Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([N:13]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH2:46]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH:46][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:13]([CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18]
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Yield: 83.7 %

Procedure:
4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (3.62 g, 10 mmol) and oxalyl chloride (3.8 mL, 30 mmol) were stirred in DCM dry (120 mL) and a few drops of dry DMF at room temperature for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (50 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (2 gr, 7.72 mmol) in dry pyridine (20 mL) was added to the cooled reaction mixture under nitrogen atmosphere. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with aqueous NaHCO3 sat. sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using AcOEt/Hexane 7:3 as the eluant, affording 3.9 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([OH:23])=[O:22]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
For the preparation of the starting material, MS: 367 (M-BOC+H), 6-(1-t-butoxyformamido)hexanoic acid and 3-amino-5-nitrobenzoic acid are reacted to give 3-[6-(1-t-butoxyformamido)hexanamido]-5-nitrobenzoic acid, MS: 396 (2, M+H), and the latter is reacted with β-alanine methyl ester to give N-[3-[6-(1-t-butoxyformamido)hexanamido]-5-nitrobenzoyl]-β-alanine methyl ester, MS: 381 (100, M-Boc+H). This is then saponified in methanolic sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28]O)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][Br:33])[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2occc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C2=C(c3cn(CCCBr)c4ccccc34)C(=O)NC2=O)c2occc2c1
Reaction time: 0.17 h

Procedure:
Dissolve 3-(5-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.058 g, 0.118 mmol) in 10 mL dichloromethane. Add carbon tetrabromide (0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent). Stir for 10 min, add another equivalent of both reagents. Stir 10 min then dilute with dichloromethane and wash with water followed by brine. Dry over magnesium sulfate then filter and concentrate. Purification by column chromatography (2% methanol:dichloromethane) affords the 3-(5-methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl)pyrrole-2,5-dione. 3-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dione is dissolved in 1.5 mL 1-methyl-2-pyrrolidinone and add dimethylamine (2M solution in tetrahydrofuran, 0.3 mL, 5 equivalents). Heat to 60° C. for 16 hrs. Extract with ethyl acetate versus water, concentrate organic layer. Redissolve in a minimal amount of methanol and load onto an SCX™ Varian column (pretreated with a 5% acetic acid: methanol solution). Wash with methanol and ethyl acetate to remove impurities, flush with 2M ammonia methanol to recover product. ES(M++H)444.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.Cl>[CH:25]([S:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=1)(=[O:28])=[O:27])=[CH2:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-aminophenylcarbamate (2.63 g, 12.63 mmol) and triethylamine (7.04 mL, 50.51 mmol) were combined in dichloromethane (50 mL) and cooled in an ice bath. After drop wise addition of 2-chloroethanesulfonyl chloride (1.45 mL, 13.9 mmol), the solution was stirred at ambient temperature for 4 h then diluted with 0.5M HCl and extracted into dichloromethane. The product was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to give 2.48 g (66%).
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7](NC3C=CC(Br)=CC=3)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CN(C)C=[O:24]>>[N:6]1[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=1[C:4]([NH:8][CH3:7])=[O:24]
Reactant: Nc1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)c1ccccn1

Procedure:
To a solution of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine (1 eq) in N,N-dimethylformamide was added sodium hydride (2 eq) and the mixture was microwaved for 8 mins at 220° C. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried with sodium sulfate and concentrated. Preparative chromatography yielded [4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)(2-pyridyl_-N-methylcarboxamide. MS: MH+=437.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Reactant: OB(O)c1ccncc1
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: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) in a 5:1 mixture of 1,4-dioxane and water (0.17 M) was added sodium carbonate (2.1 equiv). The reaction was stirred at 75° C. for 3 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (50.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9 H) 0.82-0.91 (m, 2 H) 1.74 (dtd, J=12.74, 8.37, 8.37, 3.71 Hz, 2 H) 2.01-2.16 (m, 2 H) 3.50-3.63 (m, 4 H) 3.69-3.83 (m, 2 H) 5.50 (tt, J=7.91, 3.81 Hz, 1 H) 5.59 (s, 2 H) 7.72 (d, J=6.25 Hz, 2 H) 8.12 (s, 1 H) 8.60 (d, J=6.25 Hz, 2 H); MS (ESI) m/z 461.0 [M+1]+
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 48 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.29 g, 42% yield), mp=170–172° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=−33.4° (c=1, DMSO).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[N:11]=[N:10][CH:9]=1)C>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[N:10][CH:9]=[C:8]([CH2:7][C:6]([O-:41])=[O:5])[CH:13]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22].[Na+:2]
Reactant: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(CC(=O)[O-])cnn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A 0.25 N sodium hydroxide aqueous solution (0.024 mL) was added to a solution of [6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester (Example 182-(7); 2.5 mg, 0.0047 mmol) in methanol (0.10 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure to give the title compound (2.5 mg, 100%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[OH:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[O:3][C:4]([C:7]3[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:5][N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Reactant: Nc1cccc(O)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.23 g, 0.723 mmol) and commercially available 3-aminophenol 8 (0.079 g, 0.724 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6].Cl[C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1.O>CN(C=O)C>[CH2:3]([N:7]([C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNS(=O)(=O)c1ccccc1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(c1nc2ccccc2n1C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.029 g, 0.0012 mol, 1.1 equiv) was suspended in DMF (5 mL). N-Butyl-benzenesulfonamide (0.256 g, 0.222 mL, 0.0012 mol. 1.2 equiv) was then added and stirred at room temperature for 10 minutes. To the resulting mixture was then added the 2-chloro-N-methyl benzimidazole, (0.166 g, 0.001 mol). The resulting mixture was heated to 50° C. and stirred overnight (16 hours). The resulting mixture was then poured into water (15 mL) and stirred for 1 hour. The resulting solution was extracted with DCM (20 mL) and the organic layer was separated. The organic layer was washed with 1N NaOH (20 mL), and brine (20 mL), then dried over Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC (eluent 60-80% acetonitrile) to yield the title compound as a yellowish solid. MS 343.4
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:33][CH2:32][N:31]([CH:2]([C:4]3[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CCCn1c(C(C)Br)nc2ccccc2c1=O
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Solvent: CCO
Product: CCCn1c(C(C)N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)nc2ccccc2c1=O
Yield: 13.5 %

