Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[H][H]>CO.[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1cnc2c(N(C)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 4 h

Procedure:
To a mixture of 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine (0.233 g, 0.751 mmol) in MeOH (10 mL) at RT was added a suspension of 10% palladium on carbon (0.0799 g, 0.751 mmol) in EtOAc (10 mL). The mixture was exposed to an atmosphere of hydrogen (balloon). After 4 h, the mixture was filtered over celite and concentrated in vacuo. The crude yellow foam, N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine, was advanced without further purification. MH+=281.2@1.21 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][Si:4](Cl)(Cl)Cl.C([O:11][C:12](=[O:14])[CH3:13])(=O)C>>[Cl:1][CH2:2][CH2:3][Si:4]([O:11][C:12](=[O:14])[CH3:13])([O:14][C:12](=[O:11])[CH3:13])[O:14][C:12](=[O:11])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: ClCC[Si](Cl)(Cl)Cl
Product: CC(=O)O[Si](CCCl)(OC(C)=O)OC(C)=O
Reaction time: 21 h
Yield: 80.5 %

Procedure:
An amount of 40.8 g of 2-chloroethyl-trichlorosilane is dissolved in 71.5 g of acetic acid anhydride, and the solution allowed to stand at room temperature for 21 hours in a closed vessel. The reaction product is concentrated in vacuo to obtain 44.6 g of 2-chloro-ethyl-tris-(acetyloxy)-silane, B.P.: 85° - 88° /0.1 Torr, nD20 = 1.6687.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(N(CC)C(C)C)(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:29]([O:13][C:3]2[C:2]([Br:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2ccc(O)c(Br)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
A mixture of 8-bromo-2-methylquinolin-7-ol (1.10 g, 4.62 mmol) and N,N-diisopropylethylamine (1.19 g, 9.24 mmol) were dissolved in anhydrous DCM (10 mL), and the solution was cooled to 0° C. Benzenesulfonyl chloride (0.90 g, 5.10 mmol) in 5 mL DCM was added over 10 min, and the reaction mixture was stirred for 14 h at room temperature under argon. Solvent was removed in vacuo, and residue was dissolved in EtOAc and washed twice with saturated aq. NaHCO3 and then dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue was purified by SiO2 column chromatography (Hexanes/EtOAc=1/1) to yield SO185 as a white solid (1.70 g, 4.49 mmol, 97% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ 161.588, 148.067, 145.802, 136.573, 135.924, 134.834, 129.444, 128.907, 128.029, 126.122, 123.236, 121.950, 118.038, 25.922. 1HNMR (ppm, 400 MHz, CDCl3, 298 K) δ: 8.049 (d, 1H, J=8.4 Hz), 7.976 (m, 1H), 7.958 (m, 1H), 7.758 (d, 1H, J=8.8 Hz), 7.701-7.657 (m, 1H), 7.599 (d, 1H, J=8.8 Hz), 7.554-7.507 (m, 2H), 7.346 (d, 1H, J=8.0 Hz), 2.785 (s, 3H). MS-ESI (m/z): [M+H]+ calculated for C16H13BrNO3S, 378.0 (79Br) and 380.0 (81Br); found 378.0 (79Br) and 379.9 (81Br).
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(CC)CC)C>C(#N)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@@:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH2:52][CH2:53][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]4[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:42]1)=[O:40]
Reactant: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCCC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 106.2 %

Procedure:
Reflux a solution of 2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole dihydroiodide (0.65 g, 1.12 immol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.50 g, 1.06 mmol, example 47.2), triethylamine (3.58 mmol) and acetonitrile (15 mL) for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (3×30 mL), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane and concentrate the appropriate fractions to afford 0.79 g of the title compound as a cream colored foam, Rf=0.46 (silica gel, 1.0% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (188 μL, 2.3 mmol) in dioxane (15 mL) and the resulting mixture was stirred at room temperature for 1.5 h. Then 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was added. The resulting mixture was then heated at 85° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=2:1 to 1:1) afforded the title compound (210 mg, 88%) which was obtained as a colourless oil. MS: m/e=410.4 [M+H]+.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.C(O)C>[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([NH:49][C:50]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][C:19]3[C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[CH:30][C:31]=2[F:36])=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Butyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-butyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-butyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 80%).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[Br:16]Br>C(O)(=O)C.O>[ClH:1].[Br:16][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1[CH3:3]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: BrBr
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 966 mg (4.0 mmol) of 1-(3-Methylphenyl)piperazine dihydrochloride in 9 mL of acetic acid and 1 mL of water at 0° C. was added 640 mg (4.0 mmol) of bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1>CC(=O)CC.O>[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC1CCCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 88.2 %

