Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65]C(C)(C)C)=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[Si:15]([O:14][C@H:13]1[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11][CH:10]([C@H:39]([OH:70])[C@@H:40]([C:63]([OH:65])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:9]1[OH:8])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)O)[C@@H](O)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
A solution of trifluoroacetic acid (0.3 drops) in methylene chloride (1 ml) was cooled to 0° C. tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (20 mg, 0.02 mmol, obtained from Example 10) was added and the resulting mixture was stirred at 0° C. for 20 minutes. Additional trifluoroacetic acid (0.9 ml) was gradually added over 1 hour after which the mixture was warmed to room temperature and stirred for 2 hours. The volatiles were removed in vacuo. The residue was azeotroped with toluene, and was then dissolved in methylene chloride (0.5 ml). Cold trifluoroacetic acid (0.5 ml) and the mixture was stirred for 3 hours. The volatiles were removed in vacuo and the residue was azeotroped with toluene to provide (5S,12S)-12-[(R)-[(3R,4R,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oic acid (16 mg, 95%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][N:21]=1
Reactant: OCc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Sodium hydride (60%, oily, 1.58 g) was added to a solution of 2-quinolylmethanol (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(2-quinolylmethoxy)-5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[N:29]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.[OH-].[Na+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1[C:14]2[CH:13]=[C:12]([C:19]3[CH:20]=[C:21]([C:26]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)[N:29]=[C:28]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)[N:27]=4)[CH:22]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4cc5ccccc5c5ccccc45)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Yield: 44 %

Procedure:
In a stream of argon, 1.29 g (5.81 mmol) of 9-phenanthreneboronic acid, 1.20 g (2.42 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine and 67.9 mg (0.097 mmol) of dichlorobis(triphenylphosphine)palladium were suspended in 108 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 4.53 mL (18.2 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 2 hours. Further, 0.11 g (0.50 mmol) of 9-phenanthreneboronic acid was added, and the obtained mixture was distilled under reflux for 2 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene to give 0.74 g of the target 2-[3,5-di(9-phenanthryl)-phenyl]-4,6-di-p-tolyl-1,3,5-triazine as grayish white solid (yield: 44%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21](Cl)[C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:10])[CH3:9].[H][H]>[Pd].CO>[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methanol (100 mL) and triethylamine (4.5 mL, 33 mmol) were added to 6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid (1.27 g, 3.76 mmol). 10% Palladium on carbon (350 mg) was added and the reaction was pressurized to 17 psi hydrogen. The reaction was agitated at room temperature for 3 hours. The reaction mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated to a yellow solid. The solid was diluted with water and the mixture was acidified to pH=4 with 1 N aqueous hydrochloric acid. The solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (960 mg, 84%) as a pale yellow solid. +ESI (M+H) 304.2; 1H NMR (400 MHz, CD3OD, δ): 9.19 (d, J=2.15 Hz, 1 H), 8.87 (d, J=2.15 Hz, 1 H), 8.01 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.27, 2.83 Hz, 1 H), 7.38 (d, J=2.73 Hz, 1 H), 4.78 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([NH:9]C(=O)OCC1C=CC=CC=1)([CH3:8])[CH3:7].[H][H].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)C.[Pd]>[CH3:7][C:6]([NH2:9])([C:2]1[O:1][CH:5]=[N:4][N:3]=1)[CH3:8]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1nnco1
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(N)c1nnco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 2-(1,3,4-oxadiazol-2-yl)propan-2-ylcarbamate (1 g, 30% purity) and 10% Pd/C (0.06 g) in ethanol (30 mL) was charged with hydrogen balloon and stirred at room temperature overnight. After filtration, it was concentrated to give crude product which was directly used in the next reaction step without further purification but still contained OPPh3 and PPh3; MS: m/e 128.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[CH2:13][O:12]1.[C:19]1(=O)[O:24][C:22](=[O:23])[CH:21]2[CH2:25][CH2:26][CH:27]=[CH:28][CH:20]12>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[CH:4][C:5]([N:9]2[C:22](=[O:23])[C:21]3[CH2:25][CH2:26][CH2:27][CH2:28][C:20]=3[C:19]2=[O:24])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CC1(C)CON(Cc2cc(N)c(F)cc2Cl)C1=O
Solvent: CC(=O)O
Product: CC1(C)CON(Cc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1=O

Procedure:
By the method of Example 2, Step H, 3.0 g (0.011 mole) of 2-[(2-chloro-4-fluoro-5-aminophenyl)methyl-4,4-dimethyl-3-isoxazolidinone and 1.84 g (0.012 mole) of tetrahydrophthalic anhydride were reacted in 10 ml of acetic acid, yielding 3.0 g of N-[4-chloro-2-fluoro-5[(4,4-dimethyl-3-oxoisoxazolidin-2-yl)methyl]phenyl]-3,4,5,6-tetrahydrophthalimide as a yellow solid, m.p. 136°-138° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].S1[C@@H]2CC(=[O:46])N2CC=C1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14](=[O:46])[C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1cscn1
Reactant: O=C1C[C@H]2SC=CCN12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS(=O)[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product (0.2 g) obtained in Example 3, i.e. a mixture of pivaloyloxymethyl 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate and 2-cephem isomer thereof, was dissolved in chloroform (1 ml). To this solution was added dropwise a solution of m-chloroperbenzoic acid (0.059 g) in chloroform (1 ml). The mixture was stirred for 1.5 hours at room temperature. Precipitated crystals were filtered, washed with chloroform (2 ml), and dried under reduced pressure to give the title compound (0.092 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH3:8][C:9]1[O:15]C(C)(C)[O:13][C:11](=O)[CH:10]=1>C1(C)C(C)=CC=CC=1>[C:11]([N:3]1[CH2:4][CH2:5][N:6]([C:11](=[O:13])[CH2:10][C:9]([CH3:8])=[O:15])[CH2:7][CH:2]1[CH3:1])(=[O:13])[CH2:10][C:9]([CH3:8])=[O:15]
Reactant: CC1CNCCN1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCN(C(=O)CC(C)=O)C(C)C1
Temperature: 115 °C
Yield: 98.7 %

