Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.C([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH:31]=4)[CH:26]=[N:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.F[C:43](F)(F)C(O)=O>N1C=CC=CC=1.C(O)(=O)C>[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])=[O:34])[CH:31]=4)[CH:26]=[N:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)(=[O:8])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Into dichloromethane (5 mL), 2-(trimethylsilyl)ethyl 4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoquinoline-6-carboxylate (103 mg, 0.193 mmol) synthesized in Example 16 (16a) was dissolved, to which trifluoroacetic acid (0.5 mL) was added, followed by stirring at room temperature for three hours. After concentration, the resulting mixture was diluted with dichloromethane (20 mL) and neutralized with a saturated aqueous solution of sodium bicarbonate (15 mL). The resulting organic layer was dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in pyridine (5 mL), to which anhydrous acetic acid (0.5 mL) was added, followed by stirring at room temperature overnight. After concentration, the resulting mixture was diluted with dichloromethane (20 mL) and neutralized with a saturated aqueous solution of sodium bicarbonate (15 mL). The solution thus obtained was extracted with dichloromethane (20 mL), and the resulting organic layer was dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure and the resulting product was purified by thin layer chromatography (dichloromethane:methanol=97:3) to give the desired title compound (54 mg, yield 58%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCO>O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Yield: 83.9 %

Procedure:
A mixture of ethyl 3-amino-6-chloro2-(3-methylbenzoyl)-1H-indole-1-caboxylate (step 1, 6.4 g, 18 mmol), K2CO3 (6.3 g, 45 mnmol) , EtOH (50 ml) and water (30 ml) was heated at reflux temperature for 20 h. The mixture was concentrated, and then water (30 ml) was added to the residue. The resulting mixture was extracted with dichloromethane (80 ml×2) and the combined extracts were dried (MgSO4). Removal of solvent gave 4.3 g (84%) of brown amorphous solids.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][N:38]([C:41](OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH:34]=2)O1>>[CH:18]1([O:17][C:3]2[C:2]([C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH:34]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:16])[N:8]3[C:12]([O:14][CH3:15])=[O:13])[CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(OC3CCC3)c2CC[C@@H]1C

Procedure:
Methyl (S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate according to the procedure outlined above for Example 60. 1H NMR (300 MHz, CDCl3) δ ppm 0.64-0.99 (m, 1H), 1.12-1.26 (m, 4H), 1.39-1.52 (m, 1H), 1.55-1.67 (m, 1H), 1.97-2.14 (m, 5H), 2.14-2.27 (m, 1H), 2.30-2.58 (m, 2H), 2.63 (br s, 1H), 2.73-2.78 (m, 1H), 2.79 (s, 3H), 2.84-3.09 (m, 1H), 3.15 (br s, 1H), 3.37-3.63 (m, 4H), 3.64-3.92 (m, 3H), 4.54 (s, 1H), 7.14-7.39 (m, 2H), 7.81 (d, J=8.21 Hz, 2H). MS (ESI, pos. ion) m/z 439 [M+H]+.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)(=O)C>>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[S:19][CH:20]=1
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CC(=O)Cl
Product: CCCCCC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 40.7 %

