Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])O
Reactant: Cc1ccc(N)c(N)c1C
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1ccc2[nH]cnc2c1C

Procedure:
3,4-dimethylbenzene-1,2-diamine (300 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 320 mg of Intermediate 178.1 as a tan solid. LCMS (2 min gradient) RT=0.90 min, 147.0 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH3:10][S:11]SC.N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([S:11][CH3:10])=[CH:3][N:4]=1
Reactant: CSSC
Reactant: Nc1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CSc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 36.1 %

Procedure:
A solution of 50.6 g (0.3 mol) of 3-amino-5,6-dichloropyridine in 700 ml of methylene chloride was slowly added dropwise at 40° C. to a solution of 56.6 g (0.6 mol) of dimethyl disulfide and 46.7 g (0.45 mol) of tert-butyl nitrite in 320 ml of dry methylene chloride. The mixture was then stirred for 1 hour at 40° C. and subsequently for another approximately 15 hours at approximately 20° C., whereupon 500 ml of ice-water were added to the reaction mixture. The organic phase which was separated off was washed once with 1 N hydrochloric acid and once with water, dried over sodium sulfate and finally concentrated. After the crude product had been stirred with n-hexane, 21 g of a dark solid were obtained (purity 94% according to GC). After the hexane solution was concentrated, a further 21.3 g of product of value remained which had a purity of 77% (according to GC). Total yield: 62%; m.p.: 66-67° C.; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=2.6 (s, CH3); 8.1 and 8.3 (2×d, pyr H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([S:19][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (5.64 g) and 1,4-dibromobutane (5.88 g) were added to a solution of thiophenol (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 6.67 g of 4-phenylthiobutyl bromide.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][CH:30]=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.NS(O)(=O)=[O:40].[O-]Cl=O.[Na+].ClCl>C1COCC1.O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:19]([CH2:29][C:30]([OH:40])=[O:31])=[CH:20][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: NS(=O)(=O)O
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC=O
Agent: ClCl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To the title compound of Step (B) (300 mg, 0.57 mmol) and H2NSO3H (111 mg, 1.14 mmol) in 11.4 ml THF at 0° C., an ice cooled solution of NaClO2 (103 mg, 1.14 mmol) in 11.4 ml H2O was added. The mixture was stirred at 0° C. for 2 min. 60 ml CH2 Cl2 was added. The organic layer was separated and washed with H2O and brine, dried and concentrated to afford the title compound of this step, which was relatively pure and was used in the next step without further purification.
Reaction SMILES: O.[CH3:2][C:3]([CH3:19])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])[CH3:4].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH2:30]>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[CH:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:30][N:13]1[CH:14]=[N:15][C:11]([CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:6]([O:5][C:3]([CH3:19])([CH3:2])[CH3:4])=[O:7])=[CH:12]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Water was added to a stirred suspension of N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (13.26 g) in ethanol (100 ml) and 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (14.5 g) until a clear solution was obtained. The clear solution was allowed to stand for 18 hours, and was then concentrated under reduced pressure to yield a foam which was triturated with hexane. The resulting mixture was filtered to yield 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (27.7 g), as a mixture of diastereoisomers.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]=[C:12]2[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:11]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:25]([N:22]1[C:12]2=[N:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:2][CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[C:11]2[CH:24]=[N:23]1)[CH3:26]
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 85 °C

