Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[N:3]([C:8]2[C:9]([C:20]([OH:22])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)C(C)=CC=1.Cl.NO>CCO.O.CCOC(C)=O>[NH2:3][C:8]1[C:9]([C:20]([OH:22])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (2.1 g, 6.68 mmol) was dissolved in EtOH (40 ml) and water (20 ml). To this mixture was added TEA (2.79 ml, 20.05 mmol) followed by hydroxylamine hydrochloride (4.64 g, 66.8 mmol). The resulting mixture was heated at reflux for 5 hours. After cooling to RT, the mixture was diluted with EtOAc (100 ml) and washed with aqueous HCl (1M, 100 ml). The aqueous phase was back extracted with EtOAc (100 ml) and the combined organic phases washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the product as an orange solid. The material can be used crude or recrystallised from isohexane-EtOAc (10:1) LC-MS Rt=1.0 min[M+H]+ 237 (Method 2minLC_v003)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=[O:2].[Cl-].[NH4+]>[Zn]>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][OH:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Cc1ccc(NO)cc1

Procedure:
In the above-described reaction schematic, N-(p-methylphenyl)-hydroxylamine (III) can be obtained from p-nitrotoluene (II) using the nitrobenzene reduction method as described in, for example, H. Gilman, Organic Syntheses, Collective Vol. 1, 2nd Ed., pp 445-447 (1961), John Wiley & Sons, Inc., N.Y., or Y. Ogata et al, J. Am. Chem. Soc., 86, pp 3854-3858 (1964). More specifically, for example, 1 mole of p-nitrotoluene (II) is reduced with 2 moles of zinc dust in a solution of 1 mole of ammonium chloride, and the resulting product is recrystallized from a benzene-petroleum ether mixture to obtain Compound (III) having a melting point of 94° C. Subsequently, Compound (III) is treated with a 5% sulfuric acid aqueous solution while cooling to approximately 0° C., e.g., in accordance with the method described in S. Goodwin et al, J. Am. Chem. Soc., 79, pp 179-185 (1957). After extracting the resulting product with chloroform, the concentrate thus obtained is purified with a diethyl ether-benzene mixture on a silica gel chromatographic column to obtain pure p-toluquinol (IV) having a melting point of 76° to 78° C. Compound (IV) is then partially hydrogenated in ethyl alcohol with a 5% Pd/C catalyst at room temperature (e.g., about 20°-30° C.) under a hydrogen pressure of one atm. to obtain Compound (I) having a boiling point of 101.5° to 109.5° C./2 mmHg.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 18.5 g. of 15-(trifluoromethyl)pentadecyl bromide, 17.0 g. of ethyl 4-aminobenzoate, 7.1 g. of potassium carbonate, and 75 ml. of hexamethylphosphoramide is stirred for 16 hours at 120° C., allowed to cool, diluted with water, and filtered. The solid is dissolved in methylene chloride and the solution is dried over anhydrous magnesium sulfate and evaporated. The residual brown oil is crystallized from ethanol and recrystallized from acetonitrile to yield the product as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([C:15]([OH:48])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:16]2[C:24]3[N:23]=[C:22]([O:25]CC)[N:21](C(OC(C)(C)C)=O)[C:20]=3[CH:19]=[C:18]([C:35]3[C:36]([CH3:41])=[N:37][O:38][C:39]=3[CH3:40])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH3:41][C:36]1[C:35]([C:18]2[CH:17]=[C:16]([C:15]([OH:48])([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:14]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:24]3[NH:23][C:22](=[O:25])[NH:21][C:20]=3[CH:19]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: COCCO
Reactant: CCOc1nc2c(C(O)(c3ccccn3)c3cccc(Cl)n3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cccc(C(O)(c2ccccn2)c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-methoxyethanol (25 mg, 0.33 mmol) was dissolved in THF (0.5 mL) and cooled to 0° C. Sodium hydride (8 mg, 0.33 mmol) was added in one portion and the reaction was allowed to come to rt and stir for 10 minutes. The reaction was then cooled back to 0° C. and tert-butyl 4-((6-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (24 mg, 0.04 mmol) was added and the reaction was sealed and heated to 80° C. overnight. Reaction was concentrated and the residue was taken up in EtOH (1.5 mL) and 4M HCl/dioxane (0.5 mL) and heated for 2 hours at 60° C. The reaction was cooled to rt and filtered to remove the sodium salt. Filterate was concentrated to afford the desired product as a brown film.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:19][CH:18]=1)[C:5](=[O:15])[CH2:6][CH2:7][C:8]([C:11]([O:13]C)=[O:12])([CH3:10])[CH3:9])[CH2:2][CH3:3].[OH-].[K+]>CO>[CH2:1]([N:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:21][CH:22]=1)[C:5](=[O:15])[CH2:6][CH2:7][C:8]([C:11]([OH:13])=[O:12])([CH3:10])[CH3:9])[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(C)(C)C(=O)O

