Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25](S(C)(=O)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1.CO>C1COCC1>[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25]([NH:1][CH:2]5[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(S(C)(=O)=O)nc2n(C)c1=O
Reactant: NC1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
4-Amino-tetrahydropyran (11 mg, 0.106 mmol) was dissolved in 2 mL THF, and N-cyclopropyl-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-benzamide (21 mg, 0.051 mmol) was added. The reaction mixture was stirred for 6.5 hours at room temperature, and then 1 mL MeOH was added. The resulting mixture was loaded directly onto a preparative TLC plate and eluted with 5% MeOH in methylene chloride to give N-cyclopropyl-4-methyl-3-[8-methyl-7-oxo-2-(tetrahydro-pyran-4-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-benzamide: MS (M+H)=434; MP=239.3-241.0° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].CN(C=O)C>O>[O:10]1[C:9]2[CH:14]=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCO2
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNCC(=O)Nc1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 2-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (2 mmol), potassium carbonate (10 mmol), 2-methoxyethylamine (2 mmol) and anhydrous DMF (4 mL) was stirred for 2 hours at 100° C. (monitored by TLC). The mixture was cooled to room temperature, treated with cold water (30 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to afford N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-methoxy-ethylamino)-acetamide (Compound XIa, 96 mg, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ=9.29 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=8.7, 2.4 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.32-4.15 (m, 4H), 3.46 (t, 2H, J=4.8 Hz), 3.36 (s, 3H), 3.34 (s, 2H), 2.82 (t, 2H, J=4.8 Hz), 2.17 (s, 1H). 13C NMR (75 MHz, CDCl3/CD3OD/TMS): δ=169.48, 143.16, 139.87, 131.43, 116.84, 112.74, 108.89, 71.41, 64.28, 64.12, 58.68, 52.57, 49.35.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])C.C(OCC)(=O)C.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: CCOc1ccncc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
4-Ethoxy-3-nitropyridine (10.0 g) was dissolved in a 40% methanol solution of methyl amine (100 mL), and this was heated at 80° C. for 60 hours. The solution was cooled, ethyl acetate (500 mL) was added, and the organic layer was washed twice with 300 mL of water and once with 300 mL of saturated aqueous sodium chloride solution. This was then dried over anhydrous magnesium sulfate. The solution was filtered, and concentrated under reduced pressure to give the title compound (7.00 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:20]=1[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:15]([N:5]1[CH2:6][CH2:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:3]([CH2:2][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:20]=2[CH:21]=[O:22])[CH2:4]1)(=[O:17])[CH3:16]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(=O)N1CCC(c2ccccc2)=C(CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2ccccc2)=C(COc2cccc(O)c2C=O)C1
Yield: 18.5 %

Procedure:
To a solution of 1-(3-(chloromethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (100 mg, 0.40 mmol) and 2,6-dihydroxybenzaldehyde (110 mg, 0.80 mmol) in DMF (2.5 mL) was added K2CO3 (170 mg, 1.20 mmol), after heated at 50 degree for 2 h, the reaction was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by preparative HPLC (eluted with ACN/H2O) to give 2-((1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-6-hydroxybenzaldehyde (26 mg). 1H NMR (400 MHz, CDCl3, NMR shows rotamers exist, only one set of signal was reported) δ (ppm) 11.97 (s, 1H), 10.34 (s, 1H), 7.34 (m, 4H), 7.17 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.11 (d, J=8.8 Hz, 1H), 4.48 (s, 2H), 4.33 (s, 2H), 3.69 (t, J=6.0 Hz, 2H), 2.55 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:18][CH3:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[N:7]=1.C(#N)C.N1C=CC=CC=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:18][CH3:19])=[C:15]([NH:16][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH:17]=3)[N:10]=2)[N:7]=1
Reactant: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Yield: 92.1 %

