Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:34](=[O:35])[O:33][CH2:32]2.Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([C:8]([CH3:19])([CH3:20])[CH2:9][C:10]([OH:18])([C:14]([F:15])([F:17])[F:16])[C:11]([NH:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:34](=[O:35])[O:33][CH2:32]3)=[O:13])[CH:7]=1
Reactant: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc2c(c1)COC2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.6 %

Procedure:
255 mg of 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid in 3 ml of dimethyl acetamide is mixed at 0° C. with 0.105 ml of thionyl chloride, stirred for 30 minutes at 0° C. and 45 minutes at room temperature and combined with 300 mg of 5-aminophthalide. After 16 hours at room temperature, it is mixed with 2 M hydrochloric acid and ethyl acetate, the organic phase is washed neutral with water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether, 80 mg of 5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide is obtained, flash point 200–201° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH3:18])[C:13]([OH:15])=O)[N:11]=1.C[Si](CC(N)=O)(C)C.Cl.[NH2:28][CH:29]1[C:49](=[O:50])[N:31]2[C:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC(C)=O.O1CCCC1.CN(C)C=O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH3:18])[C:13]([NH:28][CH:29]2[C:49](=[O:50])[N:31]3[C:32]([C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Phosphorus oxychloride (1.2 g.) was added all at once to a suspension of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 1.23 g.) in ethyl acetate (12 ml.) at 5° C. and stirred at 4° to 6° C. for 30 minutes. Trimethylsilylacetamide (1.0 g.) was added to the solution and stirred at 4° to 6° C. for 30 minutes. Phosphorus oxychloride (1.2 g.) was added again to the solution and stirred for 15 minutes. And further, dimethylformamide (0.5 g.) was added all at once to the solution at 4° to 6° C. and stirred for 40 minutes to give a clear solution. On the other hand, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride (1.9 g.) was added to a mixture of tetrahydrofuran (30 ml.) and acetone (10 ml.), and an aqueous solution (20 ml.) of sodium bicarbonate (0.6 g.) was added to the mixture. To the solution was added dropwise the solution obtained above at 0° to 5° C., pH 8.0. After stirring the mixture at -2° to 2° C., at pH 8.0 for 30 minutes, the insoluble substance was filtered out. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give p-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 1.6 g.).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:7](Cl)=[O:8]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:7]([NH:1][NH2:2])=[O:8]
Reactant: NN
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)ccc(Cl)c1C(=O)NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.22 mol. hydrazine in 100 ml. chloroform at -10° C. was added 0.1 mol. of 3,6-dichloro-2-methoxybenzoyl chloride. The mixture was stirred at ambient temperature for 2 hours, filtered, and the filtrate evaporated in vacuo. The residue was crystallized from methanol and water, then recrystallized from chloroform and hexane to obtain the titled product, m.p. 144°-145° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(C(F)(F)F)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-3-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.95 (d, 1H), 7.72 (d, 1H), 7.50-7.63 (m, 3H), 7.36-7.42 (m, 4H), 7.08 (t, 1H), 6.64-6.68 (m, 2H), 6.42 (d, 1H), 4.96 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[CH:12][CH:11]=[N:10]1.[N:17](OCCC(C)C)=[O:18]>CCOC(C)=O.CCO.Cl.CC(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([N:17]=[O:18])[CH:11]=[N:10]1
Reactant: CC(C)CCON=O
