Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH:17]1[CH2:21][O:20][CH:19]([O:22][C:23](=O)[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH:18]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:46](OCC)(=O)C>O1CCCC1>[CH2:9]([N:8]([CH2:16][CH:17]1[CH:18]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:19]([O:22][C:23]([C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)=[CH2:46])[O:20][CH2:21]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(C)=O
Reactant: O=C(OC1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Product: C=C(OC1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
(2SR, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester (Description 7(a); 1.03 g, 1.7 mmol) was azeotroped with tetrahydrofuran (2×10 ml), dissolved in tetrahydrofuran (15 ml) and degassed with Firestone™ valve (×3). Bis(cyclopentadiene) titanium dimethyl (1.8 ml, 2.8M in toluene) was added and the mixture was heated to 60° C. in the dark. Further bis(cyclopentadiene) titanium dimethyl (1 ml) was added and the reaction was left to stand for 18 hours. The reaction was quenched with a slurry of sodium carbonate (4 g), water (2.5 ml) and methanol (50 ml), which caused it to turn yellow, and the reaction was left to stand at 40° C. for 16 hours under nitrogen. The solid was removed by filtration and the solvent removed in vacuo to afford a yellow solid. The solid was dispersed between water (50 ml) and ethyl acetate (40 ml), the aqueous layer was washed with ethyl acetate (3×20 ml) and brine (1×50 ml), and dried over MgSO4. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel and eluting in increasing concentrations of dichloromethane in hexane (10-100%) to give the title compound (299 mg, yield 29%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([C:10]([O:12]C)=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(C(C)(C)C)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
A mixture of methyl 2-tert-butyl-5-methyloxazole-4-carboxylate (44 mg, 0.22 mmol) and lithium hydroxide hydrate (47 mg, 1.1 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for 19 hours. To the reaction was added 1 M HCl(aq) (1.1 mL, 1.1 mmol) and water, and the reaction was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated to give 2-tert-butyl-5-methyloxazole-4-carboxylic acid (40 mg, 98% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H), 1.38 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O>>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][N:1]([CH2:31][C:27]1[NH:26][CH:30]=[CH:29][N:28]=1)[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=Cc1ncc[nH]1
Product: O=C(C[C@H]1CC[C@H](N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and 1H-imidazole-2-carbaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 507 (MH)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[Br:19][CH2:14][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[O:13][N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(-c2cccc(C(F)(F)F)c2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2cc(CBr)no2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of {5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl}methane-1-ol (0.28 g, 1.15 mmol) and carbon tetrabromide (0.5 g, 1.5 mmol) in methylene chloride (10 mL) at 0° C. was added dropwise a solution of triphenylphosphine (0.41 g, 1.58 mmol) in methylene chloride (5 mL). The resulting mixture was stirred at 0° C. for 1 hour, then the reaction mixture poured into ethyl acetate and Hexanes (ethyl acetate:Hexanes=1:4, 50 mL). The resulting suspension was filtered through a thin layer of silica gel and washed with ethyl acetate and Hexanes (ethyl acetate:Hexanes=1:4). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=1:4) to afford 3-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]isoxazole.
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(Br)ccc2[nH]1
Reactant: N#Cc1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)cc3Cl)ccc2[nH]1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
A mixture of (S)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)carbamate (Preparation 14, 87 mg, 0.14 mmol), 2-chloro-4-cyanophenylboronic acid (34 mg, 0.19 mmol) and aqueous sodium carbonate solution (2M, 150 μL, 0.30 mmol) in 1,2-dimethoxyethane (0.95 mL) was sparged with argon three times, then tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) was added. The reaction mixture was heated under microwave irradiation at 120° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give the crude product. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (45 mg, 48%) as a pale tan solid.
Reaction SMILES: [Mg].[CH3:2][Si:3]([CH3:16])([CH3:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=O.Cl.S(=O)(=O)(O)O>CCOCC.C(O)(=O)C.C1COCC1>[CH3:2][Si:3]([CH3:16])([CH3:15])[C:4]1[CH:5]=[C:6]([C:18]2[CH2:17][C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C2=Cc3ccccc3C2)cc([Si](C)(C)C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Magnesium turnings (6.8 g, 0.28 mol) and anhydrous THF (100 mL) were placed in a three-necked flack under argon. A solution of 3,5-bis(trimethylsilyl)bromobenzene (85.2 g, 0.28 mol) in of THF (100 mL) was added incrementally to the THF and magnesium mixture keeping the temperature near reflux. The Grignard reaction started immediately after the addition of the first increment. The remaining solution was added over a one hour period. The resulting slurry was refluxed for an additional 30 minutes. The solution was cooled to 20° C. and a solution of 2-indanone (36.7 g, 0.28 mol) in ether (100 mL) was added dropwise over a 1 hour period. The solution was then stirred at room temperature overnight. The solution was neutralized with 1N HCl. The aqueous layer was separated and washed three times with 100 mL of ether. The organics were combined and dried over magnesium sulfate. The solvents were evaporated to yield a tan solid of the crude alcohol. This solid was taken up in acetic acid (200 mL) and cooled to 15° C. A solution of sulfuric acid (40 g) and of acetic acid (200 mL) was added slowly, keeping the temperature of the mixture near 15° C. The product separated as and oil. The acetic acid layer was diluted with 1 L of ice water and extracted with toluene. The organic layer was separated and washed twice with sodium bicarbonate solution and dried over magnesium sulfate. The solvents were evaporated. The product was then taken up in a minimal amount of hexanes and passed through a short silica gel column to remove very polar material. Attempts to crystallize the product failed and the product was distilled to yield 20.5 g (22% yield), b.p. 175-180° C. @ 0.3 mm Hg. This procedure was repeated to yield an additional 22.3 grams of material. 1H NMR (C6D6): δ 7.45 (2H, s), 7.26 (1H, s), 7.13 (2H, dd), 6.94 (1H, m), 6.85 (2H, m), 3.51 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:8])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:29]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:16][C:15]2[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:38])=[CH:40][CH:41]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ncccc2N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ncccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.25 h
Yield: 20 %

