Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=O)[C:22](OC)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36]>C(O)C>[O:23]=[C:22]1[NH:36][C:31]2[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:21]1[C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1
Reactant: COC(=O)C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4nc5ccccc5[nH]c4=O)c3c2)c1=O
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A mixture of methyl 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.7500 g, 1.81 mmol), 1,2-diaminobenzene (0.200 g, 1.84 mmol) and ethanol is stirred 16 hours at reflux and filtered hot. The filtrate is concentrated in vacuo to afford the title compound as a light yellow solid (0.480 g, 56.3%, mp >250° C.) which is identified by NMR analysis.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[N:2]1([NH:1][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NN1CCOCC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NN3CCOCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using 4-aminomorpholine (0.025 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 391 (M+1); Rt=3.12 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:24][C:25]3[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=3)[C:19](=[O:23])[CH2:20][C:21]#[N:22])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:35][CH:36]=3)[C:19](=[O:23])[CH2:20][C:21]#[N:22])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)CC#N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)CC#N)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(cyanoacetyl)amino]methyl}phenoxy)acetate and NaOH 1 N in the presence of DMF, as a white powder (20%). M− (ESI): 493.3; M+ (ESI): 495.3. HPLC, Rt: 5.01 min (Purity: 80.6%).
Reaction SMILES: NC[C:3]1O[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.C([O:20][CH:21](C)C)(C)C>C(O)C>[NH2:16][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[CH:5]=[C:4]([CH2:3][NH:9][C:10](=[N:13][C:14]#[N:15])[S:11][CH3:12])[O:20][CH:21]=2)[N:9]=1)[NH2:15]
Reactant: CC(C)OC(C)C
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CCO
Product: CSC(=NC#N)NCc1cc(-c2csc(N=C(N)N)n2)co1
Temperature: 25 °C

Procedure:
A mixture of 4-(5-aminomethylfuran-2yl)-2-(diaminomethyleneamino)thiazole (8.00 g) and dimethyl-N-cyanodithioiminocarbonate (2.54 g) in ethanol (80 ml) was refluxed for two hours with stirring. After cooling to room temperature, diisopropyl ether (80 ml) was added and the resulting precipitate was collected filtration. Recrystallization from a mixture of N,N-dimethylformamide and ethyl acetate to give 2-(diaminomethyleneamino)-4-[5-(3-cyano-2-methyl-1-isothioureido)methylfuran-3-yl]thiazole (10.2 g).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[Br:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13]C[CH:15](C3C=CC=CC=3)[CH2:16][C:17](=[N:18][C:19]#[N:20])[C:11]=2[CH:10]=1>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:17]3([O:4][N:3]([CH3:2])[C:19]([NH2:20])=[N:18]3)[CH2:16][CH2:15][O:13][C:12]2=[CH:27][CH:28]=1
Reactant: CNO
Reactant: N#CN=C1CC(c2ccccc2)COc2ccc(Br)cc21
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CN1OC2(CCOc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (42 mg, 0.5 mmol) in MeOH (10 mL) was added MeONa (0.1 mL, 25% (Wt.) in MeOH), followed by N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (170 mg, 0.5 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (140 mg, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])=[CH:5]2.I[CH2:34][C:35]([OH:37])=[O:36].[H-].[Na+]>CN(C=O)C>[C:35]([CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])=[CH:5]2)([OH:37])=[O:36]
Reactant: O=C(O)CI
Reactant: CN1C(=O)C(NC(=O)c2cc3cc(O)ccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)c2cc3cc(OCC(=O)O)ccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Dihydro-3-(5-hydroxyindole-2-carbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.1 g, 0.236 mmol) and iodoacetic acid (0.044 g, 0.236 mmol) were combined in dry DMF (2 ml) and treated with sodium hydride (18.8 mg of a 60% suspension in mineral oil; 0.472 mmol). The mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness in vacuo. To the residue were added water, dilute sodium bisulfite solution, then saturated sodium bicarbonate. The aqueous phase was washed with EtOAc, made acidic with 6N HCl, and extracted with EtOAc. The acid layer extract was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 180:10:1:1 of CH2Cl2 :MeOH:HOAc:H2O. The product fractions were evaporated to dryness in vacuo and the residue triturated with ether to give the title compound which was dried in vacuo at 90° C. overnight: (mp 150°-180° C. (↑)).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10](=[S:22])[NH2:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCN(C2CC2)CC1
Solvent: C1CCOC1
Product: NC(=S)C1CCN(C2CC2)CC1