Procedure:
A mixture of 2-(1-bromo-ethyl)-3-propyl-3H-quinazolin-4-one (30 mg, 0.1 mmol) and 1-(4-bromo-benzenesulfonyl)-piperazine (47 mg, 0.15 mmol) in ethanol (1 mL) was refluxed overnight. The reaction mixture was then concentrated in vacuo and purified by reverse phase HPLC to yield the product as a white powder (7 mg, 9%). 1H NMR (CDCl3) δ 1.03 (t, 3H, J=5.8 Hz), 1.72 (sex, 2H, J=6.0), 1.80 (d, 3H, J=5.2), 3.48 (m, 6H), 3.90 (m, 3H), 4.23 (m, 1H), 4.77 (q, 1H, J=5.2 Hz), 7.58 (m, 3H), 7.68 (d, 1H, J=6.5 Hz), 7.72 (d, 2H, J=7.1 Hz), 7.81 (t, 1H, J=6.2 Hz), 8.28 (d, 1H, J=6.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH2:28])[NH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[NH:23][CH:22]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCc1cnc[nH]1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cnc[nH]3)cc2s1
Yield: 6.6 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-(3H-imidazol-4-yl)-ethylamine (68 mg, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 404.3 (M+1, 100%). Yield=6%.
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:24])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O>[CH2:1]([NH:4][C@@H:17]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:18]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CCCC1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN[C@H](C(=O)N1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a stirred solution of N-allyl-2-nitro-N-(2-oxo-1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (66.2 g, 154 mmol) in anhydrous dimethylformamide (300 cm3) was added potassium carbonate (63.9 g, 462 mmol). The mixture was stirred at ambient temperature for 10 minutes and thiophenol (22.2 cm3, 216 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (2000 cm3) and extracted with ethyl acetate (3×500 cm3). The combined ethyl acetate extracts were washed with water (2×400 cm3), brine (1×300 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a foul smelling yellow oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:1 to 0:1 and then dichloromethane-methanol 19:1 to 9:1) to afford the title compound as a yellow viscous oil (31.9 g, 84.9%) with a positive ion ESI (M+H)+245.3.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([O:19][C:20]([NH:22][CH:23](P(OC)(OC)=O)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(N(C)C)=N>CCOC(C)=O>[CH2:12]([O:19][C:20]([NH:22][C:23](=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)OCc1ccccc1)=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc (150 mL) was added to a solution of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0 mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150 mL). The resulting solution was the stirred at ambient temperature for 72 h and then it was diluted with EtOAc (25 mL). The organic layer was washed with 1N HCl (75 mL), H2O (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via Biotage (5% to 25% EtOAc/Hexanes; 300 g column). The combined fractions containing the product were then concentrated under vacuum and the residue was re-crystallized from hexanes/EtOAc to give white crystals that corresponded to methyl 2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (6.2 g) 1H NMR (400 MHz, CDCl3-d) δ ppm 7.30-7.44 (5H, m), 6.02 (1H, br. s.), 5.15 (2H, s), 3.97 (4H, s), 3.76 (3H, br. s.), 2.84-2.92 (2H, m), 2.47 (2H, t, J=6.40 Hz), 1.74-1.83 (4H, m). LC (Cond. OL1): Rt=2.89 min. LC/MS: Anal. Calcd. For [M+Na]+ C19H23NNaO6: 745.21. found: 745.47
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]=[CH:2]1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH:2]=[CH:3]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OC1C=CC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1C=CC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 34 (79 mg, 0.69 mmol) in DMF (1 mL) was added sodium hydride (14 mg, 0.62 mmol) at 0° C. Benzyl bromide (73 μL, 0.62 mmol) was added to the mixture dropwise, under an argon atmosphere. The reaction was stirred for 16 h at room temperature. Upon completion, distilled water (3 mL) was added to the mixture and the organic layer extracted into ethyl acetate. The organic layers were combined, dried and concentrated to give a crude mixture that was purified by column chromatography (Silica gel, 10%-20% EtOAc in hexane) to give 35 as an oil.
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[CH:28][C:29]#[N:30]>C(O)(=O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)#[N:30]
Reactant: N#CC=C(N)c1ccc(F)cc1
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(c2ccc(F)cc2)N1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 117 mg (0.724 mmol) 3-amino-3-(4-fluorophenyl)prop-2-enenitrile (Example 5A) in acetic acid (2 ml) was stirred for 30 min at 110° C. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 235 mg (82% of th.) of the racemic title compound.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, off-white solid (18 mg, 27%), MS (ISP) m/z=423.3 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and ethanesulfonyl chloride.