Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=[O:13])CC[CH2:9][CH2:8]2)C=CC=C[CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([CH:7]([CH2:8][CH3:9])[C:12]([NH:29][C@@H:26]1[C@H:24]2[C@H:23]([CH2:22][N:21]([CH2:20][C:19]3[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=3)[CH2:25]2)[CH2:28][CH2:27]1)=[O:13])[CH3:2]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CCC(CC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-ethylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.90 (d, J=6.7, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.54 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.49 (s, 2H), 2.83 (ddd, J=2.9, 7.8, 16.8, 1H), 2.75 (dd, J=2.9, 9.5, 1H), 2.52-2.43 (m, 1H), 2.37 (dd, J=2.9, 9.1, 1H), 2.35-2.30 (m, 1H), 2.25 (dd, J=7.6, 9.4, 1H), 2.01 (tt, J=4.8, 9.5, 1H), 1.89 (dt, J=7.3, 11.6, 1H), 1.77 (ddt, J=7.5, 9.3, 15.2, 2H), 1.70-1.60 (m, 2H), 1.51-1.37 (m, 2H), 1.34-1.26 (m, 1H), 0.95 (t, J=7.4, 3H), 0.83 (t, J=7.4, 3H); MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:42]([O:41][C:39]([N:30]([CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]1=[O:29])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C1CCc2ccccc2N1c1ccccc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
To a solution of 0.45 g (0.00448 mole) of diisopropylamine dissolved in 20 ml of tetrahydrofuran was added dropwise 2.6 ml (0.00448 mole) of n-butyl lithium (a 1.6M hexane solution) at 0° C., and the mixture was stirred for 20 minutes. After the mixture was cooled to -78° C., to the mixture was added dropwise a solution of 1.00 g (0.00448 mole) of 1-phenyl-3,4-dihydroquinolin-2 (1H)-one dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. Next, to the mixture was added dropwise a solution of 2.06 g of di-t-butyl azodicarboxylate dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred at -78° C. for one hour. After completion of the reaction, the reaction mixture was treated with an ammonium chloride aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane (1:5 v/v)) to obtain 1.41 g of the title compound as a colorless caramel-like product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=[CH:6][N:5]=1.[SH:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.O.[OH-].[Na+]>C(O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([S:17][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[N:7]=[CH:6][N:5]=3)=[N:19][C:20]=2[CH:26]=1
Reactant: Cc1c(CCl)ncnc1N1CCCCC1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1

Procedure:
A mixture of 4-chloromethyl-5-methyl-6-piperidino pyrimidine hydrochloride (4.63 g) and 2-mercapto-5-methoxybenzimidazole (3.18 g) in ethanol (180 ml) were heated at 50° for 5 hours. The solution was stripped to a residual glass, to which water was added, the pH raised to 13 (NaOH), and extracted with chloroform. Extracts were dried (K2CO3) and stripped to a residual glass which crystallised from ethyl acetate to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 5.67 g, m.p. 94°-96°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 79%). 1H NMR (200 MHz, CDCl3): δ 3.71 (s, 7H), 4.11 (s, 4H), 6.66 (d, J=9.0 Hz, 2H), 7.10 (m, 1H), 7.22-7.25 (m, 1H), 7.38-7.54 (m, 3H), 7.65-7.68 (m, 1H), 8.19 (d, J=3.8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17](=[O:18])[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][NH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:26](Cl)[CH2:27][OH:28]>CN(C)C=O>[OH:28][CH2:27][CH2:26][N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]1
Reactant: OCCCl
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C)CC3)ncc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C)CC3)ncc2c1=O
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A mixture containing 5.0 g of ethyl 5,8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate, 70 ml of dimethylformamide, 0.90 g of 50% sodium hydride, and 3.8 g of ethylene chlorohydrin was heated at 100°C for one hour. Dimethylformamide was distilled off in vacuo, and the residue taken up in chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent distilled off. The resulting solid was recrystallized from ethanol to yield 4.6 g of the product, m.p. 197° - 199°C.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>C(O)C>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(O)CCC1C(CCCCCCC(=O)OCC)CC(O)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)O)CC(O)C1O
Yield: 45.6 %

