Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cn1cncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1C(=O)NC1CCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.3 %

Procedure:
To a solution of 1-methyl-1H-imidazole-5-carboxylic acid (45 mg, 0.36 mmol) in dichloromethane (3.6 mL) was added 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (95 mg, 0.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (83 mg, 0.43 mmol), and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). After 5 minutes, triethylamine (100 μL, 0.72 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide, brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography (10-90% acetonitrile-water (0.1% trifluoroacetic acid)) and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with magnesium sulfate to give 43 mg (36% yield) of a white solid. 1H-NMR (CDCl3): δ 9.21 (s, 1H), 7.43 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 3.81 (s, 3H), 2.67 (m, 2H), 2.21 (m, 1H), 1.90 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 0 °C

Procedure:
A mixture of 7β-amino-3-methylceph-3-em-4-carboxylic acid (16.09 g., 75.2 m.moles), dioxan (100 ml.), sulphuric acid (10 ml.) and isobutylene (90 ml.) was shaken in a pressure bottle until a clear solution resulted (21/2 hours). The solution was cooled and poured into a mixture of aqueous sodium bicarbonate (600 ml.), ice (100 g.), and ethyl acetate (150 ml.). The aqueous layer was twice more extracted with ethyl acetate and the extracts were washed with brine and dried. Evaporation left a gum which was triturated with petrol (b.p. 40° - 60°) to give off-white crystals (11.17 g., 55%). A sample was recrystallised from ether to give the pure ester, m.p. 126°, [α]D + 107° (EtOH), λmax. 271 nm. (E1cm.1% 239) (Found: C, 53.1; H, 6.5; N, 10.1; S, 11.5 C12H18N2O3S requires: C, 53.3; H, 6.7; N, 10.35; S, 11.85%).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:13]=[C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]2=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>C(O)C.CO>[C:3]1([CH2:13][CH:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]2=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1N=C2C=CC=CN2C1=Cc1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 137 mg (3.7 mmol) of sodium borohydride in 15 mL of ethanol is added a solution of 500 mg (1.8 mmol) of 3-[1-naphthalen-1-yl-methylidene]-imidazo[1,2-a]pyridin-2-one in 50 mL of methanol, dropwise at −78° C. After stirring for 10 min at −78° C., the reaction mixture is quenched with saturated aqueous ammonium chloride solution at −78° C. The product is extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=O.O.[NH2:25][NH2:26]>C(O)C>[N:25](=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[NH2:26]
Reactant: NN
Reactant: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: CN(c1ccccc1C=NN)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.40 g, 1.2 mmol) in ethanol (13 mL) is treated with hydrazine monohydrate (69 □L, 1.6 mmol). The reaction is stirred at rt overnight. The reaction is concentrated, taken up in ether-hexane, filtered and evaporated. An 87% yield (0.37 g) of N{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:10]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Product: CC(=O)NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.55 g) and acetic anhydride (16 ml) was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed successively with aqueous sodium bicarbonate and water, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate. The fractions containing the desired compound were combined and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to afford 1-(3-acetylaminopropyl)-4-benzhydrylpiperazine (0.8 g) as white crystals. mp: 240°-255° C. (dec.)
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.F[P-](F)(F)(F)(F)F.[N:29]1([O:38]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.NO>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][OH:38])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NO)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (0.15 g, 0.52 mmol) in DMF (10 mL) were added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 0.20 g, 0.52 mmol), triethylamine (0.15 mL, 1.05 mmol), and hydroxylamine hydrochloride (0.036 g, 0.52 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. It was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC to provide the title compound as a white powder (0.075 g, 48% yield). 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.26-7.38 (m, 2H), 7.08 (t, 1H, J=8.3 Hz), 6.71 (d, 1H, J=3.0 Hz), 5.64 (s, 2H). LCMS (API-ES, M+H+): 304.1 HRMS (M+H): 304.0886; cal: 304.0898 with C15H12N3O2F2. HPLC: 98% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(OCCOCC)C>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CCOCCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
1,2-Dichloro-4-methyl-5-nitrobenzene (R.J. De Lang, et al. Tetrahedron (1998), 54(12), 2953-2966.) (1 g; 4.8 mmol), morpholine (1 ml) and 1,2-diethoxyethane (1 ml) were heated in a microwave oven at 160° C. for 2 h. The reaction mixture was poured on water/2N HCl 10/1 (50 ml) and extracted with TBME three times. The combined organic phases were dried over Na2SO4, evaporated and recrystallised from hot TBME to yield the title compound as yellow crystals (670 mg; 54%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9]([C:10](=[O:17])[C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:19]([OH:21])[CH3:20].C(OCC)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:17])[C:11]=1[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:19](=[O:21])[CH3:20]
Reactant: CCO
Reactant: COCCNC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COCCN(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A few drops of concentrated sulfuric acid was added to a solution of 2-chloro-3-[(2-methoxyethyl)amino]-1,4-naphthoquinone (33 g) in acetic anhydride (100 ml) and the mixture was stirred at 45° C. for 1 hour. By adding ethanol (100 ml) to the reaction solution, excess acetic anhydride was esterified. After cooling, ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from diethyl ether to give N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (29 g) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: COc1cccc(O)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OCC(N)=O)c1
Temperature: 70 °C
Reaction time: 9 h
Yield: 82.8 %

