Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1
Temperature: 50 °C

Procedure:
4-Bromophenylacetic acid (100 g, 0.465 mol), thionyl chloride (300 mL) and DMF (about 2 mL) are charged to a 1-liter round bottom 3-necked flask equipped with a reflux condenser and a mechanical stirrer. The reaction mixture is heated under nitrogen to 50° C. for 2 hours, using a charcoal scrubber for escaping gases. The thionyl chloride is evaporated and the product, 4-bromophenylacetyl chloride, is put into an addition funnel with benzene (30 mL).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: OCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Nitrophenyl chloroformate (0.56 g, 2.8 mmol) was added to a mixture of cyclopropyl carbinol (0.20 g, 2.8 mmol) and triethylamine (0.58 mL, 4.2 mmol) in methylene chloride (5 mL). The mixture was stirred at r.t. for 2 h. After removal of solvent, the residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product.
Reaction SMILES: CS([O:5][CH2:6][C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[I-].[Na+].[SH:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C)C=O>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:32][C:6](=[O:5])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reactant: Sc1nc2ccccc2s1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Sc1nc2ccccc2s1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A solution of Nα-Boc-Nδ-Cbz-ornithinol methanesulfonate (100 mg), sodium iodide (70 mg), dimethylformamide (2.5 ml), 2-mercaptobenzothiazole (70 mg) and diisopropylethylamine (85 μl) was stirred at 70° C. for 12 h. After cooling to ambient temperature, the reaction mixture was poured into ethyl acetate and worked up. The crude material was chromatographed over silica gel (20 to 50 % ethyl acetate/hexane) to afford titled product (50 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ1.39 (s, 9H), 1.58-1.69 (m, 4H), 3.22 (m, 2H), 3.54 (m, 2H), 3.99 (m, 1H), 5.12 (s, 2H), 7.23-7.42 (m, 1H), 7.77 (d, J=10.3 Hz, 1H), and 7.86 (d, J=9.7 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:19]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:18]([NH2:28])[N:17]([C:29]3[CH:34]=[C:33]([C:35](=[O:40])[NH:36][CH:37]4[CH2:39][CH2:38]4)[CH:32]=[CH:31][C:30]=3[CH3:41])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:28][C:18]1[N:17]([C:29]2[CH:34]=[C:33]([CH:32]=[CH:31][C:30]=2[CH3:41])[C:35]([NH:36][CH:37]2[CH2:38][CH2:39]2)=[O:40])[N:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:19]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)c2ccccc2)c1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1nc(OC2CCNCC2)c(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of 4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester 8 (5.0 mg, 0.0089 mmol) in dichloromethane (2.0 ml) was added trifluoroacetic acid (0.5 ml). The mixture was stirred at room temperature for 3 h. Volatiles were removed in vacuo and the residue was washed with ether and a small amount of EtOAc to give the desired 3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide, trifluoroacetate salt 9 as a white solid (3.0 mg, 59%). HPLC (4 minute 10-90 gradient) tR1.75 min; MS m/z 460.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, 1=4.0, 1H), 8.33 (bs, 2H), 7.90 (d, J=8.0, 1H), 7.83 (s, 1H), 7.62 (d, J=7.0, 2H), 7.44-7.52 (m, 4H), 7.03 (bs, 2H), 4.82 (m, 1H), 2.97 (m, 2H), 2.85 (m, 1H), 2.73 (m, 2H), 2.27 (s, 3H), 1.91 (m, 2H), 1.73 (m, 2H), 0.71 (m, 2H), 0.57 (m, 2H) ppm.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26](Br)[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:23]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:19][N:18]=1)=[O:16])[CH3:13].C(=O)([O-])O.[Na+].CN(C=O)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O>[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:23]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:19][N:18]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(-c2cc(C=Cc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a mixture of trans-2-phenylvinylboronic acid (0.472 g, 3.2 mmol) and 5-(2,4-Bis-benzyloxy-5-bromophenyl)-isoxazole-3-carboxylic acid ethylamide (1.079 g, 2.13 mmol) was added sodium hydrogen carbonate (536 mg, 6.39 mmol) followed by DMF (25 mL) and water (5 mL). The mixture was degassed by evacuation and flushing with nitrogen (three times), followed by bubbling nitrogen gas through mixture for five minutes. Dichlorobis(triphenylphosphine)palladium (II) (149 mg, 0.21 mmol) was added and reaction mixture was heated under a nitrogen atmosphere at 80° C. for seven hours (reaction mixture becomes dark brown in colour after 10 minutes). The reaction mixture was allowed to cool to ambient temperature and the majority of solvents were removed in vacuo. The resulting residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and this mixture was filtered through a pad of celite to remove Palladium residues. The phases were separated and the organic phase was washed with water (2×50 mL), saturated aqueous sodium chloride solution (100 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a brown solid (800 mg). The celite filter cake was washed with dichloromethane then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a brown solid (541 mg). The combined product batches were purified by trituration with ethyl acetate-hexane mixture. This affords 5-(2,4-Bis-benzyloxy-5-styrylphenyl)-isoxazole-3-carboxylic acid ethylamide as a light brown solid (808 mg, 71%). LCMS: [M+H]+ 531. 