Procedure:
1-cyclopropylpiperidine-4-carboxamide was suspended in dry THF (20 mL) and Lawesson's reagent (2.7 g, 6.67 mmol) was added. After refluxing for 6 h the solvent was concentrated under reduced pressure. The residue was dissolved in a ethyl acetate/MeOH mixture and washed with saturated aqueous NaHCO3. The aqueous phase was back-extracted with ethyl acetate and evaporated to dryness. The crude product was treated with ethanol and filtered. The white solid was dried under high vacuum affording 2.7 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:31])([F:19])[F:32])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 33.3 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 2-(3-trifluoromethylphenyl)-acetyl chloride to afford the title compound (30 mg, 33.3%). 1H-NMR (δ, ppm, DMSO-d6): 3.77 (s, 2H, CH2), 6.43 (d, 1H, HPy,5, J=5.9 Hz), 6.83-6.86 (m, 1H, Harom), 7.34-7.64 (m, 7H, Harom), 7.67 (s, 1H, Harom), 7.78 (d, 1H, HPy,6, J=5.9 Hz), 10.39 (s, 1H, NHamide), 11.21 (s, 1H, NHPy7), 11.42 (s, 1H, NHPy9). LC-MS, tR=4.56 minutes, m/z: 429.05 (M+H)+, calculated for C21H16N4O3F3. HRMS (EI): m/z [M+H] calculated for C21H16N3O4F3: 429.1175; found: 429.1175.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[S:6]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]12.O>C(Cl)(Cl)(Cl)Cl>[Cl:5][S:1]([C:13]1[N:12]=[CH:11][N:8]2[CH:9]=[CH:10][S:6][C:7]=12)(=[O:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: c1cn2cncc2s1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ncn2ccsc12

