Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1>[CH3:8][S:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 61.3 %

Procedure:
A mechanically stirred solution of aniline (139.7 g, 1.5 mole) in pyridine (2 liters), under N2 is cooled in an icebath. Methanesulfonyl chloride (171.8 g, 1.5 mole) is added dropwise to this solution while the temperature is maintained at 15°-20° C., which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at ambient temperature. By TLC on silica gel (2.5% MeOH:CH2Cl2) the reaction is complete after 21/2 hours. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material. This material is filtered and washed several times with water. The filtered material is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is dissolved in hot ethyl acetate, treated with Darco (decolorizing carbon) and crystallized to yield four crops of methanesulfonanilide 157.37 g, 19.27 g, 26.55 g, 5.07 g which had a mp: 93°-94° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:1][C:2]1[NH:3][C:4]([N+:12]([O-:14])=[O:13])=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ncc([N+](=O)[O-])[nH]1

Procedure:
In a bottle of 1 liter capacity, an untreated mixture obtained by nitration of the 2-methylimidazole as in examples I, III and V were placed and while stirring and mixing, 100 g of 2-methylimidazole were dissolved in such a manner, that the temperature did not exceed 70°. Then a reflux-condenser was connected and 200 ml of nitric acid of a density of about 1.50 were added, and thereafter sulphuric acid of 1.84 density was gradually introduced such that the temperature increased to 110°. The reaction, which started at once without delay, was intensive with violent liberation of nitric oxides. Then as the intensity of the reaction declined, further quantities of sulphuric acid were added until exhaustion of a quantity of 100 ml, and after the exothermic effect diminished the reflux condenser was changed to a normal one, whereby the temperature of the mixture increased to about 140° by simultaneous distilling off several ml of volatile components. After the reaction the solution was divided, and 1/3 remained for the treatment in the same way as the following charge and from the remaining 2/3 of the solution there were isolated 98 g of 2-methyl-5-nitroimidazole corresponding to about 66% of theoretical.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:11]>C(O)C>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)cccc1F
Solvent: CCO
Product: N#Cc1c(N)cccc1F
Temperature: 140 °C
Yield: 97 %

Procedure:
A mixture of 2,6-difluorobenzonitrile (19.0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at 140° C. in an autoclave for 6 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature, evaporated to dryness and triturated with water (200 ml). The solid was filtered and left to air dry to afford 2-amino-6-fluorobenzonitrile (18.0 g, 97%) as an off-white solid: δH (360 MHz, CDCl3) 4.53 (3H, s), 6.44-6.52 (2H, m), 7.24-7.30 (1H, m).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O:13]1[CH:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>>[ClH:1].[OH:13][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NCCOc1ccc(O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Product: Oc1ccc(OCCNCC(O)COc2ccccc2)cc1
Yield: 15.6 %

Procedure:
A mixture of p-(2-aminoethoxy)phenol hydrochloride (1.89 g) triethylamine (1.01 g) and 1,2-epoxy-3-phenoxypropane (1.5 g) was heated under reflux for 24 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic layer was separated, dried (MgSO4), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen chloride was passed through the solution until no further solid precipitated. The precipitate was collected and recrystallised from methanol and ethyl acetate to give p-(2-[2-hydroxy-3-phenoxypropylamino]-ethoxy)phenol hydrochloride (0.53 g), mp, 171°-72° C.; microanalysis: found C,60.3; H,6.7; N,4.0; Cl, 10.6%; required for C17H22NClO4 : C,60.1; H,6.5; N,4.1; Cl,10.5%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:26][CH2:25][CH3:24])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1CCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCCC(c1ccccc1OC)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO3 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g, m.p.=132°-133° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[C:15]([CH:32]([CH3:34])[CH3:33])=[N:16][C:17]([CH:29]([CH3:31])[CH3:30])=[C:18]([CH2:27][OH:28])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:32]([C:15]1[C:14]([CH:13]=[O:12])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]([CH:27]=[O:28])=[C:17]([CH:29]([CH3:31])[CH3:30])[N:16]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.3 g (48 mmol) of pyridinium chlorochromate and 4.9 (48 mmol) of neutral alumina are added to a solution of 3.8 g (12 mmol) of the compound from Example 4 in 100 ml of methylene chloride p.a. and the mixture is stirred for 1 h at room temperature. The mixture is filtered over kieselgur with suction and washed with 300 ml of methylene chloride. The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (150 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 2:8).
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]>C1COCC1.O=[Mn]=O>[CH:12]([C:10]1[N:11]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[S:8][CH:9]=1)=[O:13]
Reactant: CC(C)C(=O)Nc1nc(CO)cs1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc(C=O)cs1
Yield: 50.4 %

