Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH:14](=[O:17])[CH2:15][CH3:16].CC(O)C>CCCCCC>[CH3:16][C@@H:15]([C@@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17]
Reactant: O=[N+]([O-])/C=C/CCc1ccccc1
Reactant: CCC=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@H](C=O)[C@H](CCc1ccccc1)C[N+](=O)[O-]

Procedure:
The title compound was prepared from (E)-(4-nitrobut-3-enyl)benzene and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=2:98), 1 mL/min, tmajor=15.4 min, tminor=14.4 min, the diastereomeric ratio was determined by
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[CH3:12][O:13][C@@H:14]([C@@H:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:13][C@@H:14]([C@@H:21]([NH:26][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CO[C@H](c1ccccc1)[C@@H](N)CC(C)C
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](OC)c1ccccc1

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid and 1-(S)-[α-(R)-methoxybenzyl]-3-methylbutylamine (its preparation is described in the after-mentioned Reference Example 2) to prepare the titled compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)=O>CN(C)C=O.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: FC(F)(F)CCl
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A two-necked flask having a dry ice condenser fitted on top was charged with 50 ml of dry dimethylformamide and 2 g of a 60% strength by weight suspension of sodium hydride in paraffin, and subsequently 7.3 g of 4-chlorothiophenol in 10 ml of dimethylformamide were added dropwise. Chlorotrifluoroethane was then passed in at a reaction temperature of about 60° C., until the gas began to condense in the dry ice condenser. The mixture was stirred for a further 5 hours and the course of the reaction was monitored by thin-layer chromatography (silica gel; ethyl acetate/petroleum ether 1/5). The reaction mixture was worked up by pouring into water and extracting with dichloromethane. The combined organic extracts were dried and the solvent was distilled off at reduced pressure. The oily residue was subsequently distilled (43°-45° C./0.1 mbar), giving 8.8 g of 4-chloro(2',2',2'-trifluoroethylthio)benzene
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (5.0 g, 21.2 mmol) in 100 mL of methanol at 0° C. was added dimethylamine (5.3 mL of a 40% aqueous solution). The resulting reaction mixture was stirred at 0° C. for 10 min, during which time the product crashed out as white needles. The mixture was diluted with water and filtered, washing once with water. The needles were collected and dried in vacuo to provide 2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (4.4 g, 85%), mp 72-74° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: COCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: COCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (60 mg), methoxyacetyl chloride (23 mg), and 36 μL of triethylamine in dichloromethane was stirred for 1 h. The reaction mixture was evaporated to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 17.3 mg of 120. MS (Q1) 501 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[O:20])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (0.895 g) was added to a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine (0.993 g) and pyridine (0.6 g) in methylene chloride (10 ml) and stirred at 4° C. for 16 hours under an atmosphere of nitrogen. The reaction mixture was washed with aqueous citric acid (1.0 M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine as a yellow gum (0.685 g); 1H NMR Spectrum: (DMSO d6) 1.30-1.36 (s, 9H), 1.98-2.07 (m, 1H); 2.37-2.48 (m, 1H); 2.83 (s, 3H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 4.70 (m, 1H), 5.23 (m, 1H), 8.21 (d, 2H), 8.47 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.Cl.[NH2:15]O.Cl>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]#[N:15]
Reactant: NO
Reactant: O=Cc1coc2ccccc2c1=O
Agent: Cl
Solvent: CCO
Product: N#Cc1coc2ccccc2c1=O

Procedure:
2.52 Parts of 4-oxo-4H-1-benzopyran-3-carboxaldehyde are admixed well with 2.10 parts of hydroxylamine hydrochloride, followed by the addition of 30 volume parts of 95 weight % ethyl alcohol and 0.5 volume part of concentrated hydrochloric acid. The whole mixture is refluxed for 6 hours and cooled. The resulting precipitate is recovered by filtration, treated with activated carbon and recrystallized from ethanol. This procedure yields 4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 177°-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][S:15][CH3:16].[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:8]([C:6]1[C:5]([O:12][CH3:13])=[CH:4][C:3]([CH2:14][S:15][CH3:16])=[C:2]([C:24]2[C:19]([O:18][CH3:17])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1cc(CSC)c(Br)cc1C(C)(C)C
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CSC)c(-c2cccnc2OC)cc1C(C)(C)C
Yield: 54.9 %

