 min, followed by dropwise addition of a solution of N-benzylpiperdine-4-one (26 g, 137 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the resulting mixture was washed with ether (100 mL). The aqueous layer was refluxed for 1 hr and then acidified to pH 2.5. The mixture was extracted with CHCl3 (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to obtain 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:18]([O-])(O)=O.[Na+].C(=O)=O>CO>[CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([O:11][CH3:18])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCCNC(=O)CCC(=O)O
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)CCC(=O)OC
Temperature: 25 °C

Procedure:
A solution of 4-butylamino-4-oxobutanoic acid (20 mmol) and concentrated sulfuric acid (1 ml) in MeOH (40 ml) is heated at reflux for 8 hours. The reaction is cooled to room temperature and saturated NaHCO3 is carefully added until CO2 gas no longer evolves. Most of the MeOH is removed in vacuo and the residue is partitioned between Et2O (100 ml) and H2O (40 ml). The water layer is re-extracted with Et2O (50 ml). The combined Et2O layers are washed with H2O (20 ml×2) and dried. Filtration and evaporation of solvent gives the title compound.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[CH3:29][C:30]1[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:36]([C:32]4[S:31][C:30]([CH3:29])=[N:34][C:33]=4[CH3:35])=[O:37])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (120 mg, 0.31 mmol) was dissolved in DMF (1.5 mL), and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (58 mg, 0.37 mmol) was added. PYBOP (193 mg, 0.37 mmol) and diisopropylethylamine (0.16 mL, 0.93 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (131 mg, 80%): HPLC MS RT=2.05 min, MH+=527.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 8.02 (1H, d), 7.43 (1H, d), 4.38 (2H, m), 4.32 (2H, m), 4.22 (2H, m), 4.00 (3H, s), 3.81 (2H, m), 3.53 (2H, d), 3.28 (2H, m), 2.72-2.63 (8H, m), 2.26 (2H, m), 1.13 (6H, d).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1C1C=CC=CC=1O)([CH3:4])([CH3:3])[CH3:2].[P:22]([O:37]C1C=CC=CC=1)([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+]>>[P:22]([O-:37])([O-:30])[O-:23].[P:22]([O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[O:37][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(-c2ccccc2O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(OP(Oc2ccccc2)Oc2ccccc2)c(C(C)(C)C)c1
Product: [O-]P([O-])[O-]

Procedure:
Bis (tetrahydroabietyl 2,4 di-tert-butyl phenyl) phosphite was prepared by first reacting 206 g (1 mol) of 2,4 di-tert-butylphenyl phenol with 310 g (1 mol) of triphenyl phosphite catalyzed with 2 g of sodium methylate (or phenate) to obtain a nominal 2,4 di-tert-butylphenyl diphenyl phosphite. Phenol was distilled through a 20 cm. Raschig ring packed column to 150° C. and 30 mm. The reaction terminates at 190° C. at 4 mm after distilling the calculated 1 mol of phenol. The product mixture contained approximately 85% of the desired 2,4,di-tert-butylphenyl diphenylphosphite. The remainder was identified as being predominantly a mixture of bis (2,4 -di-tert-butylphenyl) phenyl phosphite and unreacted triphenyl phosphite.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1F

Procedure:
A homogeneous mixture of 2-fluoronicotinic acid (Aldrich, 0.45 g, 3.2 mmol), in anhydrous THF (12 mL), was treated with oxalyl chloride (0.56 mL, 6.4 mmol) followed by anhydrous DMF (2 drops). After heating at reflux for 1.5 hours, the reaction mixture was concentrated in vacuo to afford 2-fluoronicotinoyl chloride as a residue which was used without further purification. The residue was dissolved in anhydrous THF (8 mL), anhydrous DCM (2 mL), pyridine (1 mL) and DMF (to a total volume of 16 mL). This homogeneous 2-fluoronicotinoyl chloride mixture (2 mL) was then added to a rapidly stirred mixture of o-toluidine (Aldrich, 0.17 mL, 1.6 mmol) in anhydrous THF (2 mL). After 15 hours, the reaction was quenched with water, and then extracted with 10% isopropanol in chloroform. The organic layer was washed once with sat. aq. NaHCO3, once with sat. aq. NaCl, then dried over anhydrous Na2SO4 and concentrated in vacuo to afford the desired product (0.084 g, 91%) as a pale orange solid which was used without further purification. MS(ESI+) m/z 231 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].ClCCl>C(O)C.O1CCOCC1.[Pd]>[CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@H](C3CCCCC3)CC2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClCCl
Product: C1CCC([C@H]2CC[C@H](N3CCNCC3)CC2)CC1

Procedure:
To a solution of benzyl 4-(trans-4-cyclohexylcyclohexyl)-1-piperazinecarboxylate (4 g) in ethanol (40 ml) and dioxane (40 ml) was added 10% palladium on carbon (0.8 g), and hydrogen gas at atmosphere pressure for 7 hours. To the reaction mixture was added dichloromethane (40 ml). The reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to give 1-(trans-4-cyclohexylcyclohexyl)piperazine (1.56 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:13]([O:12][C:10]([NH:17][CH2:18][C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[O:20])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzylalcohol (300 mg, 2.43 mmol), N-Boc-glycine (426 mg, 2.43 mmol), and 1-hydroxybenzotriazole (344 mg, 2.55 mmol) in 4.8 mL of dry N,N-dimethylformamide was added N,N-diisopropylethylamine (0.42 mL, 2.9 mmol). After addition of 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochlorde (489 mg, 2.55 mmol) at 0° C., the solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-[2-(tert-butoxycarbonylamino)acetylamino]benzylalcohol.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=1.[CH3:17]O>>[ClH:3].[CH3:17][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]=1)[NH2:5]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: N[C@@H](CC1=CCC=CC1)C(=O)O
Product: COC(=O)[C@@H](N)CC1=CCC=CC1
Product: Cl