Procedure:
11C (0.5 g, 2.5 mmol) was dissolved in THF (10 mL). To the solution at room temperature was added activated MnO2 (1.74 g, 20 mmol). The reaction mixture was refluxed overnight, then filtered. The filtrate was concentrated and dried to give a crude product 11D (0.25 g, 50% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>CC#N>[Br:25][C:13]1[N:9]2[N:10]=[CH:11][CH:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[N:15][C:14]=1[CH2:16][OH:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cn2nccc(N3CCOCC3)c2n1
Solvent: CC#N
Product: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of compound 5d (40.0 g, 171 mmol) in CH3CN (400 mL) was treated dropwise with a solution of NBS (30.2 g, 170 mmol) in CH3CN (906 mL) at −20° C. After addition, the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of 50 mL of saturated Na2S2O3 solution. The solids formed were collected by filtration and washed with diethyl ether to afford compound 83a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). found: 313.0.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:18])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: O=[O+][O-]
Solvent: CO
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Reaction time: 1.33 h

Procedure:
A 4.74 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 50 ml. of methanol, and was cooled to -12°. Ozone-containing air was bubbled through the mixture with good stirring for 80 minutes. The temperature rose as high as 0° during the ozone addition, and the mixture foamed and left solids on the flask walls above the liquid. It was necessary to wash the solid down with 20 ml. of additional methanol. Ten ml. of additional methanol was used to wash the gas frit when it began to plug from precipitated product. After the addition was complete, nitrogen was bubbled through the solution for 5 minutes, and then 1.5 ml. of dimethyl sulfide was added and the mixture was warmed to 20° and diluted with 80 ml. of water. The methanol was removed under vacuum at 40°, and the remaining mixture was filtered and the solids were washed with 50 ml. of water and dried under vacuum at 50° to obtain 2.68 g. of the desired product, m.p. 173°-176°. It was further identified by nmr analysis which showed it to be substantially identical to the product of Example 1.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([OH:22])=O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1>C1COCC1.CN(C)C=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([Cl:4])=[O:22])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1

Procedure:
Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25° C. This solution was used in the next step without further processing.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)[CH3:9])(C)(C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: COc1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: C[C@H](N)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-[1-(3-Methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (50.2 g, 210 mmol) in CH2Cl2 (500 mL) was cooled to −78° C. Boron tribromide (450 mL, 1.0M in CH2Cl2) was added slowly and the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was again cooled to 0° C. and methanol (500 mL) was added slowly. The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with 5% MeOH in EtOAc to give the title product in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A 24.8 g sample of 3,5-dinitrobenzotrifluoride purchased from Aldrich Chemical Co. was slurried in 200 ml of ethanol and 5 g of 1% palladium on carbon added. This mixture was transferred to an autoclave, pressured to 400 psi with hydrogen, and heated at 75° C. with stirring for 1 hr. A 91% yield of pure 3,5-diaminobenzotrifluoride was recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1>>[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:3]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared by Procedure W and Scheme AF using N-(3-bromo-4-methylphenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 259.1 (M−100)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].Cl.[NH2:19]O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:19][O:16][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: NO
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol), and the reaction was stirred at 115° C. for 1 hours. After cooling, saturated aqueous NaHCO3 was added to the mixture to adjust to pH 8. The solution was extracted with EtOAc, and the combined organic layers were washed with brine, dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[C:11]1([C:17]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:9]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
A solution of 5.3 g (20 mmol) of 3,6-dibromo-1,2-phenylenediamine 1, 4 g (19 mmol) of benzil 2b, 4.2 g of sodium acetate and 150 ml of glacial acetic acid were refluxed for 4 hours. The precipitate was filtered off, washed with 100 ml of water and recrystallized twice from dioxane. Drying under reduced pressure at 50° C. gave the pure product in the form of colorless crystals, which according to HPLC had a purity of about 99.5%. The yield was 6.45 g (73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzaldehyde (5.13 g, 25.4 mmol) in DMF (25 mL) were added K2CO3 (7.15 g, 51.8 mmol) and 3,4-dichloro-phenol (4.67 g, 28.8 mmol). The mixture was heated at 90° C. for 24 h and then was allowed to cool to room temperature (rt). Water was added and the mixture was extracted with Et2O. The combined organic layers were dried (MgSO4) and concentrated. The residue was diluted with DCM and hexanes and the resulting solid was collected by vacuum filtration to provide the desired product (4.74 g, 54%). 1H NMR (CDCl3): 10.36 (s, 1H), 8.06 (d, J=2.5, 1H), 7.67 (dd, J=8.8, 2.6, 1H), 7.46 (d, J=8.8, 1H), 7.17 (d, J=2.8, 1H), 6.92 (dd, J=8.8, 2.8, 1H), 6.84 (d, J=8.8, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:6]=2
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 6-bromo-4-nitro-1H-indazole (available from Sinova, 10 g, 0.041 mol), 3,4-dihydro-2H-pyran (7.85 g, 8.52 ml, 0.093 mol) and pyridine 4-methylbenzenesulfonate (0.125 g, 0.496 mol) in dichloromethane (150 ml) was heated at reflux for 4.5 hours. The reaction was allowed to cool to room temperature and was poured onto saturated aqueous sodium bicarbonate (200 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were washed with 5% aqueous citric acid (w/v, 100 ml) and brine (100 ml) and dried over magnesium sulphate. Solvent was removed in vacuo to give the title compound (12.9 g) as a dark orange solid.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[NH4+].[Cl-]>C1COCC1.[Zn]>[NH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cccnc2N1
Reaction time: 2 h

