Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 65A (0.014 g, 0.046 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.020 g, 49% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H), 2.31(s, 3H), 2.34-2.24(m, 1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H), 2.84-2.73(m, 2H), 2.97-2.88(m, 1H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.43-4.12(m, 4H), 4.55-4.52(d, J=7.72 Hz, 1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.01-6.99(m, 3H), 7.09-7.08(m, 2H), 7.24-7.20(m, 5H), 7.32-7.29(m, 1H), 7.49-7.46(d, J=9.56 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.63(d, J=4.41 Hz, 1H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([N+:21]([O-])=O)=[C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:18]=[C:17]([CH3:31])[C:16]=1[CH3:32].C(O)C>O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:16]([CH3:32])=[C:17]([CH3:31])[N:18]=[C:19]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]=1[NH2:21]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCl)c1C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
A solution of sodium dithionite (35.13 g, 171.5 mmol), available as approximately 85% pure sodium hydrosulfite, in water (130 mL) was added to a mixture of N-(4-chlorobutyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine (12 g, 34 mmol) and ethanol (340 mL). The mixture was stirred for 1.5 hours. Analysis by thin layer chromatography indicated that the reaction was not complete. Solid sodium dithionite (5 g) was added and the reaction was allowed to stir for an additional 3 hours. The reaction mixture was filtered to remove solids. The filtrate was concentrated under reduced pressure until ˜50 mL of solvent remained. The residue was diluted with dichloromethane (300 mL), washed sequentially with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 9.5 g of N4-(4-chlorobutyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[H-].[Na+].C(Cl)(=[S:20])N.Cl.[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:26](=[S:20])[N:24]([CH3:25])[CH3:23])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: NC(=S)Cl
Reactant: CN(C)C=O
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)Cn1ccc2cc(OC(=S)N(C)C)ccc21
Reaction time: 2 h

Procedure:
Compound 72B (9.12 g, 44.4 mmol) was dissolved in 50 ml DMF. NaH was added portionwise over 5 minutes. After stirring for 15 minutes a solution of thiocarbamoyl chloride (5.8 g, 46.7 mmol) in 25 ml DMF was added and allowed to stir for 2 h. 50 ml 2N HCl was added and the reaction was extracted 2×100 ml ether, washed 2×100 ml water, 1×100 ml brine, and filtered through silica. The product was eluted with 200 ml diethyl ether and concentrated. The precipitate was filtered and dried under vacuum for 16 h. MS m/z 293 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (9 g), tert-butyl bromoacetate (3.8 mL), potassium carbonate (6 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.6 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[C:61]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH2:71][C@H:70](C(O)=O)[CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([C@H:72]3[CH2:71][CH2:70][CH2:69][N:68]([C:66]([O:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:67])[CH2:73]3)=[O:24])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 1 h

Procedure:
tert-Butyl {(3S)-1-[(3-chloro-2-methylphenyl)sulfonyl]piperidin-3-yl}carbamate (58.34 mg, 0.0001500 mol) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL) at rt for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in DMF (1.0 mL) and to this was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (69.6 mg, 0.000157 mol), 4-methylmorpholine (100.0 uL, 0.0009096 mol), and (3S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (34.4 mg, 0.000150 mol) at rt. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate (5 mL) and washed with NaHCO3 (7.5%, 3×2 mL) and brine (3×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19].O1CCCC1>S(Cl)(Cl)=O.CO>[CH3:17][N:18]([CH3:19])[C:14]([C:12]1[N:13]=[C:9]([NH2:8])[S:10][CH:11]=1)=[O:16].[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:16])[N:18]([CH3:19])[CH3:17])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1csc(N)n1
Product: CN(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
2-Amino-thiazole-4-carboxylic acid dimethylamide was prepared as follows. (1) A solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (0.5 g, 2 mmol) (prepared as described in Examples 4a and 4b) in thionyl chloride (10 mL) was heated at reflux (80° C.) for 2 hours. The reaction mixture was then concentrated under reduced pressure. To the residue was added a 2 M solution of dimethylamine in tetrahydrofuran (10 mL, 20 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 20 hours and concentrated. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (4-dimethylcarbamoyl-thiazol-2-yl)-carbamic acid tert-butyl ester as a yellow foam (0.26 g, 48%).
Reaction SMILES: O[CH:2]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:15]([NH:17][C:18]1([C:27]([OH:29])=[O:28])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.Cl.[H][H]>C(O)C.CO.[Pd]>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([C:27]([OH:29])=[O:28])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:16])=[CH:13][C:12]=1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)COc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1CCOc1cccc(C)c1