Procedure:
A solution of chlorosulfuric acid in 20 ml of carbon tetrachloride was added under ice cooling to a solution of 11.18 g of imidazo[5,1-b]thiazole in 200 ml of carbon tetrachloride. The reaction mixture was heated under reflux for 6 hr. Water was added thereto under ice cooling to terminate the reaction. The mixture was extracted with dichloromethane. The organic layers were combined together. The combined organic layers were washed with a dilute aqueous sodium hydroxide solution and saturated brine in that order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. Isopropyl ether was added to the residue. The resultant powder was collected by filtration to give 4.01 g of 7-chlorosulfonylimidazo[5,1-b]thiazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([S:23][C:24]2[S:25][C:26]([NH2:29])=[N:27][N:28]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[Na].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:40][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[S:23][C:24]1[S:25][C:26]([NH2:29])=[N:27][N:28]=1)[C@H:11]([NH:10][C:8](=[O:9])[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][C:4]=1[Cl:32])=[N:30][OH:31])[C:18]2=[O:19])=[O:22])=[O:39]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NO)c3nc(N)sc3Cl)C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (65 mg, 0.117 mmol) in DMF (0.3 mL) under nitrogen was added iodomethyl pivalate (31 mg, 0.128 mmol). After 1 h, water was added dropwise, and the precipitated product was removed by filtration to give 60.9 mg of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:21])=[C:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>C1COCC1>[CH:16]1([C:15]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([CH3:21])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)=C1C=CC=C1
Solvent: C1CCOC1
Product: CC(C)(c1cccc2c1Cc1ccccc1-2)C1C=CC=C1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
To 200 ml of THF and 16.5 g of fluorene cooled to a temperature of -50° C. or lower in a 500-ml flask thoroughly purged with nitrogen was added 67 ml of a dil. methyllithium diethyl ether solution (1.4 M) dropwise over 30 minutes. The mixture was warmed gradually to room temperature and subjected to reaction for 3 hours. The reaction mixture was cooled back to a temperature of -50° C. or lower and 10 g of 6,6-dimethylfulvene was added dropwise over 30 minutes. After the addition was completed, the solution was warmed slowly to room temperature and subjected to reaction for 2 days. The reaction was terminated by the addition of 60 ml of H2O, and the ether layer was separated and dehydrated over anhydrous MgSO4. Drying ether by evaporation, gave 17.6 g of 2-cyclopentadienyl-2-fluorenylpropane as crude crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(Cl)c1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 2-chloro-4-cyanophenol (2.15 g), 3-bromo-1-chloropropane (2.3 g), dimethylformamide (3 ml) and potassium carbonate (1.5 g) was heated at 100° C. for one hour. The inorganic salt was then filtered off and the solvent was distilled off. The residue was dissolved in chloroform, chromatographed on a column of silica gel (80 g), and eluted with a solution of petroleum ether-ethyl acetate (10:1) to give 3-(2-chloro-4-cyanophenoxy)propyl chloride as a colorless oil (3.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12].O.[NH2:18][NH2:19]>CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[NH:19][N:18]=1
Reactant: NN
Reactant: COC(=O)C(=O)CC(=O)c1ccccc1Br
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2Br)n[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of methyl 4-(2-bromophenyl)-2,4-dioxobutanoate (540 mg, 0.0019 mol) in AcOH (4 mL) was added hydrazine monohydrate (67 mg, 0.00208 mol). The reaction mixture was allowed to stir at 130° C. overnight and then concentrated. The residue was dissolved in EtOAc, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give methyl 3-(2-bromophenyl)-1H-pyrazole-5-carboxylate (0.516 g, 97%) as a white solid. LCMS: (FA) ES+ 283.2, ES-281.2.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10](=O)[CH:11]=[CH:12][CH:13]=[CH:14][CH3:15].[BH4-].[Na+]>C(O)C>[CH2:10]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH3:15]
Reactant: CC=CC=CC=O
Reactant: C[C@H](N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C/C=C/C=C/CN[C@@H](C)c1ccccc1
Temperature: 0 °C
Yield: 90.9 %

Procedure:
To a solution of (S)-α-methylbenzylamine (1) (1.00 g, 8.25 mmol) in ethanol (20 ml) was added 2,4-hexadienal (0.833 g, 8.66 mmol) and the resulting mixture was refluxed for 1 hour. The solution was cooled to 0° C. and sodium borohydride (0.468 g, 12.38 mmol) was slowly added in portions. This solution was allowed slowly to warm to room temperature overnight (16 hours) after which the ethanol was removed under reduced pressure and the residue dissolved in ethyl acetate (50 ml). This solution was washed with brine (30 ml), dried (magnesium sulphate), filtered and evaporated to give an orange oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:4)], followed by distillation under reduced pressure [130° C. 1 mmHg] to afford the title compound (3) as a colourless oil (1.51 g, 91%), δH (300 MHz; CDCl3) 7.37-7.21 (5H, m, Ph), 6.08 (2H, m, CH=CH--CH=CH), 5.63 (2H, m, CH=CH--CH=CH), 3.80 (1H, q, J=6.6, PhCHCH3), 3.10 (2H, d, J=6.5, NCH2), 1.74 (3H, d, J=6.8, CH=CHCH3), 1.49 (1H, br s, NH), 1.36 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].CCO.[OH-].[Na+]>O>[Cl:1][C:2]1[N:6]([CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(Cn1c(Cl)nc2ccccc21)OCC