Procedure:
Ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (2.6 g.) [prepared as described in (p) above], ethanol (50 ml.) and 2N aqueous sodium hydroxide solution (50 ml.) were heated together at reflux for 18 hours. The ethanol was removed in vacuo, water (25 ml.) was added and the mixture was washed with diethyl ether. The aqueous phase {which was a solution of sodium 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate} was acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, extracted with diethyl ether, and the ethereal extract dried over magnesium sulphate and evaporated in vacuo to give 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (1.1 g.).
Reaction SMILES: [CH:1]1([N:7]([CH3:31])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][OH:28])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C1COCC1>[CH:1]1([N:7]([CH3:31])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][O:28][C:32](=[O:34])[CH3:33])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCO)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCCn1c(NC(=O)c2cccs2)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.8 %

Procedure:
To a solution of 1-(3-hydroxy-propyl)-2-[(thiophene-2-carbonyl)-amino]-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide (Example 4) (0.07 g, 0.16 mmol) in THF (10 mL) was added acetic anhydride (0.02 mL, 0.19 mmol), followed by triethylamine (0.02 mL, 0.17 mmol), and the mixture was stirred at room temperature for 48 h. The resulting solution was washed with 1M HCl (10 mL) and the organic layer was dried over magnesium sulfate. The solvent was evaporated and the resulting oil was purified by flash chromatography with 5% MeOH/dichloromethane to give the title compound (0.05 g, 65%), m.p. 74-76° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([CH2:2][CH2:3][N:7]([CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: CNc1ccccc1
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCC(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
Acrylic acid (36.03 g; 0.5 mol) was added to N-methylaniline (53.58 g; 0.5 mol) and an exothermic reaction took place after which reaction was virtually complete. The mixture was stood overnight at room temperature and then diluted with water and made alkaline by the addition of sodium carbonate. The mixture was washed with dichloromethane and then the aqueous layer was cautiously acidified to pH 4.5 by the addition of concentrated hydrochloric acid SG 1.18. The resulting mixture was extracted into dichloromethane and washed with water The organic extract was dried (MgSO4) and the solvent removed by evaporation under reduced pressure to give a pale brown oil (57.32 g; 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (1 g, 3.52 mmol) in tetrahydrofuran (14.1 ml) at −40° C. was added isopropylmagnesium chloride (1.85 ml, 3.70 mmol). After 2 h, H2O (3.52 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (470 mg, 2.04 mmol, 58% yield) as a white solid: LCMS (ES) m/e 204, 206 (M, M+2)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]=[CH:21][CH2:22][CH2:23][CH:24](O)[CH2:25][CH2:26][CH:27]=[CH2:28].C1(=O)[NH:34]C(=O)C2=CC=CC=C12.N(C(OCC)=O)=NC(OCC)=O.O.NN>O1CCCC1.CO.CCCCCC>[CH2:20]=[CH:21][CH2:22][CH2:23][CH:24]([NH2:34])[CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCC(O)CCC=C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: C=CCCC(N)CCC=C
Reaction time: 0.5 h