Procedure:
The compound of example 114 (20 mg, 0.043 mmol) was dissolved in ethanol (2 ml), a 0.5 M solution of hydrogen chloride in methanol (0.2 ml) was added and the mixture was hydrogenated overnight in the presence of palladium on charcoal (10%) at room temperature at a hydrogen pressure of 5 bar (complete conversion of the starting compound). After filtration over a small plug of silica gel and evaporation, the residue was purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:56]([C:58]1[C:59]([C:64](O)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]>CC(N(C)C)=O>[CH2:56]([C:58]1[C:59]([C:64]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]
Reactant: CCc1cccnc1C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 69.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), HATU (180 mg, 0.473 mmol), triethylamine (132 μL, 0.945 mmol), and 3-ethylpicolinic acid (71 mg, 0.473 mmol) were stirred at room temperature for 2 hours in anhydrous dimethylacetamide (10 mL). The reaction mixture was post-treated in a conventional manner to give the title compound (98 mg, yield 69%).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[C:12]2=[O:19])=[CH:7][CH:6]=1.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>ClCCl>[F:33][C:32]([F:34])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([NH:22][C:23]([N:15]2[CH2:14][CH:13]3[CH:17]([CH2:18][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:20])[F:21])=[CH:6][CH:7]=4)[C:12]3=[O:19])[CH2:16]2)=[O:24])=[CH:30][CH:29]=1
Reactant: O=C1C2CNCC2CN1c1ccc(OC(F)(F)F)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrol-1-one, hydrochloride (0.11 g, 0.36 mmol), 1-isocyanato-4-(trifluoromethoxy)benzene (0.15 g, 0.72 mmol) and Et3N (0.15 g, 1.44 mmol) were added to dichloromethane (2 mL), the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure, purified by prep-HPLC to yield the title compound (50 mg, 28%) as white solid. 1H NMR (300 MHz, CDCl3): δ 7.68-7.65 (m, 2H), 7.42-7.40 (m, 2H), 7.39-7.13 (m, 4H), 4.18-4.03 (m, 3H), 3.79-3.69 (m, 2H), 3.45-3.38 (m, 2H), 3.22-3.20 (m, 1H); LC-MS: 489.8 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C1C(=O)N([Br:32])C(=O)C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:21])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Yield: 97.1 %

Procedure:
Combined 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (2.19 g, 6.55 mmol), NBS (1.749 g, 9.83 mmol), and sodium bicarbonate (1.651 g, 19.65 mmol) in DMF (20 mL) and stirred at 20° C. for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL, then 2×50 mL). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on a 120 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.348 g, 97% yield) as a white solid. MS m/z 369, 371 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.6 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.3 Hz, 2H) 4.05 (s, 3H) 7.79 (dd, J=8.6, 0.5 Hz, 1H) 7.85 (s, 1H) 8.38 (dd, J=8.6, 2.3 Hz, 1H) 8.74 (t, J=5.6 Hz, 1H) 8.96 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 36.3 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and morpholine (0.019 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (29 mg, 0.069 mmol, yield 36%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl N-(2-hydroxyethyl)carbamate (6.0 g), triethylamine (5.68 ml) were dissolved in DCM (50 ml) and methanesulfonyl chloride (3.02 ml) was added dropwise to the reaction mixture at 0° C. The mixture was stirred for 30 min at 0° C. and stirring was continued for 2 h at RT. Water was added and the mixture was extracted with DCM. Combined organic phases were washed with water and brine, dried with Na2SO4 and evaporated. The product was stored under nitrogen. Yield 8.64 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.39 (s, 9H), 3.16 (s, 3H), 3.23 (q, 2H), 4.16 (t, 2H), 7.04 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Solvent: CCCCO
Product: COCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 72 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (10 mg, 0.385 mmol) and 2-methoxyethylamine in 2 ml of butanol were heated at 120° C. for 9 hours in autoclave. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (83 mg, yield 72%).
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:14])[CH3:13])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:2].Br[CH2:16]CC(OCC)=O.CC1CCCC(C)N1.[ClH:31]>O.C(O)C>[ClH:31].[CH3:14][CH:12]1[CH2:13][CH2:16][CH2:2][CH:1]([CH3:3])[N:4]1[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCBr
Reactant: CCOC(=O)CCN(C(C)C)C(C)C
Agent: CC1CCCC(C)N1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN1C(C)CCCC1C