Procedure:
step 2—A sealed tube containing 80 (50 mg), 2-methoxy-3-pyridine boronic acid (38 mg), Na2CO3 (43 g) and Pd(PPh3)4 (19 mg) in a mixture of MeOH (4 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 120° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 50% EtOAc/hexane to afford 30 mg of 3-(5-tert-butyl-4-methoxy-2-methylsulfanylmethyl-phenyl)-2-methoxy-pyridine (82).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].Cl>CN(C)C=O.[OH-].[Na+]>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Reactant: CCCCCCC(N)CCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCC(CCCCCCCCCCC(=O)O)NC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0 331 616) is suspended in 100 ml of dimethylformamide and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 11.36 g (38 mmol) of 12-aminooctadecanoic acid. After stirring overnight at room temperature, it is concentrated by evaporation in a vacuum, and the residue is absorptively precipitated with 500 ml of diethyl ether. It is suctioned off and the dried reaction product is dissolved in 50 ml of 2 n sodium hydroxide solution. After three hours of stirring, it is neutralized with dilute hydrochloric acid, evaporated to dryness in a vacuum and recrystallized from water. 15.64 g (61% of theory) of a gray powder is obtained.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[H-].[Na+]>CN(C=O)C>[OH:1][C:3]1([CH2:2][N:27]2[CH:28]=[C:24]([B:19]3[O:18][C:17]([CH3:29])([CH3:16])[C:21]([CH3:23])([CH3:22])[O:20]3)[CH:25]=[N:26]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A reaction mixture of compound (3-2) (214 mg; 1.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3-3, 194 mg; 1.0 mmol) with NaH 60% dispersion in mineral oil (60 mg; 1.5 mmol) in 3 mL of DMF was stirred at 90° C. for 3 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated by vacuum to give 361 mg of (3-4) as a yellow grease (89% yield). 1H NMR (400 MHz, chloroform-D) δ ppm 1.21-1.34 (m, 12H) 1.39-1.50 (m, 9H) 1.56-1.78 (m, 4H) 3.14 (s, 2H) 3.72-3.91 (m, J=32.34 Hz, 2H) 4.05 (s, 2H) 7.65 (s, 1H) 7.80 (s, 1H) 8.00 (s, 1H). LCMS calcd for C20H34BN3O5 (M+H) 408, found 408. HPLC purity 85%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:19]=1.FC(F)(F)C(O)=O.[Na].[OH-]>ClCCl>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNC(=O)OC(C)(C)C)c2c1C
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCN)c2c1C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of tert-butyl 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate (6.70 g, 15.8 mmol) in dichloromethane (50 mL) was slowly added to a chilled (0° C.) mixture of trifluoroacetic acid (60 mL) and dichloromethane (100 mL). The reaction mixture was allowed to warn to ambient temperature and then left overnight. The reaction mixtures was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and the solution was made basic (pH 14) with 5% aqueous sodium;hydroxide. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 4.50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylamine as a brown oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:1]1([C:7]2[C:8]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCNC2)ccc1-3
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(S(C)(=O)=O)C2)ccc1-3
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (43 mg, 0.091 mmol) in pyridine (0.5 ml) was added dropwise methanesulfonyl chloride (8.5 μl, 0.11 mmol), and the mixture was stirred at 0° C. for 2 hr. Toluene was added to the reaction mixture and the solvent was evaporated under reduced pressure. Hexane and ethyl acetate were added to the obtained residue, and the precipitate was collected by filtration, washed with hexane, and dried in vacuo to give methyl 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (47 mg, yield 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>C(O)(=O)C.C(O)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[NH:1][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=1)[N:6]([CH2:7][C:8]([NH:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:14])[C:4]2=[O:5]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)NC(=O)CN1C(=O)c2cc(Br)ccc2NC1c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
In a capped 20 mL scintillation vial, a solution of 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (0.65 g, 2.0 mmol), 3-chlorobenzaldehyde (0.27 mL, 2.4 mmol) and catalytic glacial acetic acid (2 drops) in anhydrous ethanol (10 mL) was heated with stirring at 85° C. for 16 h. The resulting white suspension was cooled to room temperature, the white solid collected by suction filtration and washed with cold EtOH to give 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-N-tert-butylacetamide (0.53 g, 1.21 mmol, 58%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:24])[C:22]=1[OH:23])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][C:21]1[CH:20]=[C:17]([CH:18]=[O:19])[CH:16]=[C:15]([CH3:14])[C:22]=1[O:23][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COC(=O)C(Br)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(C)cc(C=O)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of 1.260 g (4.80 mmol) of methyl α-bromo-(3-chlorophenyl)acetate and 0.600 g (4.00 mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde in 16 mL acetone was added 1.10 g (8.00 mmol) of potassium carbonate and the resulting mixture was stirred and heated at reflux for 3.5 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 1.260 g (95%) of the title compound.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:11]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][CH:20]([CH2:23][NH2:24])[CH2:21][CH2:22]4)[C:14]([C:32]([NH2:33])=[O:34])=[CH:13][N:12]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46]1)(=[O:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(On3nnc4ccccc43)ncc2C(N)=O)CC1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(N4CCC(CN)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A mixture of tert-butyl (1-(2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (138 mg, 0.294 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (84 mg, 0.38 mmol) and p-toluenesulfonic acid (56 mg, 0.294 mmol) in dioxane (4 mL) was stirred at 100° C. for 3 h. dioxane was removed in vacuo. The residue was dissolved in CH2C12 (5 mL) and TFA (5 mL). The solution was stirred at room temperature for 30 min. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (15 mg). MS 453.6 (M+H); UV 222.8, 263.8 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml) is added a solution of 3-trifluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30 min. The suspension formed is stirred for 1 h at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of about 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes/dichloromethane 1:1 and hexanes. Vacuum drying over night at room temperatures gives light yellow fine needles: HPLC: tR=6.72 min (purity: >99%, gradient A), ESI-MS: 325.2 [MH]+
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[CH:3]=O.C1(P(=[CH:31][C:32]2[CH2:33][S:34][C@@H:35]3[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[C:54](=[O:65])[N:36]3[C:37]=2[C:38]([O:40][CH:41]([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)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:11][C:8]([Cl:9])([Cl:10])[CH2:7][O:6][C:2]([CH:3]=[CH:31][C:32]1[CH2:33][S:34][C@@H:35]2[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)[C:54](=[O:65])[N:36]2[C:37]=1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:5]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CC(=O)OCC(Cl)(Cl)Cl)CS[C@H]12
Yield: 47 %