Procedure:
A solution of 3,3-dibromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.0 g, 7.2 mmol) in THF (50 mL) was stirred at room temperature, and a saturated aqueous solution of NH4Cl was added. Activated zinc powder was added, and the reaction mixture was stirred for 2 h. The zinc was removed by filtration through a pad of diatomaceous earth, and the organic layer was separated. The aqueous layer was extracted with THF (10 mL), and the combined organic layers were dried over anhydrous MgSO4, filtered and evaporated. The residue was slurried in 10:1 CHCl3:MeOH (15 mL) and filtered through a pad of silica gel, and the filtrate was evaporated. The residue was triturated with water, and the solid was collected by filtration and dried under vacuum to give the title compound, 0.668 g (70%). 1H NMR (d6-DMSO) δ 10.94 (s, 1H), 8.02 (d, 1H, J=5.2 Hz), 7.52 (d, 1H, J=6.8 Hz), 6.90 (dd, 1H, J=6.8, 5.2 Hz), 3.53 (s, 2H). MS (AP−ve) 133 (100)(M−H)
Reaction SMILES: [CH:1]([O:14][C:15](=[O:44])/[C:16](/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:22][CH:23]=1)=[N:17]\[OH:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:52][C:53]#[N:54].C(OCC)C>CS(C)=O>[CH:1]([O:14][C:15](=[O:44])/[C:16](=[N:17]\[O:18][CH2:52][C:53]#[N:54])/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:22][CH:23]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
In 70 ml of dimethylsulfoxide was dissolved 11.9 g (0.02 mole) of (Z)-2-(2-tritylamino-4-thiazolyl)-2-(hydroxyimino)acetic acid benzhydryl ester and after adding thereto 2.76 g of a powder of potassium carbonate and 1.7 g (0.0225 mole) of of chloroacetonitrile, the mixture was allowed to react overnight at room temperature. After the reaction was over, the reaction mixture was poured into 150 ml of ice water, the product was extracted first with 150 ml of ethyl acetate and then with 100 ml of ethyl acetate. The organic layers were collected, and washed twice with 50 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution. The ethyl acetate layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off to provide a caramel. To the caramel was added 100 ml of ethyl ether to powder the caramel. 11.5 g (yield: 90.7%) of (Z)-2-(cyanomethyloxyimino)-2-(2-tritylamino-4-thiazolyl)acetic acid benzhydryl ester was obtained. ##STR15##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:45][CH2:46][CH2:47][CH2:48]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:48][CH2:47][CH2:46][Br:45])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A mixture of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [950 mg, 1.79 mmol, Intermediate (49)], cesium carbonate (1.75 g, 5.37 mmol), and 1,3-dibromopropane (6.0 mL) was heated at 90° C. under nitrogen. After 1.5 hours, the mixture was cooled to ambient temperature, filtered, and the insolubles washed twice with dichloromethane (10 mL). The filtrate was concentrated in vacuo to yield a cloudy oil. The crude product was chromatographed on silica, eluting first with 80% dichloromethane/heptane and then 100% dichloromethane to give 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [760 mg, 65%, intermediate 50] as a white foam. TLC Rf 0.37 (silica, dichloromethane); LC/MS: 674 (M+Na), RT=2.60 minutes.