Procedure:
Thionyl chloride (15 ml.) is added to methanol (150 ml.) while stirring in a dry ice bath. The mixture is allowed to come to room temperature and 2,5-dihydro-L-phenylalanine (5.0 g.) is added. After refluxing for 30 minutes, the solvent is removed in vacuo and the residue is crystallized from ether and then recrystallized from acetonitrile. Yield: 4.95 g.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>CO>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=3)[C:6]2=[O:5])=[CH:28][CH:27]=1
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
[Step 2] To a solution of 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (1.03 g) in methanol (100 ml) were added 4-aminomethyl-benzoic acid methyl ester hydrochloride (3.02 g) and triethylamine (4.2 ml) and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→3/1) to give the title compound (220 mg, 15%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:15]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH:12]2[C:37]([CH:26]2[CH2:28][CH2:27]2)([CH:36]2[CH2:34][CH2:35]2)[OH:33])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: OC(C1CC1)(C1CC1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of ethyl 1,4-bis(phenylmethyl)-2-piperazine carboxylate (5.0 g, 15 mmol) in tetrahydrofuran (70 mL) was added dropwise over 20 minutes a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (100 mL, 50 mmol) with ice cooling, and the mixture was stirred for 30 minutes with ice cooling. After further stirring at room temperature overnight, to the reaction solution was added an aqueous saturated ammonium chloride solution (300 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain the title compound (1.3 g, yield 24%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CS([O-])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 2.5 h
Yield: 81.53 %

Procedure:
To a solution of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dimethylformamide (9.5 parts, dried over Molecular Sieves) cooling at -50° C. under nitrogen are added triethylamine (4 equivalents) and then methanesulfonyl chloride (2 equivalents) over 3 minutes at -52° to -45° C. After 2.5 hours at -55° to -45° C., the produced methanesulfonate (3) solution is stirred for 50 minutes at -15° to -12° C. diluted with ethyl acetate, washed with water, 5% hydrochloric acid, and water, dried over sodium sulfate, and concentrated. The residue is crystallized from methanol to give 7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (6). (Yield: 81.53%). mp. 166° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:10])[CH2:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)cn1)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 368.5 g (1.39 mol) of 2-(3-chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone (Example 121, Step B) in dioxane (1.5 L) at 80° C. was added DBU (207 mL, 1.39 mole, 1 eq), followed by dropwise addition of methyl acrylate (124.7 mL, 1.39 mol, 1 eq) at 80° C. The reaction was stirred at 80° C. for 1 h 30 min and then allowed to cool to ambient temperature. It was quenched with 2 M aqueous HCl solution (56.5 eq) and then basified to pH 7 with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×4 L). The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated. Purification by flash chromatography on silica gel (eluent: 40 to 100% DCM/hexanes) provided the title compound as a yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])=[C:15]([NH:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])[CH:16]=[N:17]2)=[N:12][CH:11]=1>C(O)C>[Br:9][C:10]1[CH:11]=[N:12][C:13]2[C:14]3[N:27]([CH2:28][C:29]([CH3:31])([OH:32])[CH3:30])[C:21]([CH2:22][O:23][CH2:24][CH3:25])=[N:20][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Temperature: 77 °C
Yield: 90.9 %

Procedure:
Potassium carbonate (113 g) and deionized water (565 mL) were sequentially added to a solution of N-{7-bromo-4-[(2-hydroxy-2-methylpropyl)amino][1,5]naphthyridin-3-yl}-2-ethoxyacetamide hydrochloride (113 g, 261 mmol) in denatured ethanol (1.695 L), and the resulting mixture was heated at reflux (77° C.) overnight and allowed to cool to room temperature. The ethanol was removed under reduced pressure, and the resulting mixture was filtered to isolate a solid. The solid was washed with deionized water (100 mL) and dried over two nights in a vacuum oven at 40° C. to provide 90 g of 1-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a brown solid. Material from a separate run was used in the next step.
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[C:2]1C=CC=C[CH:3]=1.C(O)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O1CCOCC1>[CH2:2]([O:1][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])[CH3:3]
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)NC(N)=O

Procedure:
Phenoxycarbonylpropyleneurea of 1 g (4.5 mmol) and ethanol of 10 g (21.7 mmol) were dissolved in dioxane of 20 ml by heating. Dibutyltin dilaurate of 10 mg (1%) was added to the resulting solution and the resulting mixture was heated for 5 hours with stirring. After confirming the completion of the reaction by the thin layer chromatography, the reaction product was concentrated and the resulting crude crystals were washed with ether to obtain the aimed substance of 567 mg (80%).
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[C:21](#[N:24])[CH:22]=[CH2:23].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:1]([C:3]1[C:7](/[CH:23]=[CH:22]/[C:21]#[N:24])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: C=CC#N
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#C/C=C/c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.864 g), acrylonitrile (0.264 g), triethylamine (0.4 ml), palladium acetate (0.04 g) and dimethylformamide (10 ml) were stirred under an atmosphere of nitogen at 70° C. for 24 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid m.p. 144-145° C.