Procedure:
This compound is prepared according to a protocol identical to that described for Example 355, with the compound of Example 362 and hexanoyl chloride respectively replacing intermediate 355.2 and acetyl chloride in Stage 355.3. The expected product is obtained in the form of a brown solid with a yield of 40.7%. Melting point: 192.0-194.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12](C)(=[O:14])=[O:13])[CH2:5]2.C(N[CH:20]([CH3:22])[CH3:21])(C)C.[Li].CI.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH:20]([CH3:21])[CH3:22])(=[O:14])=[O:13])[CH2:5]2
Reactant: CC(C)NC(C)C
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Agent: [Li]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.8 mmol) of 5-chloro-2-methylsulfonylindan-1-ol were dissolved in 5 ml of dry tetrahydrofuran. The solution was cooled to −70° C., and 0.4 ml (0.8 mmol) of lithium diisopropylamine (2 M solution in tetrahydrofuran) was added dropwise under an atmosphere of nitrogen. The reaction solution was stirred at −70° C. for 30 min, and 62.2 μl (1 mmol) of methyl iodide were then added. The reaction mixture was warmed to 0° C., water and then ethyl acetate were added, the organic phase was separated off, dried over magnesium sulfate and filtered and the filtrate was concentrated. Chromatographic purification of the residue (silica gel; heptane/ethyl acetate 1/1) gave 5-chloro-2-(propane-2-sulfonyl)indan-1-ol as a wax-like substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3([CH3:28])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: CC1(C(=O)O)CC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(C)CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 1-methyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=361.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5RS)-[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methanol (6.0 g, 0.023 M, see Pharmacia & Upjohn WO 98-07708), triethyl amine (3.9 mL, 0.028 M), and 4-(dimethylamino)pyridine (0.56 g, 4.58 mM), were combined in dichloromethane (36 mL). A solution of tert-butyldimethylsilyl chloride (1 M in dichloromethane, 26 mL, 0.028 M) was added and the resulting mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water and extracted with dichloromethane. The combined organics were dried (magnesium sulfate), filtered and evaporated. The crude material was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to give 8.4 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)[CH2:3][CH2:2]1)=[O:31])([CH3:25])([CH3:23])[CH3:24]
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Reactant: CC(C)(C)NC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83.2 mg (0.299 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo[b,f]azepine, 62.2 mg (0.359 mmol) of 4-(t-butylamino)-4-oxobutanoic acid and 82.6 mg (0.431 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 5 ml of dichloromethane. 0.06 ml (0.431 mmol) of triethylamine and 3.67 mg (0.03 mmol) of 4-dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added thereto. After washing with 1 N aqueous hydrochloric acid solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane:methanol=9:1) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.[Br:18]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:18])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A solution of 51 parts of p-nitrobenzal bromide in 500 parts of carbon tetrachloride is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in 2,000 parts of water at 50° C. The mixture is stirred with a mechanical stirrer for 2.5 hours. The carbon tetrachloride layer is separated, dried and evaporated to give 58 parts (90% yield) of p-nitrobenzotribromide, m.p. 81-3° C.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[CH2:20][CH:21]=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:8])=[O:7].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:1][CH:20]([C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7])[CH:21]=[O:22]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc(CC=O)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(C)C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
Sodium bicarbonate (318 mg) was added to the mixture of ethyl 3-nitro-4-(2-oxoethyl)benzoate (401 mg) and MeI (426 mg) in DMF (5 ml), stirred for over night at r.t., diluted with ethyl acetate, washed with water and saturated saline water in that order, and dried with sodium sulfate. This was filtered, concentrated, and purified through silica gel column (hexane/ethyl acetate) to give title compound (227 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[O:5][C:6]1([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:19]([OH:21])[CH:20]=3)=[N:13][N:14]=[C:7]12.C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH3:44].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[O:5][C:6]1([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:19]([O:21][CH2:43][CH3:44])[CH:20]=3)=[N:13][N:14]=[C:7]12
Reactant: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(Oc3ccc(F)c(F)c3)C(C)(C)O)cc2O)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2nnc3n2CCCC3(Oc2ccc(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Reaction time: 8 h