Procedure:
A flask is charged with 5-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylaniline (4.00 g, 0.0146 mol), acetonitrile (120 mL) and pyridine (3.54 mL, 0.0438 mol). The mixture is stirred and trimethylacetyl chloride (1.98 mL, 0.0161 mol) is added and the mixture stirred for 16 hr at room temp. When the reaction is complete the mixture is diluted with water (500 mL) and stirred for 1 hour, and solid collected, washed with water (3×50 mL). Crude product is purified by silica gel chromatography (0-50% EtOAc in CH2Cl2) to give the title compound (4.8 g, 92%). LCMS m/z=357.5, 359.4 [M+H]+, tR=2.57 min.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[CH:46]([OH:48])[CH3:47])=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[CH:46]([OH:48])[CH3:47])=[CH:33][CH:34]=1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)O)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(O)c1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (137 mg, 0.325 mmol) obtained in Example (28-5) and methyl [4′-hydroxy-2-(1-hydroxyethyl)-1,1′-biphenyl-4-yl]acetate (93 mg, 0.325 mmol) obtained in Example (88-1), the title compound was obtained as a pale yellow oil (60 mg, yield: 34%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=NO1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)=NO1

Procedure:
5.7 g (51 mmol) of thionyl chloride were added dropwise at room temperature to a solution of 13.0 g (41 mmol) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 250 ml of dry toluene. The mixture was subsequently refluxed until the reaction was complete. After cooling, the solvent was distilled off. This gave 14.2 g of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methyl-benzoyl chloride in quantitative yield.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:26][N:27]1[C:31]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])=[CH:30][N:29]=[C:28]1[CH3:39]>ClCCl.N1C=CC=CC=1>[CH3:39][C:28]1[N:27]([CH3:26])[C:31]([C:32]2[CH:33]=[C:34]([NH:35][C:12]([C:10]3[S:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])[CH:36]=[CH:37][CH:38]=2)=[CH:30][N:29]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)s1
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncc(-c2cccc(NC(=O)c3ccc(-c4ccccc4)s3)c2)n1C
Yield: 83.1 %

Procedure:
To a suspension of 5-phenylthiophene-2-carboxylic acid (102 mg) and oxalyl chloride (0.2 ml) in dichloromethane (2 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for an hour. The resultant solution was evaporated under reduced pressure to give a crude acid chloride. To a suspension of 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and pyridine (0.12 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane (2 ml) followed by stirring for 12 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-imidazol4-yl)-phenyl]-5-phenyl-thiophene-2-carboxamide (155 mg, 82.9%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[S:51]([NH2:55])([NH2:54])(=[O:53])=[O:52].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH:54][S:51](=[O:53])(=[O:52])[NH2:55])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: NS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)NS(N)(=O)=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 158 mg (0.293 mmol) of N-(4-iso-propylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acid form of the product of Example 58) and 71 mg (0.440 mmol) of 1,1'-carbonyldiimidazole in 1 mL of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 mmol) of sulfamide and 110 μL (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600E HPLC system with a 4.6×250 mm 5 μM Zorbax-RX C8 at 40° C. and eluting isocratically 1.5 mL/min using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector. After 2.0 hour of additional refluxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diluted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 5500 HPLC by applying the compound in a 4.5 mL total volume (2.5 mL methanol and 2 mL water) onto two in series 21.2×250 mm Zorbax ODS C18 columns and eluting at 15 mL/min with 60% acetonitrile and 40% water both with 0.1% TFA. The column effluent was monitored 254 nM with a Kratos Spectroflow 783 UV detector. Combination and evaporation of the purified fractions afforded 50 mg (28%) of the title compound. The mixed fractions were combined and subjected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65% water and 35% acetonitrile both with 0.1% TFA to 65% acetonitrile and 35% water both with 0.1% TFA, holding all other conditions from the previous chromatography. The purified fractions were combined and concentrated to afford 57 mg (31%) of the title compound, which was combined with the previously purified material to provide a total of 107 mg (59%) of the title compound as an amorphous solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[I-].[K+]>CN(C=O)C>[CH3:17]/[N:18]=[C:19]1\[S:20][CH:21]=[CH:22][N:23]\1[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reactant: CNc1nccs1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/N=c1\sccn1CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 22 %