Procedure:
A solution of N2-(4-methoxybenzoyl)-2,3-pyridinediamine (92 mg, 0.38 mmol) in tetrahydrofuran (1 mL) was treated with potassium hexamethyldisilazide (160 mg, 0.80 mmol). After 0.25 hr, the mixture was treated with 4-tert-butylbenzoyl chloride. After 0.75 hr, the mixture was poured into a mixture of aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed twice with water, once with saturated sodium chloride solution, dried (magnesium sulfate), and filtered. Concentration in vacuo and purification of the residue by flash cromatography (silica gel, methylene chloride/ethyl acetate) followed by recrystallization from ethyl acetate/hexanes yielded 31 mg (20%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[N+:15]=[N-:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[CH:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.CC(O)(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:30]=[C:29]([CH2:28][O:27][C:24]3[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[CH:22][CH:23]=3)[N:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Reactant: C#CCOc1ccc(S(C)(=O)=O)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Reaction time: 8 h

Procedure:
4-Azido-piperidine-1-carboxylic acid tert-butyl ester (1 eq) and 1-methanesulfonyl-4-prop-2-ynyloxy-benzene (1 eq) were suspended in H2O/t-BuOH (1:1). Sodium ascorbate (0.1 eq) was added followed by CuSO4.5H2O (0.01 eq). The mixture was stirred vigorously overnight. The mixture was diluted with water and a precipitate formed. The precipitate was collected by filtration and purified on silica gel to give the desired product. 1H NMR (CDCl3): δ 7.88 (2H, d), 7.67 (1H, s), 7.14 (2H, d), 5.29 (2H, s), 4.64 (1H, m), 4.28 92H, m), 3.05 (3H, s), 2.94 (2H, m), 2.2 (2H, m), 1.96 (2H, m), 1.48 (9H, s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.C[Si](I)(C)C.[S-]CC.[Na+].[S-]C1C=CC=CC=1.[K+].[C-]#N.[Na+].Br>ClCCl.CS(C)=O.[Br-].[Br-].[Br-].[Al+3].C(S)C>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: CCCNc1ccc(OC)c(OC)c1
Agent: Br
Agent: BrB(Br)Br
Agent: CC[S-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCS
Product: CCCNc1ccc(O)c(O)c1

Procedure:
In general, reductive amination of 3,4-dimethoxyphenyl acetone (see FIG. 1) is carried out by using an appropriate amine (ammonia, methylamine, or ethylamine) in the presence of a reducing agent, preferably sodium borohydride or sodium cyanoborohydride, at a temperature from 0° C. to 25° C. to give the desired 3,4-dimethoxyphenyl propylamine (1A). The latter intermediate is then demethylated to give the 3,4-dihydroxyphenyl propylamine. Typically, demethylation of phenolic derivatives is carried out by reaction with boron tribromide in dichloromethane at −70° C. to room temperature. A variety of demethylation reactions are known in the art, for example, trimethylsilyl-iodide, sodium thioethoxide, potassium thiophenoxide, sodium cyanide in DMSO, aluminium tribromide in ethanethiol, and hydrobromic acid (Greene, T. and Wuts, P., “Protective groups in organic synthesis”, 2nd edition, Wiley-Intersciences, 1991). Preferably the demethylation of the 3,4-dimethoxyphenyl propylamine derivative (1A) is carried out in the presence of 48% HBr under reflux conditions for 3-4 hours to give 1B. The amino group of the 3,4-dihydroxyphenyl propylamine 1B is then protected.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=2)[NH:12][N:11]=1)([O-])=O.C(O)C.Cl>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3[N+](=O)[O-])c2c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3N)c2c1
Yield: 15.3 %