Procedure:
Ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride may be obtained by working according to the method described in Example 6 for the preparation of ethyl 3- diisopropylaminopropionate, but starting with ethyl 3bromopropionate (18.1 g), 2,6-dimethylpiperidine (27 cc) and ethanol (30 cc). The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is taken up with water (50 cc) and 4N aqueous hydrochloric acid solution (30 cc). The aqueous phase is washed with ethyl ether (2×80 cc) and neutralized with 4N aqueous sodium hydroxide solution (40 cc). The insoluble oil is extracted with ethyl ether (3×120 cc); the organic extracts are then washed with water (2×80 cc) and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is dissolved in ethyl ether (100 cc). A 4.5N solution (13.4 cc) of gaseous hydrochloric acid in ethyl ether is added to the solution obtained. A product precipitates. It is separated by filtration, washed and dried in the air. Ethyl 3-(2,6-dimetylpiperidino)-propionate hydrochloride (14.4 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](F)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[ClH:26]>>[C:1]([NH:5][C:6]1[C:7]([Cl:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)c1cccc2nc(F)c(NC(C)(C)C)nc12
Solvent: C1COCCO1
Product: CC(=O)c1cccc2nc(Cl)c(NC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 1-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)ethanone (343b) (300 mg, 1.14 mmol) in 4 M HCl in dioxane (2.87 mL, 11.48 mmol) was stirred at RT for 16 h under a drying tube. Lcms indicated the reaction was not completed. The reaction mixture was heated at 70° C. for 1.5 h. The reaction was quenched with saturated aq. NaHCO3 (200 mL), diluted with DCM (100 mL), added to a separatory funnel, and extracted with DCM (3×100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give 1-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)ethanone (345a, 285 mg, 1.02 mmol, 89% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.57 (s, 9H) 2.86 (s, 3H) 5.73 (br. s., 1H) 7.39 (t, J=8.02 Hz, 1H) 7.83 (dd, J=7.43, 1.56 Hz, 1H) 7.89 (dd, J=8.22, 1.57 Hz, 1H). MS (ESI, pos. ion) m/z: 278.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][C:25](N(OC)C)=[O:26])[CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH3:21])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:32]1[S:33][CH:34]=[C:35]([Cl:37])[N:36]=1>C1COCC1>[Cl:37][C:35]1[N:36]=[C:32]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][N:10]2[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[C:17]3[C:12]([N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[CH:11]2)[S:33][CH:34]=1
Reactant: CON(C)C(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Reactant: Clc1csc(Br)n1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 2.067 ml, 2.69 mmol) was added dropwise to a solution of 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylbutanamide (1 g, 2.442 mmol) and 2-bromo-4-chlorothiazole (Intermediate Q, step 2) (0.533 g, 2.69 mmol) in THF (24.42 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. A further portion of isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 2.067 ml, 2.69 mmol) was added at 0° C. and the mixture was stirred for a further 30 minutes at 0° C. The reaction was quenched with saturated NH4Cl(aq) (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with saturated NaHCO3(aq) (10 mL), dried over magnesium sulfate and evaporated under reduced pressure. Trituration with methanol afforded the title compound.
Reaction SMILES: [NH2:1][C:2](=[S:14])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Br[CH2:16][C:17]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([OH:28])=[C:21]([OH:29])[CH:20]=1)=O>C(O)C>[OH:29][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([NH:3][S:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)(=[O:5])=[O:6])[S:14][CH:16]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]=1[OH:28]
Reactant: Cc1ccc(S(=O)(=O)NC(N)=S)cc1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(O)c(O)c([N+](=O)[O-])c3)cs2)cc1

Procedure:
A mixture of 0.24 g of N-(aminothioxomethyl)-4-methyl-benzene-sulfonamide and 0.2 g of 2-bromo-1-(3,4-dihydroxy-5-nitrophenyl)ethanone was dissolved in 5 ml of ethanol and boiled under reflux for 1 h. 0.26 g of N-[4-(3,4-dihydroxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as red crystals upon cooling.