Procedure:
To a solution of tert-butyl 4-(2-bromoethyl)-1-piperidinecarboxylate (D. Brundish et al., J. Med. Chem., 42, 4584 (1999); 5.0 g) and 2-methylaminothiazole (O. Kemal et al., J. Chem. Soc. Perkin I, 5, 1569 (1981); 3.9 g) in DMF (50 ml) was added potassium iodide (5.7 g), and mixed at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and a saturated aqueous potassium hydrogen carbonate solution. The organic layer was collected by separation, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a brown oil (1.25 g, 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
Under argon, 4-hydroxyphenyl 3-methylphenyl ketone (307 mg) obtained in Example 132 and 4-dimethylaminopyridine (194 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (324 mg) was added, and the admixture was then refluxed with heat for 23 hours. The reaction mixture was treated in the same manner as described in Example 122 to obtain 262 mg of the title compound (yield: 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.[H-].[Na+].[Cl-].[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)n[nH]c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
To a solution of 2.56 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1H-indazole in 30 ml of dimethylformamide was added 0.50 g of sodium hydride at room temperature, and the mixture was stirred at the same temperature for 15 minutes. At the same temperature, 2.34 g of triphenylmethane chloride was added and the mixture was stirred at the same temperature for one day. Water was added to the reaction mixture and the mixture was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10) and the resulting crystals were washed with diethyl ether, to give 1.94 g of the title compound as colorless crystals.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:12])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc([Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1.1 equivalents) was added dropwise to a solution of 4-methylthiazole (1.0 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (1.0 equivalent) was added dropwise. The mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work-up in the normal fashion and vacuum distillation then gave the title compound. B.p. 42° C. at 1 mm Hg.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 140 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argon at 140° C. for 2 hours. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. 377.9721
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A mixture of 15.1 g (0.062 mol) 4-(4-fluorobenzoyl)piperidine hydrochloride, 13.77 g (0.062 mol) of 2-(bromomethyl)naphthalene and 13.6 g (0.16 mol) of sodium bicarbonate in 500 mL of absolute ethanol was stirred at room temperature for 16 hr. The solvent was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from 400 mL of methanol to give 11.81 g (54.9%) of white crystalline solid, mp 131°-134° C. The filtrate was subjected to flash chromatography (silica gel, gradiently eluted with CH3OH/CH2Cl2) to give an additional 2.84 g (13.2%) of the title compound.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]=C=O)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])=[CH:43][CH:42]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccc(F)cc1
Yield: 5 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 4-fluorophenyl isocyanate as described in Example 16 in a 5% yield; ESMS, (M+1)+464.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), neopentylamine (530 mg, 6.0 mmol) and triethylamine (1 mL) in acetonitrile (20 mL) was stirred at room temp for 4 h. After the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to afford the product (1.11 g, 87%). C11H13ClFN3 MS m/e=242 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:37])([CH3:36])NC(=O)C1C=CC=CC=1.NS(O)(=O)=O.[Br:43]N1C(=O)CCC1=O>ClCCl>[Br:43][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:37])([CH3:36])[CH3:25])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: C[Si](C)(C)NC(=O)c1ccccc1
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 42 %

Procedure:
601.5 mg (1.73 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were silylated by refluxing in 50 ml of dichloromethane for one hour with 503 mg (2.61 mmoles) of N-trimethylsilylbenzamide. 0.1 g of amidosulfonic acid (1 mmole) were added to the clear, slightly yellow solution obtained and after cooling in an ice-bath, bromination was carried out in half an hour with 464.8 mg (2.61 mmoles) of N-bromosuccinimide to obtain a yield of 42% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.