Procedure:
A solution of 0.450 g of 4-methoxycarbonyl-4-methyl-pentanoic acid N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amide and 2.0 ml of 2N potassium hydroxide solution in 10 ml of methanol is heated under reflux for 6 hours. When cool, the mixture is acidified and concentrated by evaporation. The residue is purified by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (95:5) as eluant to yield pure 4-carboxy-4-methyl-pentanoic acid N-propyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amide that has an Rf value of 0.40 [CH2Cl2 /CH3OH (4:1)].
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:15][CH2:14][C@@:13]34[C:16]5[C:22]6[CH2:23][C@@H:7]2[C@:8]3([OH:39])[CH2:9][CH2:10][C:11](=[O:38])[C@@H:12]4[O:18][C:17]=5[C:19]([C:24]([NH:26]CC2C=CC(OC)=CC=2OC)=[O:25])=[CH:20][CH:21]=6)[CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([CH2:5][N:6]2[CH2:15][CH2:14][C@@:13]34[C:16]5[C:22]6[CH2:23][C@@H:7]2[C@:8]3([OH:39])[CH2:9][CH2:10][C:11](=[O:38])[C@@H:12]4[O:18][C:17]=5[C:19]([C:24]([NH2:26])=[O:25])=[CH:20][CH:21]=6)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CNC(=O)c2ccc3c4c2O[C@H]2C(=O)CC[C@@]5(O)[C@@H](C3)N(CC3CCC3)CC[C@]425)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A mixture of (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-N-(2,4-dimethoxybenzyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (14.4 g, 27.0 mmol) in trifluoroacetic acid was stirred at ambient temperature for 2 hours. The trifluoroacetic acid was removed under reduced pressure and the residue quenched with 300 mL of ammonium hydroxide (6%). The product was extracted twice into dichloromethane (300 mL), the organic phases combined and dried (MgSO4). Filtration and removal of to the solvent under reduced pressure gave (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (9.0 g, 87% yield); LC/MS (M+H)+=383.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9](OC)=[O:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1.[Cl-].[NH4+]>[CH3:1][O:2][C:3]([C:5]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)CCC1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.6 %

Procedure:
To a solution of 1,1-cyclobutanedicarboxylic acid dimethyl ester (available from Lancaster Synthesis Ltd, UK) (2.0 g, 11.6 mmol) in tetrahydrofuran (20 ml) at room temperature was added lithium tri-tert-butoxyaluminium hydride (25.5 ml of a 1M solution in tetrahydrofuran, 25.5 mmol) dropwise over 10 minutes. The reaction mixture was heated to gentle reflux for 3 hours, cooled to room temperature and stirred for 18 hours. The resulting suspension was diluted with saturated aqueous ammonium chloride (30 ml) and stirred vigorously for 15 minutes before filtering. The solid was washed with diethyl ether (50 ml), the organic layer separated and the aqueous layer extracted with diethyl ether (50 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound as a colourless oil (1.8 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O>[Cu].C1(C)C=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([CH:2]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A 100-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with 2,5-dichlorobenzoic acid (5.0 g, 26.2 mmol) and copper powder (5.0 g, 78.5 mmol). Sulfuric acid (98%; 35 mL) was added, and the resulting mixture was heated to 130°-135° C. Additional copper (0.83 g, 13.1 mmol) was added after 1 hour in order to complete the delhalogenation. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (1.5 hours). The reaction mixture was cooled to room temperature and transferred to a 500-mL Erlenmeyer flask. Water (100 mL) and toluene (100 mL) were added. The resulting mixture was filtered and the solids were washed with toluene. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting pale tan organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum, affording 3.49 g of 3-chlorobenzoic acid as a white solid, mp 152°-153° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:7](=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:1]([C:3]1[C:11]2[C:7](=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc2c(-c3ccccc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2c(-c3ccccc3)onc12
Reaction time: 2.5 h