1H NMR (400 MHz, CDCl3) δ 1.12 (t, 3H), 3.37 (m, 2H), 4.95 (s, 2H), 5.07 (s, 2H), 6.46 (s, 1H), 6.70 (brt, 1H). 7.11 (s, 1H), 7.17 (d, 1H), 7.23 (d, 1H), 7.32-7.44 (m, 15H), 8.09 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH:13]([NH:15][CH2:16][CH2:17][C:18](=O)[CH3:19])=[O:14].B(F)(F)F>C1C=CC=CC=1>[CH3:19][C:18]1([CH2:17][CH2:16][NH:15][CH:13]=[O:14])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CCNC=O
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(CCNC=O)OCCC2=C1Cc1ccccc12

Procedure:
A mixture of indene-3-ethanol (1.6 g), 4-(formylamino)-2-butanone (1.2 g), described by H. Bredereck, et al., Chem. Ber., 2423 (1960), benzene (40 ml) and boron-trifluoride etherate (3 ml) is stirred at reflux temperature for 3 hr. The reaction mixture is washed with saturated sodium bicarbonate solution, dried and evaporated to dryness to afford the N-formyl derivative, 1-methyl-1-[2-(formylamino)ethyl]-1,3,4,9-tetrahydroindeno[2,1-c]pyran, nmr (CDCl)3 δ 3.3 (m, 4H), 6.5 (broad, 1H), 7.25 (m, 4H), 8.08 (s, 1H).
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].CC(C)([O-])C.[K+].[CH:37]([C:39]1[CH:40]=[C:41](/[CH:44]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])[S:42][CH:43]=1)=O.Cl.[Cl-].[Na+]>CN(C)C=O>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]=[CH:37][C:39]2[CH:40]=[C:41](/[CH:44]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])[S:42][CH:43]=2)[N:10]=1)(=[O:4])[CH3:3]
Reactant: COC(=O)/C=C/c1cc(C=O)cs1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(C=Cc2csc(NC(C)=O)n2)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphoniumchloride (6.602 g, 14.58 mmol) was added anhydrous N,N-dimethylformamide (30 ml), and the mixture was cooled to 0° C. Potassium tert-butoxide (3.146 g, 28.03 mmol) was added, and the mixture was stirred at 0° C. for 15 min. A solution of methyl (2E)-3-(4-formylthiophen-2-yl)acrylate (2.200 g, 11.21 mmol) in anhydrous N,N-dimethylformamide (30 ml) was added dropwise, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice-cooled dil. hydrochloric acid (600 ml, containing 15 mmol as HCl). Sodium chloride (10 g) was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 500 g, ethyl acetate:hexane=1:1) to give methyl (2E)-3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophen-2-yl)acrylate (3.090 g, 9.241 mmol, 82.4%) as a yellowish-white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])[CH2:30][OH:31]>>[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])[CH2:30][OH:31]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(CO)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(CO)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B. 16) according to general procedure II. Light yellow solid. MS (ISP) 623.1 [(M−H)−]; mp 215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
A solution of 50 g of 3,4,5-trimethoxybenzoic acid in 500 ml dry methanol containing 4.8 ml of conc. sulfuric acid was refluxed under anhydrous condition for 18 hr and concentrated to half the volume. The solution was poured into ice water and extracted with methylene chloride. The organic extract was washed with cold 0.5 N sodium hydroxide and water, dried over sodium sulfate, evaporated and crystallized from hexane to give 3,4,5-trimethoxybenzoic acid methyl ester, mp 65°-66° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.C([O-])(O)=O.[Na+].[ClH:21]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:21])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) was dissolved in hydrochloric acid (HCl, 4 M in dioxane; 65 mL) in a 100 mL Hastalloy stiffed Parr reactor. The reactor was heated to 100° C. for 2 h. Upon standing at room temperature overnight, a yellow crystalline solid formed. This solid was not soluble in EtOAc, but did dissolve upon shaking with satd aq NaHCO3 solution (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (5×50 mL) and then brine. The extracts were dried (MgSO4) and concentrated under vacuum to provide an off-white solid. The crude product was purified by column chromatography (120 g silica column; 0-100% hexane-EtOAc gradient) to give a white solid (2.11 g, 46%): mp 190.7-192.4° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.543 (d, JF-H=5.7 Hz, 1H), 6.91 (br s, 2H, NH2), 5.09 (septet, J=6 Hz, 1H, CHMe2), 1.29 (d, J=6 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8 (CO2R), 144.8 (d, JF-C=12 Hz, C2/C4), 143.4 (d, JF-C=254 Hz, C5), 142.7 (d, JF-C=4.8 Hz, C2/C4), 136.5 (d, JF-C=17 Hz, C6), 112.8 (d, JF-C=5 Hz, C3), 68.9 (CHMe2), 21.6 (Me); 19F NMR (376 MHz, DMSO-d6) δ −141.0 (d, JF-H=6 Hz). Anal. Calcd for C9H10ClFN2O2: C, 46.47; H, 4.33; N, 12.04. Found: C, 46.50; H, 4.33; N, 11.96.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 3.5 h