Procedure:
A mixture of 2-chloro-1H-benzimidazole (6.10 g), bromoacetaldehyde diethyl acetal (7.22 mL), EtOH (70 mL), and 8 M NaOH aqueous solution (10 mL) was refluxed for 3 d. The reaction mixture was poured into water and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (10/1) to give 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (5.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:23][N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:15]([NH:17][CH:18]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH2:40][C:39]([N:38]([CH3:43])[CH3:37])=[O:42])[CH2:28][CH2:29]4)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH2:13]3)[CH2:6]1)[CH2:14]2)=[O:4]
Reactant: COC(=O)C(CN1CCNCC1)NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reactant: CN(C)C(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CN1CCN(CC(=O)N(C)C)CC1)NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reaction time: 4 h

Procedure:
Methyl 2-(3-Methoxycarbonyladamant-1-ylcarbonylamino)-3-(piperazin-1-yl)propionate (114 mg, 0.28 mol) was dissolved in anhydrous dichloromethane (10 mL) and Et3N (3.0 eq) and N,N-dimethyl 2-chloroacetamide (3.0 eq) were added. The reaction mixture was refuxed at 50° C. for 4 hours. The solvent was then evaporated under reduced pressure and the crude material was purified by column chromatography (silica gel; CHCl3/MeOH 9:1) to afford the title compound.
Reaction SMILES: C(O[CH:4]([O:17]CC)[CH2:5][CH2:6][N:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:8]([NH2:10])=[O:9])C.C1C=CC2N(O)N=NC=2C=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([S:41]([CH2:44][C@@H:45]([OH:49])[C:46](O)=[O:47])(=[O:43])=[O:42])[CH:35]=[CH:34]2.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([S:41]([CH2:44][C@@H:45]([OH:49])[C:46]([N:14]1[CH2:13][CH2:12][CH:11]([N:7]3[CH2:6][CH2:5][CH:4]([OH:17])[NH:10][C:8]3=[O:9])[CH2:16][CH2:15]1)=[O:47])(=[O:42])=[O:43])[CH:35]=[CH:34]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(CCN(C(N)=O)C1CCNCC1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCC(O)NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of N-(3,3-diethoxypropyl)-N-piperidin-4-yl urea (7.79 g) obtained in Example 46a), HOBt (4.81 g) and (2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropionic acid (9.88 g) in DMF (200 mL) was added WSC (6.02 g) at room temperature. The mixture was stirred at room temperature overnight, and DMF was distilled off under reduced pressure. The residue was diluted with chloroform, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (from ethyl acetate to ethyl acetate/ethanol=97/3) to obtain the title compound (9.41 g, 52%) as a white powder.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:15]2)=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:15]1)=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@H]4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@@H]4CCN(C=N)C4)C3)[C@H](C)[C@H]12
Yield: 51 %

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-1-(N-4-nitrobenzyloxycarbonylformimidoyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 12 ml of 1:1 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 23(b), to give 50 mg of the title compound as a powder.
Reaction SMILES: [CH:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:9]3[CH:31]=[C:32]([CH3:36])[C:33]([CH3:35])=[CH:34][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:16][CH:17]=3)[C:9]3[CH:31]=[C:32]([CH3:36])[C:33]([CH3:35])=[CH:34][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2nc(C3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nc(C3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclopentyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:7][C:6]1[O:5][C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CCl
Temperature: 25 °C

Procedure:
4.20 g {4-Methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-yl}-methanol were dissolved in 20 ml dichloromethane and cooled in an ice bath. 3.10 ml triethylamine were added, followed by the addition of 1.37 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 4.0 g 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[N:16]=1>CN(C)C=O.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:18]=1
Reactant: Cc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (1.70 g, 0.0021×5.0 mol) and sodium hydride (0.42 g, (ca.60% in mineral oil), 0.0021×5.0 mol) in dimethylformamide, 2-chloro-4-methyl-6-(3-thienylmethyloxy)pyridine (0.5 g, 0.0021 mol) and CuI (0.20 g, 0.0021×0.5 mol) were successively added and the resultant solution was refluxed for about 5 hours.