Procedure:
To a solution of 12.2 g (0.054 mole) of 7-ethyl-3-phenyl-2,1-benzisoxazole in 60 ml of carbon tetrachloride was added 10.5 g (0.059 mole) of N-bromosuccinimide and 0.1 g of dibenzoylperoxide. The stirred reaction mixture was heated at reflux under flood light illumination and an argon atmosphere for 2.5 hr. The cooled reaction mixture was filtered and the filter cake was washed with 40 ml of carbon tetrachloride. The combined filtrates were washed with three 100 ml portions of 10% sodium bicarbonate, twice with 100 ml portions of water and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was treated with charcoal and filtered. The filtrate was concentrated to give 16.2 g (98%) of slightly impure title compound as a light brown oil that solidified upon standing. A sample was recrystallized from diethyl ether-petroleum ether (30°-60° C.) to give yellow crystals, m.p. 73°-77° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[O:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
A solution of [2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.8 mmol) from Step 4 above in 10% TFA/CH2Cl2 was stirred at room temperature for 20 minutes. The reaction was concentrated by rotary evaporation and used as is without further purification.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[NH2:2].[C:15]([O-])([O-])(OCC)[CH3:16]>C(O)(=O)C>[CH3:15][C:16]1[N:8]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:6][CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1cccc(-c2ccccn2)n1
Solvent: CC(=O)O
Product: Cc1nnc2cccc(-c3ccccn3)n12

Procedure:
A mixture of 1.0 g of 6'-hydrazino-2,2'-bipyridine, 50 ml of ethyl orthoacetate and 5 drops of acetic acid was heated on a steam bath for 2.5 days. The volatiles were removed under vacuum and the residue crystallized from ether-hexane. These crystals were dissolved in dichloromethane and the solution passed through a short pad of hydrous magnesium silicate. Concentration of the filtrate gave 460 mg of the desired product as crystals, mp 168°-170° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@:9]3([CH3:49])[O:12][CH:13]=[CH:14][C@H:15]([O:47][CH3:48])[C@@H:16]([CH3:46])[C@@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:18]([CH3:41])[C@H:19]([OH:40])[C@H:20]([CH3:39])[C@@H:21]([OH:38])[C@@H:22]([CH3:37])[CH:23]=[CH:24][CH:25]=[C:26]([CH3:36])[C:27]([NH:29][C:30]4[C:34](=[O:35])[C:4](=[C:5]([C:32](=[O:33])[CH:31]=4)[C:6]=2[C:10]3=[O:11])[C:3]=1[OH:50])=[O:28].[N-:51]=[N+]=[N-].[Na+]>N1CCCC1=O>[CH3:37][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH3:39])[C@@H:19]([OH:40])[C@@H:18]([CH3:41])[C@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:16]([CH3:46])[C@@H:15]([O:47][CH3:48])[CH:14]=[CH:13][O:12][C@:9]2([CH3:49])[C:10](=[O:11])[C:6]3[C:7]([O:8]2)=[C:2]([CH3:1])[C:3]([OH:50])=[C:4]2[C:34](=[O:35])[C:30](=[C:31]([NH2:51])[C:32]([C:5]=32)=[O:33])[NH:29][C:27](=[O:28])[C:26]([CH3:36])=[CH:25][CH:24]=[CH:23]1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: [N-]=[N+]=[N-]
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: O=C1CCCN1
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
14 g rifamycin S were dissolved in 70 ml pyrrolidone and added with 2.6 g sodium azide. The solution was heated at 60° C for 15 min., then at 80° C for further 15 min. The reaction mixture was then treated as in Example 3 to obtain 3.2 g 3-amino-rifamycin S identical to that described in Example 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:25]([O:32][C:33]1[C:40]([Br:41])=[CH:39][C:36]([CH:37]=[O:38])=[C:35]([CH3:42])[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:25]([O:32][C:33]1[C:40]([Br:41])=[CH:39][C:36]([CH:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=2)[OH:38])=[C:35]([CH3:42])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C=O
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2C)cc1
Reaction time: 0.25 h