Procedure:
9.21 g (35 mmol) of triphenylphosphine, 4.50 g (32 mmol) of 1,8-nonadiene-5-ol (8), and 6.03 g (41 mmol) of phthalimide were dissolved in 150 ml of tetrahydrofuran. This solution thus obtained was stirred for 30 minutes, and at room temperature, 15 ml (33 mmol) of diethyl azodicarboxylate (2.2 mol/l solution in toluene) was thereafter dropped in the solution, which was then stirred for 12 hours. Subsequently, hexane was added to the solution, and a precipitate was filtered off, and the filtrate thus obtained was dried over sodium sulfate. The solvent was distilled off, and the crude product thus obtained was purified by silica gel column chromatography (eluent: hexane:ethyl acetate of 5:1). The product thus obtained was dissolved in 50 ml of methanol, and 3 ml of hydrazine hydrate was added to the solution thus obtained, which was then refluxed for 1 hour. The reaction solution thus obtained was cooled, and a white precipitate was obtained by filtration and was washed with methanol. The filtrate thus obtained was concentrated, hexane was then added to the filtrate, and a white precipitate thus produced was obtained by re-filtration and was washed with hexane. Then, the solvent was distilled off from this filtrate. Thus, 2.58 g (18 mmol) of a slightly yellow liquid was obtained as an intended compound (9). A yield of the compound (9) was 57%. 1,8-nonadiene-5-ol (8) as a synthetic starting material can be synthesized in the same manner as in Reference Example 8 (synthesis of starting material for Example 13) described below, for example. Values obtained by instrumental analysis of the compound (9) are shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Reactant: NC1CCCC1
Product: N#Cc1c(NC2CCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of cyclopentylamine to give 12 mg (11% of theory) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C1COCC1.C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[N:6]1[CH:7]=[CH:8][C:9]([Br:17])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(n1cccc1)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(n1ccc(Br)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-(tert-butyldiisopropylsilyl)-1H-pyrrole (1.0 g, 4.48 mmol) in THF was added N-bromosuccinimide at −78° C. The reaction mixture was slowly warmed to RT and stirred for 24 hours. The reaction mixture was concentrated to obtain dark black residue, which was suspended in CCl4 (100 mL) and stirred for 15 min and filtered. The filtrate was concentrated to obtain 1-(tert-butyldiisopropylsilyl)-3-bromo-1H-pyrrole as oily liquid (1.0 g).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12.O.CN1CCOCC1.[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44](Cl)=[O:45])=[N+:34]=[N-:35]>CC(C)=O>[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:16][N:17]=[N:18][N:19]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12)=[O:45])=[N+:34]=[N-:35]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)Cl
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: [N-]=[N+]=NCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3 g., 0.008 mole) was suspended in 50 ml. of water. The suspension was cooled to 0° C. and then N-methylmorpholine (3 g., 0.03 mole) was added. After a solution was obtained, 50 ml. of acetone was added. An acetone solution of 2-azidomethylphenylacetyl chloride (prepared from 2 g. of 2-azidomethylphenyl acetic acid and 2 ml. of thionyl chloride in 100 ml. of methylene chloride) was added dropwise at 0° to 5° C. over 10 minutes. The resulting mixture was stirred for one hour and then the acetone was distilled off with the aid of vacuum. The aqueous layer was extracted once with 50 ml. of toluene. To the aqueous layer was added 50 ml. of ethyl acetate and the pH was adjusted to 2.6 using phosphoric acid (85% diluted with equal volume of water). The ethyl acetate layer was carbon treated and dried over anhydrous sodium sulfate. After filtration the solution was concentrated to give 7-(2-azidomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-caboxylic acid as a foam-like product which weighed 3.6 g. NMR and IR spectroscopy data were consistent with the expected structure. A small sample was hydrogenated in water using Raney nickel as catalyst to give a product which was identical in every way to an authentic sample of 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (III).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(N)Cc1cccc([N+](=O)[O-])c1
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.52 cm3 of acetic anhydride are added dropwise to 12 g of ethyl 2-amino-3-(3-nitrophenyl)propanoate at a temperature in the region of 0° C. After stirring at 0° C. for 1 hour, the mixture sets to a solid. 10 cm3 of acetic anhydride are then added and stirring is continued at 0° C. for a further 1 hour. The precipitate is filtered off on a sinter funnel, washed with 3 times 25 cm3 of water and dried in a fume cupboard and then in an oven under vacuum (10 Pa) at a temperature in the region of 50° C. 12 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the form of white crystals melting at 91° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 1.14 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.04 (dd, J=14 and 9 Hz: 1H); 3.18 (t, J=14 and 4 Hz: 1H); 4.08 (q, J=7 Hz: 2H); 4.52 (mt: 1H); 7.61 (broad t, J=8 Hz: 1H); 7.72 (broad d, J=8 Hz: 1H); 8.12 (mt: 2H); 8.42 (d, J=8.5 Hz: 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:28][CH3:29])[CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:35]>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:28][CH3:29])[CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:35])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Product: CCN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2c1CCCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 70%). 1H NMR (500 MHz, CDCl3): 0.9-4.2 (cm, 18H), 5.9 (s, <1H), 6.9-7.5 (cm, 6H), 8.0 (s, <1H), 9.7 (m, 1H). LCMS: m/z 393 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19](=O)[CH2:20]Br)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:37][C:38]([NH2:40])=[S:39].CC([O-])=O.[Na+]>CCO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]3[N:37]=[C:38]([NH2:40])[S:39][CH:20]=3)[CH:18]=2)=[O:12])=[CH:35][CH:36]=1)(=[O:3])=[O:4]
Reactant: NC(N)=S
Reactant: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2csc(N)n2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 69 %

Procedure:
5-Bromoacetyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (Example 50 (c), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 90° C.) for 20 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLC giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:26]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2′,3′,5′-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2′,3′,5′-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.