Procedure:
1,1-Dimethylethyl 4-{4-[(3-chloropropyl)oxy]phenyl}-1-piperazinecarboxylate (D9) (1.6 g), was dissolved in 2-butanone (10 ml). Potassium carbonate (1.38 g) and a catalytic amount of potassium iodide were added, followed by 2-methylpiperidine (0.99 g). The mixture was heated at reflux for 72 h under nitrogen. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phases were separated using a hydrophobic frit, combined and evaporated in vacuo. The residue was purified on a 100 g silica SPE bond elut cartridge, eluting with a gradient of 0% to 20% [0.880 ammonia-methanol (1:9)]-dichloromethane mixtures, to give the title compound (1.66 g). LCMS RT=2.48 min.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O)([O-])=O>C(O)C>[C:1]([N:5]1[CH:11]=[C:10]2[C:9]([CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)n1cc2ccc([N+](=O)[O-])cc2n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Tert-butylamine (2 mL) was added to a solution of 2,4-dinitrobenzaldehyde (1.96 g) in ethanol (10 mL), and the reaction solution was stirred at 40° C. for 30 minutes. The solvent was evaporated under vacuum, then tert-butylamine (1 mL) was added to the resultant residue, and the reaction solution was heated at 50° C. for 30 minutes. The solvent was evaporated under vacuum, then trimethyl phosphite (6 mL) was added, and the reaction solution was stirred at 110° C. for 1 hour. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate). Thereafter, isopropyl ether was added to the resultant residue, and the precipitate was filtrated to obtain 2-(tert-butyl)-6-nitro-2H-indazole as a white solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([NH:32][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCCCC1CO1
Reactant: NCc1ccccc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCCCCCCCC(O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of 1,2-epoxydodecane (1.84 g, 10.0 mmol) in anhydrous acetonitrile (5 mL) is added anhydrous magnesium perchlorate (2.23 g, 10.0 mmol). After 15 minutes, benzylamine (1.1 mL, 10.0 mmol) is added dropwise and the solution is stirred for 50 hours at room temperature. The mixture is concentrated, diluted with water, and extracted twice with ethyl acetate. The combined organic extracts are washed with water, brine, dried over magnesium sulfate, and concentrated to afford 2.9 g of the title compound as a white solid; 1H NMR (200 MHz, CDCl3)δ7.38-7.25 (m, 5 H), 3.87 (d, J=2 Hz, 2 H), 3.80-3.65 (m, 1 H), 3.00-2.75 (m, 3 H), 2.60-2.45 (m, 1 H), 1.40-1.20 (m, 18 H), 0.88 (t, J=7 Hz, 3 H).
Reaction SMILES: Cl.CS([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17]>>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[O:29])(=[O:18])=[O:17].[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[N:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NNc1ccccc1
Agent: CNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)cc1

Procedure:
1H-indole-2,3-dione-5-sulfonic acid methylamide was prepared from N-methylsulfonamidoaniline hydrochloride according to Procedure A: 1H NMR (DMSO-d6): δ2.37 (d, J=4.7 Hz, 3H), 7.04 (d, J=8.4 Hz, 1H), 7.45 (q, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 11.38 (s, 1H); APCI−MS m/z 239 (M−H)−. The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid methylamide and 4-(N-methylsulfonamido)-phenylhydrazine according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ2.38 (d, J=4.9 Hz, 6H), 7.08 (d, J=8.2 Hz, 1H), 7.33(q, J=5.2 Hz, 1H), 7.35 (q, J=4.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.66 (dd, J=8.1, 1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.91 (d, J=1.5 Hz, 1H), 11.48 (s, 1H), 12.77 (s, 1H); APCI−MS m/z 422 (M−H)−. Anal. Calcd for C16H17N5O5S2: C, 45.38; H, 4.05; N, 16.54. Found: C, 45.46; H, 4.04; N, 16.45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C.[Cl-].[NH4+]>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[C:5]([Br:15])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cc([C@@H]2CNC(=O)C2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Seven and one-half (7.5) g (35.71 mmol) of (4R)-4-(3-amino-4-chlorophenyl)-pyrrolidin-2-one was dissolved in 170 mL chloroform (0.25 M) and 3 mL of acetic acid. To this solution, 6.3 g of solid N-bromosuccinimide was added portion-wise. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (50 mL). The aqueous solution was extracted with dichloromethane (2×50 mL), dried over MgSO4 and the solvent evaporated to dryness. Water was added to the oil and the pH adjusted to 9 with 1N NaOH. The solid was filtered, washed consecutively with water, ether, and hexane and dried under a high vacuum to give 9.3 g of the title compound (88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>O>[C:20]([O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Yield: 81 %