Procedure:
To a tetrahydrofuran solution (1 L) of 1-bromo-4-[2-(methoxymethoxy)ethyl]benzene (50.2 g, 0.205 mol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M n-butyllithium solution in hexane (78.8 mL, 0.205 mol), and the mixture was stirred for 15 minutes at the same temperature. Then a tetrahydrofuran solution (150 mL) of 4-benzyloxy-5-bromo-2-methyl benzaldehyde (56.9 g, 0.195 mol) was added dropwise over an hour, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain [4-(benzyloxy)-5-bromo-2-methylphenyl][4-[2-(methoxymethoxy)ethyl]phenyl]methanol.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CC(C)=O>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCBr)cc1
Yield: 61 %

Procedure:
K2CO3 (1.82 g, 13 mmol) and 1,3-dibromopropane (3.05 mL, 30 mmol) were added to a solution of 4-hydroxy-benzaldehyde (1.22 g, 10 mmol) in acetone (30 mL). The mixture was heated under reflux for 8.5 hrs. Then the reaction mixture was filtered and the solvent was removed by evaporation. The resulting residue was mixed with ether and then washed consecutively with 5% NaOH, water, and brine. After drying with MgSO4 and evaporation of the solvent, flash column chromatography (silica gel, hexane 100%>EtOAc:hexane=10:90>20:80) gave the desired compound as a pale yellow oil: Rf=0.71 (silica gel, EtOAc:hexane=35:65); yield 61%; 1H-NMR (300 MHz, CDCl3) δ 9.86 (1H, s), 7.82-7.79 (2H, dd, J=6.9 and 1.8 Hz), 7.00-6.97 (2H, dd, j=7.1 and 1.6 Hz), 4.19-4.15 (2H, t, J=5.8 Hz), 3.61-3.56 (2H, t, 6.4 Hz), 2.37-2.28 (2H, qui, 6 Hz).
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([O:18][C:19]([NH:21][C@H:22]([C:34](O)=[O:35])[CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
91 mg (0.90 mmol) of 4-methylmorpholine and 98 mg (0.90 mmol) of ethyl chloroformate are added to a solution of 300 mg (0.90 mmol) of N2,N5-bis(tert-butoxycarbonyl)-L-ornithine in 10 ml of tetrahydrofuran at −10° C., and the mixture is stirred for 30 min. At this temperature, 1.81 ml (1.81 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran are slowly added dropwise. The mixture is slowly warmed to RT and stirred at RT for 12 h. While cooling in ice, 0.1 ml of water and 0.15 ml of a 4.5% sodium hydroxide solution are cautiously added, and the mixture is stirred at RT for a further 3 h. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and again evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of N-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (150 mg) in pyridine (2 ml) is added a solution of benzoyl chloride (43 mg) in methylene chloride (0.4 ml), and the mixture is stirred at room temperature for two hours. To the reaction solution is added 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/n-hexane to give N-(6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl)benzamide (161 mg) as crystals.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C(NN)=O.[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25].[Br:27]NC(=O)CCC(N)=O>C(O)C>[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([Br:27])[C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: NC(=O)CCC(=O)NBr
Agent: NNC(=O)c1cc2ccccc2[nH]1
Solvent: CCO
Product: COC(=O)c1cc(Br)c(N)cc1OC

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme Vor VI to form a compound of the invention