Reactant: CCNc1ccnn1-c1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCNc1c(N=O)cnn1-c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 1-(2,4-difluorophenyl)-N-ethyl-1H-pyrazol-5-amine (1.15 g, 5.16 mmol) in 4.0 mL of EtOAc, 2.0 mL of EtOH and 4.0 mL of 5-6 N HCl in 2-propanol was cooled in an ice/brine bath and treated with isoamyl nitrite (0.70 mL, 5.28 mmol) drop wise. After stirring at this temperature for 15 min, the reaction was quenched by the addition of 28-30% NH4OH solution and EtOAc, forming a deep blue solution. The EtOAc layer was separated, washed with brine, dried and concentrated to afford the title compound as a brown crystalline solid. MS (ES+): 253.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](Br)[C@H:9]([O:13][C:14]([CH3:16])=[O:15])[C@@H:8]([O:17][C:18]([CH3:20])=[O:19])[C@@H:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH3:25][O:26][C:27](=[O:30])[CH2:28][OH:29]>[Hg]=O.[Hg](Br)Br>[CH3:25][O:26][C:27]([CH2:28][O:29][CH:10]1[O:11][C@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[C@@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:9]1[O:13][C:14](=[O:15])[CH3:16])=[O:30]
Reactant: COC(=O)CO
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Br[Hg]Br
Agent: O=[Hg]
Product: COC(=O)COC1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 60 %

Procedure:
The yields of the compounds of general formula I, which can be achieved with the process according to the invention, are good. For known compounds in which a comparison with the prior art is possible, they exceed the yields of the prior art. Thus, for example, (WO 96/35700), in the reaction of acetobromoglucose with glycolic acid methyl ester under the influence of mercury oxide and mercury(II) bromide according to Koenigs-Knorr, the 1-O-methyloxycarbonylmethyl-2,3,4,6-tetra-O-acetyl-glucopyranose is obtained with a yield of 60%. The saponification to the free acid would be connected with a further loss in yield. EP 882733 also describes the production of this compound, but without yield information. According to the process of the invention, the acid is also obtained in a two-stage process. Here, the yield is 78%, however (Example 24 of this application).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1C=CC2N(O)N=[N:19]C=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:19])=[O:12]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1cc2ccccc2[nH]1
Reaction time: 16 h
Yield: 236.8 %

Procedure:
To intermediate 34 G (102.9 mg, 0.24 mmol) in DCM (5 mL) was added 2-indole carboxylic acid (47 mg, 0.29 mmol), HOBT (39 mg, 0.29 mmol), EDC (56 mg, 0.29 mmol) and 2d triethylamine. The reaction mixture was stirred for 16 h, diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2×20 mL), 1N aqueous HCl (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to give the indole amide (110 mg, 80%). Rf =0.58 (10% methanol/DCM); 1HNMR (300 MHz, CDCl3) d 1.04 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H), 1,39 (s, 6H), 3.58 (d, J=16.6 Hz, 1H), 3.83 (s, 3H), 4.59 (d, J=16.6 Hz, 1H), 4.76 (d, J=8.5 Hz, 1H), 5.03 (m, 1H), 6.89 (m, 2H), 6.98 (m, 3H), 7.13 (m, 2H), 7.45 (m, 3H), 7.61 (m, 2H), 8.98 (s, 1H); MS(FAB) m/z 571.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 200 mg (0.55 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 109.4 mg (1.1 mmol) of 2-aminothiazole. Yield: 3.3 mg.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([N:12]2[CH2:15][CH:14]([N:16]([CH3:25])[CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:13]2)[CH:9]=[CH:8][CH:7]=1.C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:25][N:16]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:14]1[CH2:13][N:12]([C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[CH2:15]1
Reactant: CN(CCN1CCOCC1)C1CN(c2cccc(C3OCCO3)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CN(CCN1CCOCC1)C1CN(c2cccc(C=O)n2)C1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a mixed solution of 1-(6-(1,3-dioxolan-2-yl)pyridin-2-yl)-N-methyl-N-(2-(morpholin-4-yl)ethyl)azetidine-3-amine (157 mg, 0.451 mmol) described in Production Example 29-3, acetonitrile (5.00 mL) and water (0.500 mL) was added p-toluenesulfonic acid monohydrate (386 mg, 2.03 mmol). The resultant mixture was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, and then the solvent was evaporated under a reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the resultant solution was extracted with dichloromethane three times. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure to give a crude product (122 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-])=O)[CH3:2].C(O)C>[C].[Pd].C(OCC)(=O)C>[CH2:14]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11])[CH3:15]