Procedure:
A mixture of Example 179A (0.18 g, 0.7 mmol), acetic anhydride (0.2 mL), and pyridin (1 mL) was stirred at room temperature for 18 h. The solution was diluted with water (3 mL) and extracted with ethyl acetate (2×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (hexane to 5% ethyl acetate/hexane) afforded product as a colorless oil (0.17 g, 81%). 1H NMR (300 MHz, CDCl3) δ ppm 0.66 (m, 1 H), 0.76 (dd, J=9.56, 6.62 Hz, 6 H), 0.89 (m, 1 H), 1.38 (m, 1 H), 1.61 (m, 1 H), 1.81 (s, 3 H), 1.95 (m, 1 H), 3.50 (s, 2 H), 3.58 (s, 3 H), 4.24 (d, J=10.66 Hz, 1 H), 4.42 (d, J=10.66 Hz, 1 H), 5.01 (t, J=3.49 Hz, 1 H), 7.20 (m, 4 H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].O>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of 2.08 g (10 mmol) of 1-benzylbenzimidazole in 200 ml of dry tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 8.0 ml (20 mmol) of n-butyllithium. The resulting solution was warmed to 0° C. for 0.5 h, recooled to -78° C., and poured into a mixture of excess dry ice in 200 ml of tetrahydrofuran. After being allowed to warm, the solution was treated with 200 ml of water, washed with ether, neutralized, and washed with ether. The aqueous layer was concentrated in vacuo, after which the residue was triturated with 2% methanol in chloroform and filtered. The filtrate was dried over MgSO4 and concentrated to give 2.01 g (80%) of the desired compound as a white powder. Mass spectrum: (M-OH)+ =235.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:36][CH2:35][C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[C:12]1=[O:37].C1COCC1>[Pd].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N:11]2[CH2:36][CH2:35][C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[C:12]2=[O:37])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.199 mmol) in the mixed solvent of THF (3 ml) and methanol (3 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [23] as a off white solid [Yield: 83.0 mg, 88.3%]
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24](N)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(NC1SC=C(CC(O)=O)N=1)=O)(C)(C)C.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH2:24][C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2CC(=O)N12
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 103.7 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl) acetic acid (287 mg : 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N- methylmorpholine (0.27 ml: 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 40 minutes. The reaction mixture is quenched with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=3:1) to give 7β-2-(2-t-butoxycarbonylaminothiazol- 4-yl) acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (812 mg) as pale yellow foam Yield : 77%.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)O)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 15 (2.90 g, 9.98 mmol) in THF/water, (3:1, 80 mL) was added lithium hydroxide monohydrate (838 mg, 20.0 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was extracted with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organic fractions were dried and evaporated to yield the title compound (2.62 g, 9.98 mmol, 100%) as white needles, which had spectral data in agreement with that reported.122 Mp 170-172° C. (lit. 200° C.)122 1H NMR (D6 acetone, 300 MHz): δ 7.09 (s, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.94 (m, 1H, H2″); 5.27 (dd J=1.3 Hz, 17.3 Hz, 1H, H3a″); 5.10 (dd J=1.3, 10.5 Hz, 1H, H3b″); 4.52 (m, 1H, H2); 4.41 (d J=5.5 Hz, 2H, H1″); 2.98 (dd, J=5.7, 14.1 Hz, 2H, H3a); 2.79 (dd, J=8.1, 14.1 Hz, 2H, H3b); 1.75 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH+]. HRMS calcd for C14H18NO4 264.1236, found 264.1246.