Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH3:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(O)c1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with 6% ethyl acetate in hexane to afford the 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[I:15](O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:15][C:4]1[CH:5]=[C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [O-][I+2]([O-])O
Reactant: COc1ccc(C2CNC(=O)C2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CNC(=O)C2)cc1I
Temperature: 80 °C
Reaction time: 10 h
Yield: 414.5 %

Procedure:
A solution of 19.1 g of 4-(4-methoxyphenyl)-pyrrolidin-2-one (100 mmol) in 200 ml of glacial acetic acid, 4.8 ml of water and 1.2 ml of concentrated sulfuric acid is combined with 3.44 g (19.55 mmol) of iodic acid and 8.64 g (70 mmol) of iodine and stirred at a bath temperature of 80° C. for 10 hours. Subsequently, the mixture is concentrated on a rotary evaporator up to onset of crystallization, cooled, the crystalline precipitate is suctioned off and recrystallized from ethyl acetate, thus obtaining 25.7 g (81% of theory) of 4-(3-iodo-4-methoxyphenyl)pyrrolidin-2-one, mp 158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11]C=O)=[C:7]([C:14](=O)[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1)[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:14](=[N:28][OH:29])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1ccc(NC=O)c(C(=O)CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N)c(C(CCNC(=O)OC(C)(C)C)=NO)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A solution of ethyl-4-formylamino-3-[3'-(N-tert-butyloxycarbonylamino)propionyl]benzoate (7.04 g, 20 mmol) and hydroxylamine hydrochloride (7.65 g, 110 mmol) in pyridine (200 ml), was heated at reflux for 15 hours. After this time the solution was cooled to ambient temperature and the solvent evaporated in vacuo. The residue was chromatographed (eluent 1:1 petrol:ethyl acetate) to give the title oxime (5.0 g, 71%) as a solid. m.p. 138°-140° C. NMR δ (250 MHz, CDCl3) 1.40 (12H, m), 3.13 (2H, t, J=7 Hz), 3.40 (2H, m), 4.31 (2H, q, J=7 Hz), 5.19 (1H, br s), 6.11 (2H, br s), 6.66 (1H, d, J=9 Hz), 7.73 (1H, dd, J=9 and 2 Hz), 8.10 (1H, br s), 10.46 (1H, br s).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:15])[C@@H:12]([NH2:14])[CH3:13])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[C:4](=[O:20])[N:3]1[CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:14][C@@H:12]([CH3:13])[C:11]([NH:10][CH:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[C:4](=[O:20])[N:3]([CH:21]([CH3:23])[CH3:22])[N:2]([CH3:1])[C:8]2=[O:9])=[O:15])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CC(C)N1C(=O)c2ccccc2C(NC(=O)[C@H](C)N)C(=O)N1C
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)N1C(=O)c2ccccc2C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N1C
Yield: 75 %