Reactant: CCC(CC)CCn1ccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)CCn1ccnc1N
Reaction time: 20 h
Yield: 96.1 %

Procedure:
A solution of the 1-(3-ethylpentyl)-2-nitro-1H-imidazole (370 mg) and 10% palladium-carbon (200 mg) in an ethanol (5 ml)-ethyl acetate (5 ml) mixture was stirred at room temperature and normal pressure for 20 hours under a hydrogen stream. After filtering the reaction mixture through celite, it was washed with ethyl acetate-methanol. The filtrate was distilled off under reduced pressure to yield a crude product of 1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg) as a light yellow solid. A solution of the 1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg, 1.68 mmol) and 2-bromo-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1-ethanone (660 mg, 2.02 mmol) in methanol (20 ml) was heated at 60° C. for 3 hours. The reaction mixture was distilled under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate. After washing the crystals with diethyl ether, they were dried to yield the target compound (700 mg) as a colorless amorphous solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]Cl)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:26]
Reactant: c1cnc2nc(CCCc3ccc4[nH]ccc4c3)ccc2c1
Reactant: CCOC(=O)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.180 g, 0.627 mmol) in DMF (2 mL) was added sodium hydride (24.0 mg. 1.00 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After cooling to 0° C., 3-chloro-propionic acid ethyl ester (85.0 mg, 0.63 mmol) was added and stirred overnight at room temperature. Ice water was added and the resulting mixture was extracted with methylene chloride. The combined organic layers were washed with water and brine, and dried over Na2SO4. Chromatography of the crude product on silica gel (methylene chloride/methanol, 95:5) gave the title product (0.11 g, 45% yield). 1H NMR (CDCl3) δ 9.08 (d, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.30-7.50 (m, 4H), 7.10 (m, 2M), 6.40 (dd, 1H), 4.40 (t, 2H), 4.10 (m, 2H), 3.10 (t, 2H), 2.80 (m, 4H), 2.25 (m, 2H), 1.20 (q, 3H).
Reaction SMILES: ClCCl.[CH:4]1([NH:9][C:10]([C:12]2[CH:53]=[CH:52][C:15]3[N:16]([CH:38]4[CH2:43][CH2:42][CH:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[C:17]([NH:19][C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=5)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:21]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Si:45]([O:44][CH:41]1[CH2:40][CH2:39][CH:38]([N:16]2[C:15]3[CH:52]=[CH:53][C:12]([C:10]([NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8]4)=[O:11])=[CH:13][C:14]=3[N:18]=[C:17]2[NH:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=4[O:55][CH3:54])[CH:27]=3)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[N:21]=2)[CH2:43][CH2:42]1)([C:48]([CH3:49])([CH3:50])[CH3:51])([CH3:47])[CH3:46]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)NC4CCCC4)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccccc1-c1ccc2c(c1)c(Nc1nc3cc(C(=O)NC4CCCC4)ccc3n1C1CCC(O[Si](C)(C)C(C)(C)C)CC1)nn2COCC[Si](C)(C)C

Procedure:
A mixture of (1,1-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complexed with dichloromethane (1:1) (1.9 mg, 0.0000023 mol), 50 uL of 0.20 M 2-(5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-ylamino)-1-(4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid cyclopentylamide (0.0000116 mol) in dioxane and 92 uL of 0.25 M 2-methoxyphenylboronic acid (3.54 mg, 0.0000233 mol) in dioxane and 29 uL 2.0 M sodium carbonate in water was heated at 120° C. for 4 hours. The reaction mixture was cooled, and 2 mL of H2O was added followed by extraction with 2 mL of methylene chloride 3 times. The combined organic phases were concentrated and purified by flash chromatography with 50% EtOAc/Hexanes to give the title compound.