Procedure:
4-Aminotetrahydropyran hydrochloride (Intermediate 21, 0.413 g, 3.0 mmol) was added to a mixture of Intermediate 58 (0.268 g, 1.0 mmol) and N,N-diisopropylethylamine (0.87 ml, 5.0 mmol) in acetonitrile (3 ml). The resulting mixture was heated at 85° C. for 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5 ml) and applied to a SPE cartridge (silica, 5 g). The cartridge was eluted successively with Et2O, EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intermediate 51). Further purification using a SPE cartridge (silica, 5 g) eluting with ethyl acetate-cyclohexane (1:3) afforded Intermediate 59 (0.248 g). LCMS showed MH+=333; TRET=2.75 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])(=[O:23])[CH3:22]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:21](=[O:23])[CH3:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 16.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 1 mmol) and o-acetylaniline (90 mg, 0.67 mmol) to give 50 mg of the title compound (21%) after chromatography of the crude product on a silica gel column with 1% acetic acid/ethyl acetate as an eluent: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 11.12 (s, 1H), 8.20 (bd, 1H, J=8.1 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J =2 Hz), 7.17 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.64~2.76 (m, 2H), 2.60 (s, 3H), 2.16 (dm, 1H, J=13.5 Hz), 1.82~1.97 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][O:4]1.F[C:16]1[N:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[NH:24][C:23]2=[O:30])=[CH:18][C:17]=1[CH3:31].CN(C=O)C>O>[CH3:28][C:25]1([CH3:29])[NH:24][C:23](=[O:30])[N:22]([C:19]2[CH:20]=[N:21][C:16]([O:12][C:9]3[CH:8]=[CH:7][C:6]4[CH2:5][O:4][CH:3]([C:2]([F:1])([F:13])[F:14])[C:11]=4[CH:10]=3)=[C:17]([CH3:31])[CH:18]=2)[C:26]1=[O:27]
Reactant: Oc1ccc2c(c1)C(C(F)(F)F)OC2
Reactant: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)cnc1Oc1ccc2c(c1)C(C(F)(F)F)OC2
Temperature: 110 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
To a solution of 3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (enantiomer 1) (Intermediate 28, 20 mg, 0.098 mmol) and 3-(6-fluoro-5-methyl-3-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 6, 27.9 mg, 0.118 mmol) in DMF (1 mL) dipotassium carbonate (27.1 mg, 0.196 mmol) was added and the reaction mixture was stirred for 48 hours at 110° C. After cooling the mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by reverse phase flash chromatography on C18 column (MEGA BE Varian, 5 g) using water/acetonitrile from 100:0 to 0:100 as eluent affording the title compound (5 mg) as white solid.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>O1CCCC1>[CH:1]1([NH:6][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1CCCC1)Oc1ccccc1
Yield: 81 %

Procedure:
Cyclopentylamine (9.9 ml, 100 mmol) was dissolved in tetrahydrofuran (400 ml); pyridine (8.9 ml, 110 mmol) was added thereto; and the reaction mixture was stirred. The reaction mixture was cooled with ice; phenyl chloroformate (13.8 ml, 110 mmol) was added dropwise for 5 minutes while stirring; and the reaction mixture was stirred at room temperature for 24.5 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in a solvent mixture of hexane:ethyl acetate=5:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (16.6 g, 81 mmol, 81%).
Reaction SMILES: C([S:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.S(=O)(=O)(O)O.[N:33]([O-])=O.[Na+]>O>[Cl:27][C:18]1[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[N:33][S:8][C:9]=2[CH:15]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(Oc2ccc3nnsc3c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of 1C was added to an ice-cold solution of 50% aqueous sulfuric acid, and the mixture maintained below 10° C. during the addition of a solution of 0.7 g of sodium nitrite in 10 ml of water. This mixture was then stirred for 1 hour, allowed to reach ambient temperature, and then extracted with ether. The organic layer was separated, solvent removed and the resulting red oil chromatographically purified and recrystallized to yield 1, as a crystalline solid, m.p.: 72°-73° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH3:31])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:31])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 54.4 %

Procedure:
The title compound was prepared from 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (7.87 g, 24.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich, 5.65 g, 29.9 mmol) following the experimental procedure described in Preparation 45a. 6.6 g (51% yield) of the desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>C1COCC1>[CH3:1][C:2]1[N:3]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:19])([F:18])[F:7])=[CH:10][CH:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
2-Methylimidazole (1.0 g, 12 mmol) was dissolved in 35 mL THF. 4-(Trifluoromethyl)phenylboronic acid (2.66 g, 14 mmol) and [Cu(OH)TMEDA]2Cl2 (1.13 g, 2 mmol) were added. Oxygen was bubbled through the reaction mixture for 30 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad, washed with 80 ml THF and evaporated. The crude product was purified by flash chromatography on silica gel with ethyl acetate. The desired compound was obtained as a light yellow solid (1.6 g, 58%), MS: m/e=227.2 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Br.[Br:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCBr
Reaction time: 1 h