Procedure:
In a manner similar to example 1, the title compound was prepared by the reaction of 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-amino-1-oxopropyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione with 3,5-difluorophenylacetic acid. The compound was purified on prep HPLC using the column YMC S5 ODS (20×100 mm) with a flow rate of 40 ml/min and gradient time of 10 min., starting with solvent A (10% MeOH—90% H2O—0.1% TFA), and ending with solvent B (90% MeOH—10% H2O—0.1% TFA). (75% yield). MS (ESI) 473.09 (M+H); Rf 1.31
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.[Li]C(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-Bromo-2-ethoxy-1-methoxybenzene (4.00 g, 17.3 mmol) in THF (75 mL) was cooled to −78° C.; during cooling, a precicipitate formed. t-BuLi (22.4 mL, 1.7 M in pentane, 38.1 mmol) was added dropwise, while maintaining the temperature at −78° C. The mixture was stirred at −78° C. for 1 hour following completion of the addition. B(Oi-Pr)3 (9.76 g, 51.9 mmol) was added. The mixture was allowed to gradually warm to room temperature, and then stirred under nitrogen for 16 hours. 3N HCl (20 mL) was added, and the mixture stirred for 10 minutes. The mixture was poured into water (100 mL) and extracted with diethyl ether (3×75 mL), and the combined ethereal layers were washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 3.15 g of the product in 93% yield: 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 3.75 (s, 3H), 3.99 (q, J=7.0 Hz, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.35-7.37 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.[OH:29]O>C(Cl)CCl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)=[O:29]
Reactant: Cc1cc(C(C)(C)C)ccc1SCCCCOc1ccc2c(c1)CCC(=O)N2
Reactant: OO
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc(C(C)(C)C)ccc1S(=O)CCCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
Prepared analogous to Example 123 from 6-[4-(2-methyl-4-tert. butylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide. Resinous substance. Rf -value: 0.54 (silica gel fluorescent plate; eluant: ethylene chloride/methanol=95/5).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[CH2:23][CH3:24])=[O:6])[CH3:3]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1CC
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a mixture of 10.0 g of (2S,4R)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride, 15.5 g of potassium carbonate and 50 ml of chloroform, 9.46 g of diethyl sulfate were dropwise added. At 40° C., the mixture was stirred for 4 hours and then allowed to cool, washed with water, added with an aqueous dilute HCl solution and the formed aqueous layer was separated. This aqueous layer was neutralized with potassium carbonate, extracted with chloroform and the extract was washed with water, dried and concentrated under reduced pressure to obtain (2S,4R)-2-ethoxycarbonyl-N-ethyl4-hydroxy pyrrolidine as an oily product. Yield 8.15 g.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CS(C)=O.[OH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CC(C)=O.O>[O:28]1[CH2:27][C@H:26]1[CH2:25][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
Powdered K2CO3 (40 grams, 289 mmol, 300 mesh) was added to dimethyl sulfoxide (DMSO) (200 mL) containing H2O (4 mL) under N2 at room temperature and the mixture was stirred for 30 minutes. 4-Hydroxyindole (25.2 grams, 189 mmol) was added to the mixture (slight exotherm to 27° C.) and the mixture was stirred for 10 minutes. (S)-Glycidyl nosylate (50.0 grams, 193 mmol, 98.5% ee) was added (slight endotherm). The slurry was stirred for 30 minutes at 20-25° C. and for 23 hours at 25-27° C. until the reaction was complete. The mixture was diluted with acetone (400 mL) and filtered. The cake was washed with acetone (400 mL) and the combined filtrates were concentrated to a volume of ca. 250 mL under vacuum while maintaining the temperature below 35° C. This concentrate was added dropwise, over ca. 2 hours, to deionized H2O (650 mL) held at a temperature of 15-20° C. with an ice/water bath. The product slurry was stirred for 1 hour at this temperature and for 30 minutes at 5-10° C. The solid was isolated by filtration and washed with cold deionized H2O (150 mL). The solid was dried under vacuum at 35° C. to yield 30.3 grams of product.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[F:1][S:2]([F:10])([F:11])([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cccc(S(F)(F)(F)(F)F)c1

Procedure:
15 g (68.44 mmol) of 3-pentafluorosulfanylphenylamine was suspended with 10.14 g (68.44 mmol) of phthalic anhydride in 40 ml of a acetic acid and boiled under reflux for 2 h. The cool reaction mixture was admixed with 400 ml of water, heated in an ultrasound bath for 30 min and filtered. The residue was washed with water and subsequently with a little ethanol and dried under reduced pressure. 2-(3-Pentafluorosulfanylphenyl)isoindole-1,3-dione was obtained with a melting point of 188-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(Cl)cc5)cn4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2)cn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Ethyl 6-chloro-7-(4-(5-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (30 mg, 0.053 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (266 μl, 0.27 mmol) and ethanol (200 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the desired compound (27 mg, 0.050 mmol, 95% yield). MS (ESI)=535.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1.[OH-].[Na+]>CN(C=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][NH:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc(-c2oc3ncnc(NCC4OCCO4)c3c2-c2ccccc2)cc1
Temperature: 150 °C
Yield: 57.5 %

Procedure:
A stirred mixture of 4-amino-5,6-diphenylfuro[2,3-d]pyrimidine (100 mg, 0.34 mmol), 2-bromomethyl-1,3-dioxolane (116 mg, 0.69 mmol) and sodium hydroxide granules (42 mg, 1.05 mmol) in DMF (1.5 mL) was heated at 150° C. for 1 hour. The resulting mixture was filtered and purified by preparative HPLC to give a beige solid (73 mg). 1H NMR (CDCl3): 8.50 (1H, s), 7.62-7.49 (7H, m), 7.32-7.25 (3H, m), 5.70 (1H, br s), 5.00 (1H, br s), 3.85-3.63 (6H, m). LC/MS: 374 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])=[CH:7][CH:6]=1.F[C:26](F)(F)[CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[S:28]([CH2:27][CH3:26])(=[O:30])=[O:29])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(Nc1ccc(Oc2ccc(F)cc2F)cc1)c1cccnc1
Product: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)cc1)C(C)c1cccnc1