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[CH3:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][N:12]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:10][C:11]1[N:15]([CH2:16][CH:17]=[O:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][N:12]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ncc([N+](=O)[O-])n1CC=O
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To 160 ml of CH2Cl2 was added dropwise 2 ml (22 mmol) of oxalyl chloride under nitrogen gas. The solution was cooled to -50° C. and 17 ml (240 mmol) of Me2SO was added dropwise to the stirred solution. About 20 min later, 3.42 g (20 mmol) of metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] dissolved in 15 ml of Me2SO was added After 20 min of additional stirring, 33 ml (240 mmol) of triethylamine was added. The reaction mixture was stirred for another 10 min and then allowed to warm to room temperature. The mixture was diluted with 400 ml of ethyl acetate and washed 4 times with water, first with 100 ml and then 3 times with 50 ml. The 250 ml water volume was extracted 3 times with 250 ml of ethyl acetate and the ethyl acetate was added to the CH2Cl2. The mixture was washed with 100 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered, and concentrated to dryness in a rotary evaporator. The resulting crude residue was purified by flash silica gel chromatography to give the pure desired aldehyde (2-methyl-5-nitroimidazol-1-yl-acetaldehyde).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])C1C=CC=CC=1>C(Cl)Cl>[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](CCCCN)C(=O)O
Solvent: ClCCl
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, three fold molar excess of resin capacity of benzyl-Boc-L-lysine [Lus (Z), Peninsula, supra.] dissolved in methylene chloride is added to the residue of Step (D) above. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide dissolved in 10-15 ml. of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed with methylene chloride, ethanol and dried.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)=O)(C)(C)C>>[NH:27]1[CH:31]=[C:30]([C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(-c3cn[nH]c3)n2n1)c1ccccc1
Yield: 31.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg; 0.24 mmol; 1.0 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (139 mg; 0.47 mmol; 2.0 eq.), at 140° C. for 14 h. Further treatment with a 1 N methanolic HCl solution (0.5 mL) and purification by flash chromatography on silica (EtOAc/c-Hex, 80:20) gave the title compound as a white powder (23 mg, 32%). HPLC, Rt: 2.07 min. (purity 96.9%). LC/MS, M+(ESI): 305.3, M−(ESI): 303.3.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[S-2].[Na+].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
10 parts of the nitroanthraquinone used in Example 1 was made pasty with 23.9 parts of sodium sulfide flakes (60% purity) and 11 parts of water, and this dark green paste was poured into 800 parts of hot water of 95°-98° C. and the remainder was poured by washing with 170 parts of cold water. This was followed by additional 2-hour agitation at 97°-100° C. The reaction mixture was then filtered at 70°-80° C., washed and dried to obtain 8.38 parts of an aminoanthraquinone with purity of 75.0%. The yield of 1-aminoanthraquinone was 96.0%. The aminoanthraquinone crystals mostly had the size of 1 to 2μ as shown in FIG. 4, but a part of the crystals had size of 5 to 10μ. Filterability of the product was very bad as in the case of Referential Examples 1 and 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH3:23])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1
Reactant: CSc1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
2-(4-Bromo-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.57 g, 6.9 mmol), 2-(methylthio)benzene boronic acid (1.4 g, 8.3 mmol), and tetrabutylammonium bromide (110 mg, 0.33 mmol) were combined in 30 mL toluene, added 6.9 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.40 g, 0.34 mmol). Heated reaction at reflux overnight, cooled, concentrated, redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200 mL), dried with MgSO4, filtered, and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (1.75 g, 60%) APCI (AP−): 411.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][C:10]([F:14])([F:13])[F:9]
Reactant: Oc1ccccc1Br
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccccc1Br
Temperature: 60 °C

Procedure:
A solution of 2-bromophenol (5.89 g, 34.0 mmol) and 2,2,2-trifluoroethyliodide (16.8 g, 80.0 mmol) in DMF (60 mL) was treated with potassium carbonate (24.1 g, 174 mmol) at room temperature. The resulting mixture was heated in an oil bath (60° C., 2 d). The solvent was removed in vacuo and the residue dissolved in ether and water. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with three portions of 1M NaOH solution and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound (50).