Yield: 63.8 %

Procedure:
To a solution of p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylate (syn isomer, 1.25 g.) in methanol (40 ml.) and tetrahydrofuran (50 ml.) was added 10% palladium carbon (0.65 g.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours. After removing the catalyst from the reaction mixture, the filtrate was concentrated under reduced pressure. Water (80 ml.) was added to the residue, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate, and then the insoluble substance was filtered off. The filtrate was washed with ethyl acetate (50 ml.), and then ethyl acetate (100 ml.) was added to the solution. After adjusting to pH 1.5 with 10% hydrochloric acid, the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate (80 ml.) twice, and the extracts were combined with the ethyl acetate layer obtained above, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 0.60 g.), m.p. 176° to 183° C. (dec.).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[NH2:17])C=CC=CC=1.[Cl:30][CH2:31][CH2:32][O:33][CH2:34]Cl>C(Cl)Cl>[Cl:30][CH2:31][CH2:32][O:33][CH2:34][N:15]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[N:8]=[CH:16]1
Reactant: ClCCOCCl
Reactant: Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Nc1ncnc2ncn(COCCCl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 11 (1.79 g, 4.74 mmol) in CH2Cl2 (70 mL) was added (2-chloroethoxy)methyl chloride (0.65 g, 5.0 mmol). The reaction mixture was stirred at 25° C. for 8.0 h to afford a solid. Filteration and crystallization from MeOH gave 12 (1.66 g, 4.27 mmol) in 90% yield: mp 184-186° C.; Rf (hexanes/EtOAc=1:2) 0.28; UV (EtOH) λmax 267 (ε 14,600); 1H NMR (DMSO-d6) δ 3.73 (t, J=4.5 Hz, 2 H, CH2Cl), 3.86 (t, J=4.5 Hz, 2 H, OCH2), 5.76 (s, 2 H, H2C1′), 8.49 (s, 1 H, HC2), 8.74 (s, 1 H, HC8), 9.32, 10.05 (2 br, 2 H, NH2); 13C NMR (DMSO-d6) δ 43.13 (CH2Cl), 68.82 OCH2 78.10 (C1′), 118.20 (C5), 143.53 (C2), 146.50 (C8), 149.39 (C4), 151.60 (C6); MS m/z 227 (M+, Cl-cluster). Anal. (C8H10ClN5O) C, H, N, Cl; calcd (%): 42.20, 4.43, 30.76, 15.59; found (%): 42.32, 4.50, 30.69, 15.62.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[N:22]=[C:21]([C:28](O)=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[N:22]=[C:21]([C:28]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)NS(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (0.66 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A81. A solution of 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (233.8 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B81. Solution B81 was added to Solution A81 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-methanesulfonamide (115.1 mg, 40%) as a white solid: MS (ESI) M+1=412.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCc1ccccc1
Reaction time: 10 h
Yield: 63.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.02 ml (0.016 mol) of 2-phenylethylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. The product was crystallized in hexane/ethyl acetate. There were obtained 3.13 g (64%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-2H-benzo[e]indol-2-one as white crystals with m.p. 89°-90°.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:40][C:35]2=[CH:36][N:37]=[CH:38][CH:39]=[C:34]2[CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([CH:32]4[S:40][C:35]5=[CH:36][N:37]=[CH:38][CH:39]=[C:34]5[CH2:33]4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Brc1cc2ccncc2s1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1nc(C2Cc3ccncc3S2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 22.2 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (165.5 mg, 0.401 mmol), 2-bromothieno[2,3-c]pyridine (128.9 mg, 0.602 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (1.20 mL, 1.20 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (23.2 mg, 0.02 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give brown solids, 37.4 mg (yield 22.2%). 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.77 (dd, J=5.5, 1.1 Hz, 1H), 7.59 (s, 1H), 5.52 (p, J=6.0 Hz, 1H), 3.72 (m, 1H), 3.50-3.36 (m, 1H), 3.24 (m, 1H), 2.99-2.80 (m, 1H), 2.36 (dd, J=8.6, 1.3 Hz, 2H), 1.48 (d, J=6.1 Hz, 3H), 1.15 (m, 2H), 1.12-1.00 (m, 2H) ppm; MS (ESI+) m/z 420.14 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:17][CH2:25][C:26]([OH:28])=[O:27])=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2cc(Cl)c(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(=O)c3ccccc3oc2cc1Cl
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 3-chloro-2-hydroxy-9-oxo-9H-xanthene (1.5 g), potassium carbonate (2.5 g), ethyl bromoacetate (3.1 g) and DMF (40 ml) was stirred at 65°-75° C. for 2 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 3-chloro-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 237°-238° C. This compound showed a mass spectrum having a molecular ion peak at m/e 304.