Procedure:
A suspension of 2,2,2-trichloroethyl glyoxylate monohydrate (435 mg., 1.86 mmole) in dry methylene chloride (25 ml.) was stirred at 23° and treated, over 10 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (765 mg., 1 mmole). After stirring for 45 minutes, the solvent was removed in vacuo and the residue was extracted with ethyl acetate (50 ml.); the insoluble material was filtered off and the filtrate was washed well with water (2 × 50 ml.) and brine (50 ml.), dried, and evaporated to an oil (1.07 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel, with benzene; ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave the title compound (325 mg., 47%), as an amorphous white solid, m.p. 70° to 81° (decomp.), [α] - 72.2° (CHCl3), λmax. 313 nm (ε 9,300) with an inflexion at 237 nm. (ε 14,900), νmax. (CHBr3) 3415 (NH), 1789 (β-lactam), 1728 (--CO2R), and 1682 and 1510 cm.-1 (CONH); the p.m.r. spectrum (CDCl3) indicated that this compound was mainly the cis-isomer, with signals at τ 3.50 (NH, d, J 9 Hz.); 4.08 and ca. 2.60 (CH=CH), two d, JAB 12 Hz.), 4.09 (C(7) --H, dd, J 5, 9 Hz.); 4.93 (C(6) --H, d, J 5 Hz.); 5.33 (--CH2CCl3, s); 6.16 (--CH2CONH--, s); and 6.29 and 6.61 (C(2) --CH2, AB-q J 18 Hz.), together with the trans-isomer (10 to 15%) with signals at τ 3.88 and 1.96 (CH=CH, two d, J 16 Hz.) [Found: C, 53.4; H, 3.6; N, 3.8; S, 9.1; Cl, 15.25; C31H25Cl3N2O6S2 (692.0) requires C, 53.8; H, 3.6; N, 4.05; S, 9.3; Cl, 15.4%]. Rf 0.54 (Merck GF254 + 266 plates, with benzene: ethyl acetate = 5:1 for development).