Procedure:
N-[3-(2-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: 59 mg of powdered iron are added in small fractions to a solution, at reflux, of 280 mg of N-[3-(2-nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide, 10 ml of ethanol, 82 μl of distilled water and 51 μl of 12 N hydrochloric acid, and the reaction medium is then brought to reflux for 3 hours. After returning to a temperature in the region of 20° C., the suspension is filtered, and washed with ethanol. The filtrate is diluted with water and brought to a pH in the region of 10 with a 1 N sodium hydroxide solution. The filtrate is extracted with ethyl acetate and the remaining insoluble material is removed by filtration. The organic phase is washed with distilled water, dried with magnesium sulfate, treated with 3S black, filtered and concentrated to dryness under reduced pressure. The foam thus obtained is triturated with diisopropyl ether, filtered and dried. 40 mg of N-[3-(2-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white amorphous solid solvated with 1 mol of diisopropyl ether (analysis C20H18N4O4S2C6H14O % calculated C, 57.33; H, 5.92; N, 10.29; O, 14.69; S, 11.77. % found C, 57.41; H, 5.96; N, 10.01; S, 11.26).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10](=[O:12])/[CH:9]=[CH:8]/[C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][CH:6]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Reactant: Nc1ccc2ncsc2c1
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 6-aminobenzothiazole (75 mg, 0.50 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a white solid. MP 196° C. MS (ESI, pos. ion) m/z: 364 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:30])[C:27]([Cl:29])=[O:28]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:13]=[C:12]2[C:26](=[O:30])[C:27]([Cl:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(Cn2ccc3cc(OCc4ccccc4)ccc32)cc1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 5-benzyloxy-1-(4-fluorobenzyl)indole in 200 ml of THF is cooled under a N2 atmosphere to 0° C. While stirring and cooling further, a solution of oxalyl chloride in 100 ml of THF is added dropwise in such a way that the internal temperature does not exceed 10° C. The reaction mixture is then boiled under reflux for 2 hours. The solvent is distilled out as completely as possible in vacuo at a bath temperature of 50–60° C. The crude product remains as residue and crystallizes on cooling. It is employed without further working up in the next reaction stage.
Reaction SMILES: C[O:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:37]=[CH:36][C:15]([CH2:16][NH:17][C:18]([C:20]3[C:21]4[CH:28]=[N:27][N:26]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)[C:22]=4[CH:23]=[N:24][CH:25]=3)=[O:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1.B(Br)(Br)Br>ClCCl>[OH:2][CH:3]1[CH2:4][CH2:5][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]([C:20]3[C:21]4[CH:28]=[N:27][N:26]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)[C:22]=4[CH:23]=[N:24][CH:25]=3)=[O:19])=[CH:36][CH:37]=2)(=[O:11])=[O:10])[CH2:7][CH2:8]1
Reactant: COC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)cc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid 4-(4-methoxy-piperidine-1-sulfonyl)-benzylamide (0.080 g, 0.15 mmol) in dichloromethane (5 mL) was added a 1 M solution of boron tribromide (0.2 mL, 0.2 mmol) in dichloromethane. The mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC-MS indicating partial conversion. Additional boron tribromide (0.4 mL, 0.4 mmol) was added. After 30 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate and was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×5 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-30% acetonitrile in EtOAc to afford the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:29])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:19]([C:4]1([CH2:1][C:2](=[O:29])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CCCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CCCCC1(CC(C)=O)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reaction time: 16.5 h

Procedure:
2-allyl-2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (40 mg, 0.12 mmol) was dissolved in acetonitrile (0.36 mL) and treated with benzoquinone (20 mg, 0.18 mmol), Pd(OAc)2 (5 mg. 0.02 mmol), water (0.018 mL) and perchloric acid (70%, 0.005 mL) to give an orange solution. This solution was stirred under an air atmosphere for 16.5 hours, then purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 4:1 hexane-EtOAc. The band at Rf 0.53-0.59 was eluted with 5% MeOH in CH2Cl2 to give 2-butyl-5-chloro-7-fluoro-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-2H-naphthalen-1-one as a slightly yellow oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and Cul (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).