Procedure:
To a mixture of 5-[8-(3,4-difluorophenoxy)-8-(1-hydroxy-1-methylethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]-2-(2-methyl-1,3-oxazol-5-yl)phenol (41.1 mg) and potassium carbonate (24 mg) in DMF (0.43 ml) was added iodoethane (60 μL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (38.1 mg).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][Cl:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][Cl:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCl)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCl)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.75 g.) and conc. hydrochloric acid (0.3 g.) in methanol (5.25 ml.) was stirred at 30° C. for 3 hours. After removing the solvent in vacuo, ethyl acetate and water were added to the residue and adjusted to pH 7.0 with sodium bicarbonate. The aqueous solution was separated, washed with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.43 g.).
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=C\CC)[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[CH2:38][C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)SCSc1c[nH]nn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2CC(=O)N12
Reaction time: 0.33 h
Yield: 111.4 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg : 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred for 20 minutes, mixed with a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-pentenoylamino]-3-methanesulfonyloxy-3-cephem -4- carboxylic acid diphenylmethyl ester (740 mg : 1 mMol.) in dimethylformamide (3 ml), and stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 10% hydrochloric acid (2 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene : ethyl acetate=2:1) to give 7β-(Z)-2-(2- t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4- ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (553 mg) as colorless foam. Yield : 70%.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:21](Cl)=[O:22].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][C:21](=[O:22])[CH:20]([Br:19])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC(Br)C(=O)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a rapidly-stirred slurry of 5.18 g (20.0 mmol) methyl (R)-3-hydroxytetradecanoate and 5.03 g (20.8 mmol) 2-bromooctanoyl chloride in 100 mL hexanes at 0° C. in a flame-dried flask under N2 was added 1.67 mL (20.6 mmol) pyridine all at once. After stirring for 10 minutes the cloudy white mixture was poured into a separatory funnel containing a mixture of 200 mL tap H2O/100 mL ether. This mixture was shaken and the layers separated. The aqueous layer was extracted with 2×100 mL ethr. The combined ether layers were washed with 200 mL brine, and 3×200 mL H2O. The ether was dried over MgSO4 and removed by rotary evaporation, giving 8.95 g crude product. This yellow oil was dissolved in 30 mL CH2Cl2 and suction filtered through a 1" pad of silica gel 60 in a 60 mL coarse sintered glass funnel, washing with 150 mL CH2Cl2. Rotary evaporation gave 8.10 g (87%) (R)-3-[(2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester as a yellow oil. The oil was found to be suitable for use in the cyclization reaction producing the lactone of Example 5. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:51])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[C:38]([O:43]CC6C=CC=CC=6)[CH:39]=5)[CH:34]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[Pd]>[C:1]([O:5][C:6](=[O:52])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:51])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[C:38]([OH:43])[CH:39]=5)[CH:34]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(OCc6ccccc6)ccc5c4)cc4ccnn34)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc5cc(O)ccc5c4)cc4ccnn34)cc2)cc1
Yield: 48 %

Procedure:
A mixture of (4-{4-[5-(6-benzyloxy-naphthalen-2-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenylcarbamoyl}-benzyl)-carbamic acid tert-butyl ester (compound A2)(750 mg) and Pd/C (10%, 100 mg) in dioxane (100 ml) is hydrogenated (1.1 bar) at 80° C. for 3 days. The reaction mixture is filtered and the filtrate is evaporated. After silica gel flash chromatography the product is obtained as colorless solid in 48% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)[CH2:2][CH3:3].S(=O)(O)[O-].[Na+].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CN(C)C=O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:26]([C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][N:18]=3)=[N:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CCCc1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 200 °C

Procedure:
A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, Reference Example 30(d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml) was treated with indazole-3-carboxaldehyde [Reference Example 6(l)]. The reaction mixture was heated in a Smith Creator microwave at 200° C. for 13 minutes then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3:1) to give 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole (74 mg) as a pale brown solid. MS: 277.3 (M+H)+. HPLC (METHOD B1): RT=12.81 minutes. (b) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(OC(C=C([NH:36][CH2:37][C:38]([O-])=[O:39])C)=O)C.[Na+].[K+].[Br-]>>[NH2:36][CH2:37][C:38]([NH:1][CH:2]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]12)=[O:4])=[O:39]
Reactant: CCOC(=O)C=C(C)NCC(=O)[O-]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CN)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Yield: 45 %

Procedure:
The title compound is prepared in 45% yield from 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetate, using the procedure of Example XC. The product has m.p. 173°-188° C. (dec.). IR (KBr disc): 1785 cm-1 (β-lactam). NMR (DMSO-d6): 7.55-7.10 ppm (m, 2H), 7.00-6.00 ppm (m, 2H), 5.75-5.40 ppm (m, 3H), 5.10 ppm (s, 1H), 3.65 ppm (m, 2H), 1.55 ppm (s, 3H), 0.95 ppm (s, 3H).