Procedure:
To 2-methylpiperazine (81.90 g, 0.819 mol) in xylene (525 ml) at 133° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.48 g, 1.637 mol) in xylene (525 ml) over 10 minutes, during which the temperature decreased to 100° C. After heating to 115° C over 5 minutes vigorous effervescence commenced, and after heating to 124° C. over another 5 minutes distillation of acetone (through a Vigreux column) also commenced. Pot temperature was increased to 139° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 20° C. overnight, supernatant liquid was separated from deposited syrup, which was dissolved in dichloromethane. Removal of solvent from combined solutions and drying (92° C./100 Pa) gave N,N′-bis(acetoacetyl)-2-methylpiperazine (BAAMPZ) as a viscous syrup (216.66 g, 99%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1CC[CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]([CH2:35][CH3:36])[CH2:21][CH3:23])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CCC(CC)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.08 g, 0.18 mmol) in tetrahydrofuran (7 mL) and methanol (0.015 mL, 0.36 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.135 mL, 0.27 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (m, 6 H) 1.29 (m, 4 H) 3.03 (m, 1 H) 5.76 (d, J=3.68 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=6.99 Hz, 1 H) 7.54 (m, 1 H) 7.65 (d, J=7.72 Hz, 1 H) 7.74 (d, J=5.15 Hz, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])O.[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:6][CH:5]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2ccc(N)cc21
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A suspension of 6-nitroindoline (1.0 g, 6.1 mmol) and sodium hydrogen carbonate (0.6 g, 7.1 mmol) in DMF (60 ml) was stirred at room temperature. Methyl bromoacetate (0.68 mL, 1.09 g, 7.1 mmol) was added slowly and the mixture was heated at 90° C. for 1 hour. The mixture was cooled, the solvents evaporated under reduced pressure, and the residue partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was dried over MgSO4 and then evaporated to give an orange solid. The solid was dissolved in methanol (100 ml), 5% Pd/C (50 mg, cat.) was added and the suspension was stirred under an atmosphere of hydrogen for 2 hours, during which time the yellow colour disappeared. The catalyst was removed by filtration through celite and the solvent was evaporated to give the amine as a brown oil (0.95 g, 75%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccsc1Br
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a stirred solution of methyl (2-bromothiophen-3-yl)acetate (120 mg, 0.51 mmol) and 4-iodo-3-nitrobenzoyl chloride (150 mg, 0.48 mmol) in anhydrous CH2Cl2 (10 mL) was added AlCl3 (260 mg, 1.95 mmol) in four portions in 10-minute intervals at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 2 as a light yellow solid (158 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.70 (dd, J=2.0, 8.2 Hz, 1H), 7.48 (s, 1H), 3.74 (s, 3H), and 3.68 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 183.8, 170.0, 153.2, 142.9, 141.9, 138.3, 136.5, 135.8, 133.1, 125.7, 124.5, 91.8, 52.6, and 35.0.
Reaction SMILES: Br.[NH2:2][C@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[NH2:2][C@H:3]1[C:9](=[O:10])[N:8]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
With 40 ml of dimethylformamide is mixed 3 g of cis-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)- one hydrobromide in the same manner as in (iv) of Example 1, and 0.72 g of 60% sodium hydride is added to the mixture under ice-cooling. After the temperature is gradually elevated to room temperature, the mixture is stirred for 2 hours. After the temperature of the reaction mixture is again cooled to about 10° C., 5 ml of a dimethylformamide solution containing 1.1 ml of ethyl bromoacetate is added dropwise thereto. Then, the reaction temperature is elevated to room temperature, and the reaction mixture is stirred for 6 hours, followed by concentration under reduced pressure. By adding ice water and chloroform to the residue, the organic substance is extracted. The chloroform layer is washed with water and dried. Thereafter, the solvent is distilled off under reduced pressure. The purification of the obtained residue by silica gel chromatography gives 3.0 g of ethyl cis-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Yield: 62.7 %

Procedure:
N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.144 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0903 mmol, 63%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-methoxy-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M28) (293 mg, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (180 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:35][C:36]1[C:37]([C:38]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[N:13]=[CH:14][N:15]=3)[CH2:23][CH2:24]2)=[O:39])=[CH:41][CH:42]=[CH:43][N:44]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4Cl)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A25 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), 2-chloro-nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.91 (m,1H), 2.00 (m, 1H), 2.14 (m, 2H), 3.08 (s, 3H), 3.36 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 5.72 (m, 1H), 7.36 (m,1H), 7.69 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (m, 1H), 8.47 (m, 1H), 10.20 (s, 1H). Exact mass calculated for C22H21ClN6O6S 532.09, found 533.3 (MH+).