Procedure:
Diketene (1.22 mL, 15.7 mmol 1.50 equiv) was added at room temperature to a stirred mixture of 3-bromopropylamine hydrobromide (2.30 g, 10.5 mmol, 1.00 equiv) and triethylamine (1.46 mL, 10.5 mmol, 1.00 equiv) in anhydrous THF (20 mL) under argon, and stirring was continued at room temperature for 1 hour. The solvent was removed and the residue was purified by flash chromatography (SiO2, MeOH—CH2Cl2 0:1 to 1:18) to afford a light yellow oil, 2.10 g (90%), which was characterized spectroscopically.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 31.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 126 mg, 0.283 mmol), (1R,2S)-2-phenylcyclohexanol (50.0 mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0 mL), to yield the title compound (53.6 mg, 31%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCCCCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 79.1 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added heptanoyl chloride (0.59 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (79%) of product as an off-white solid: mp 200–202° C.; 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 9.65 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 5.15 (dd, J=4.8 and 12.2 Hz, 1H), 2.97–2.87 (m, 1H), 2.65–2.43 (m, 4H), 2.10–2.06 (m, 1H), 1.61–1.58 (m, 2H), 1.28 (bs, 6H), 0.85 (bs, 3H); 13C NMR (DMSO-d6) δ 172.67, 171.96, 169.69, 167.78, 166.61, 136.62, 136.04, 131.36, 125.97, 118.13, 116.67, 48.93, 36.56, 30.95, 28.16, 24.69, 21.94, 13.84; Anal. Calcd. For C20H23N3O5: C, 62.3 3; H, 6.02; N, 10.90. Found: C, 62.14; H, 6.05; N, 10.72.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH2:17])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[CH3:18][CH:19]([CH3:23])[CH2:20][CH:21]=O.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:16])[CH3:15])([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)c1cc(Br)cs1
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (216 mg, 0.642 mmol) was dissolved in 1.5 mL MeOH. Molecular sieves (3 Å) and 3-methylbutanal (79 μL, 0.739 mmol) were then added. The resulting mixture was stirred at room temperature overnight. Sodium borohydride (36.4 mg, 0.963 mmol) was added and the mixture was stirred for 1 hour, and then quenched with aqueous sodium hydrogen carbonate. DCM was added and the phases separated. The solvent was removed under reduced pressure. The resulting solid was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=O)=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)(=[O:20])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added N-methylpiperazine (13.7 g, 0.137 moles) in one portion, the mixture is stirred until a clear solution is obtained, and concentrated on a rotary evaporator. The residue is taken up in water, filtered, recrystallized from ethanol, and dried at 48° to yield 5.12 grams of 1-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]4-methylpiperazine, mp 305°-307° C.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Br)[CH:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1cc(Br)sn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cc(CN2CCCCC2)ns1
Yield: 76.1 %

Procedure:
5-Bromo-3-bromomethylisothiazole (1.92 g, 7.5 mmol), triethylamine (1.57 mL, 11.2 mmol) and piperidine (1.5 mL, 15.0 mmol) in DCM (10 mL) were stirred for 16 h at ambient temperature. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (1.49 g, 97%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.25 (s, 1H), 3.59 (s, 2H), 2.46-2.33 (m, 4H), 1.62-1.53 (m, 4H), 1.48-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.71-1.80 (m, 2 H) 2.47 (s, 3 H) 4.27 (t, 2 H) 6.81 (s, 1 H) 7.73 (d, 1 H) 7.99 (d, 1 H) 8.22 (s, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].NC[C@@H]1CCCN1CC.C(=O)C>>[CH3:14][S:15]([N:11]1[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: CS(=O)(=O)N1CC[C@H](N)C1

Procedure:
By using (S)-(−)-3-(t-butoxycarbonylamino)pyrrolidine (2.0 g) and methanesulfonyl chloride (1 ml) as starting materials, the title compound (1.03 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).