Procedure:
Using the method of Example 342 using N-(4-(2,4-difluorophenoxy)phenyl)-1-pyrid-3-ylethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 95:5 to 85:15 CHCl3/ethyl acetate gave the title compound. Anal Calcd for C21H17F5N2O3S.0.2H2O: C, 52.98; H, 3.68; N, 5.89. Found: C, 52.88; H, 3.73; N, 5.67. MS found 473.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NCC)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CCOCC>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A resealable tube was flame-dried under high vacuum. The vacuum was broken by the addition of dry argon, and the flask was allowed to cool to room temperature. The flask was charged with 5.0 g (18.1 mmol) of ethyl 4-bromobenzoate, 7.7 mL (54.3 mmol) of (trimethylsilyl)acetylene, and 65 mL of diethylamine. The solution was purged with argon for 15 minutes and bis(triphenylphosphine)palladium (II) chloride (320 mg, 0.45 mmol) and copper (I) iodide (87 mg, 0.45 mmol) were added, the tube sealed, and the solution stirred at 55° C. for 3 days. The solution was poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted 3 times with ether. The combined ether layers were washed once with brine, and dried over magnesium sulfate, and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatography (95:5. hexane:ethyl acetate) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:27]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:28]=[C:19]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (100 mg, 0.363 mmol) and o-phenylene diamine (40 mg, 0.369 mmol) were dissolved in dry THF (8 mL), and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 9.60 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.0 & 9.2 Hz), 7.87 (m, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.47 (m, 1H), 7.28 (m, 2H), 5.77 (dd, 1H, J=2.4 and 8.8 Hz), 4.00 (m, 1H), 3.76 (m, 1H), 2.53 (m, 1H), 2.13 (m, 2H), 1.77 (m, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18].[OH2:19]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][N:15]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:17][NH:18][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NCCNCCN
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
This compound was synthesized following the procedure of Atkins, T. J.; Richman, J. E.; and Oettle, W. F.; Org. Synth., 58, 86-98 (1978). To a stirred solution of p-toluenesulfonyl chloride (618 g, 3.24 mole) in pyridine (1500 ml) at 0° C. was added a solution of 1,4,7-triazaheptane (95.5 g, 0.926 mole) in pyridine (150 ml) under a dry argon atmosphere, maintaining the temperature≤50° C. The addition required 30 minutes. After the mixture was allowed to cool to room temperature slowly while stirring for 3 h, H2O(2 l) was slowly added to the cooled (ice bath) mixture. The heavy white precipitate which formed was filtered and washed thoroughly with H2O. The pale yellow solid was dissolved in DMF (3 l) and 0.1 N HCl (4 l) was slowly added at 5° C. The slurry was filtered and the pale yellow solid was washed thoroughly with H2O and dried in vacuo to give 486 g (93% yield) of the product: mp 180-1° C.; 1H NMR(DMSO-d6) δ 2.39 (s,3 H), 2.40 (s, 6 H), 2.84 (m, 4 H), 3.04 (t, J=6.9 Hz, 4 H) 7.40 (d, J=8. l Hz, 4 H), 7.59 (d, J=8.3 Hz, 2 H), 7.67 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 62.1 %

Procedure:
6-Chloronicotinoyl chloride (0.83 g) was dissolved in toluene (15 mL), and the solution was cooled to 0° C. 4-(Trifluoromethyl)aniline (1.6 g) was added thereto at 0° C., and the mixture was stirred at room temperature for 10 hours. Ethyl acetate was added thereto, and the organic layer was washed with a 1 N aqueous sodium hydroxide solution and water and dried over sodium sulfate. After concentration under reduced pressure, the obtained solid was collected by filtration and washed with diethyl ether. The solid was dried under reduced pressure to obtain the title compound (0.88 g) as a white solid (yield: 29%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=1.[OH-].[K+].CO.C(O)C>O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][C:6]=1[C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 15.0 g of product from Example 130. 7.24 g of potassium hydroxide, 100 ml methyl alcohol, 40 ml ethyl alcohol and 10 ml of water is heated at reflux temperature for 18 hours. The reaction is cooled to room temperature, made acidic to pH 2, concentrated in vacuo, swirled with water and the solid collected. The solid residue is washed with water and dried in a vacuum oven to give 13 g of the desired product as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH2:8][CH2:7]2.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([NH:1][CH2:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:10]2=[O:12])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(N2CCc3cccc(N)c3C2=O)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCc3cccc(NCc4ccncc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the amine (Step E) and CH2Cl2 (5 mL) was added 4-pyridinecarboxaldehyde and NaBH(OAc)3. The reaction was stirred at RT for 18 h. Purification by silica flash chromatography (25-75% EtOAc:hexane) gave the desired product as a light-yellow oil. MS m/e 386 (M+H)+. Calc'd for C25H27N3O-385.50.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:23]1([S:33]([Cl:36])(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[ClH:36].[C:23]1([S:33]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Cl
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared according 4-(4-boc-piperazinyl)-indole and naphthylsulfonylchloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.03 (br, 1 H), 8.63 (d, J=8 Hz, 1 H), 8.43 (d, J=8 Hz, 1 H), 8.34 (d, J=8 Hz, 1 H), 8.15–8.05 (m, 2 H), 7.80–7.65 (m, 3 H), 7.41 (d, J=8 Hz, 1 H), 7.18 (t, J=8 Hz, 1 H), 6.93 (d, J=5Hz, 1 H), 6.74 (d, J=8Hz, 1 H), 3.30–3.20 (m, 8 H); MS (ESI+) for m/z 392 (M+H)+.