Procedure:
A mixture of 3-methoxyphenol (2.48 g, 20.0 mmol), 2-bromoacetamide (3.31 g, 24.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (30 mL) was stirred at 70° C. for 9 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (3.0 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][OH:19])[O:13]3)[C:6]=2[N:7]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 62.7 %

Procedure:
To a solution of 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38b, 3.8 g, 12.7 mmol) in DMF (30 mL) was added imidazole (2.6 g, 38 mmol) and tert-butylchlorodimethylsilane (4.2 g, 28 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine, dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:5 EtOAc in petroleum ether) to afford 3.3 g of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38d).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:47])[CH:44]([CH3:46])[CH3:45])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-valine benzyl ester hydrochloride (244 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (256 mg, 55%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:9]=2)[NH:4][CH2:3]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][CH:71]=1)[NH2:68]>CN(C)C=O>[Cl:64][C:65]1[CH:66]=[C:67]([N:68]2[C:16](=[O:18])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]2([C:8]2[CH:9]=[C:10]3[C:5]([NH:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[OH:13])[CH:69]=[CH:70][CH:71]=1
Reactant: O=C1CNc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CNc2ccc(C3(O)c4ccccc4C(=O)N3c3cccc(Cl)c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)carbonyl]benzoic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (2.0 mL), HOAt (40 mg, 0.28 mmol), HATU (90 mg, 0.23 mmol) and NMM (0.1 mL, 0.80 mmol) was added and the reaction mixture was stirred for 20 minutes at room temperature, followed by the addition of 3-chloro-aniline (24 μL, 0.23 mmol). The reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the resulting crude was purified by reverse phase preparative HPLC (CH3CN/H2O with 0.1% TFA). The fractions were collected and the aqueous solution was lyophilized to give 7-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-3,4-dihydroquinoxalin-2(1H)-one (36 mg, 39% yield.). 1H NMR (400 MHz, DMSO-d6): 12.25 (s, 1H), 10.44 (s, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.59 (d, 1H), 7.47 (m, 2H), 7.43 (dd, 1H), 7.33 (m, 3H), 7.08 (m, 3H), 4.22 (s, 2H); MS (EI) for C22H16ClN3O3: 406 (MH+).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]3[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23][C:22]3=[O:38])[CH3:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]>O.C(O)(=O)C>[N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]([N:21]4[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:23][C:22]4=[O:38])[CH3:20])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[NH:5][N:1]=1
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc3nn[nH]c3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A solution of NaNO2 (0.16 g) in water (2 mL) was added dropwise to an ice-cold solution of 3-[(S)-1-(3′,4′-diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.43 g) in acetic acid (10 mL). The resulting mixture was stirred with cooling for 2 h and at room temperature for another 1 h. Then, water (100 mL) was added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCO3 solution, water, and brine and dried (Na2SO4). The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/MeOH 98:2→80:20) to afford the title compound as a foam-like solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18](O)[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[CH2:7]([O:14][C:15]1([CH3:31])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:4])[C:17]=2[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(C)(OCc1ccccc1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (5.2 g) is added to 200 mL of DMF dropwise under stirring and cooling keeping the temperature below -20°. Stirring is continued for 0.5 hour at the same temperature. To the mixture 7.0 g of ethyl 6-benzyloxy-4-hydroxy-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in small portions and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with sat. NAHCO3, dried (MgSO4) and evaporated to dryness to an oil which is chromatographed on silica gel to yield ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=2[O:10][CH3:11])[CH2:22][CH2:21]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1ccc(Br)cc1CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 235 %

Procedure:
A mixture of 1.1 g of 2-(chloromethyl)-4-bromoanisole, 1 g of 1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr, cooled to room temperature, washed with 1 N NaOH and water. The solvent was removed by evaporation under reduced pressure to yield 3.6 g of 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
600 mg 1-(2,6-dichloro-phenyl)-1,3-dihydro-indol-2-one are dissolved in 5 ml concentrated sulphuric acid and cooled to 0° C. To this is added dropwise a solution of 160 μl concentrated nitric acid in 1 ml concentrated sulphuric acid. The mixture is stirred for 30 minutes and then added to 50 g ice. Then the mixture is stirred for 1 hour and the solid is suction filtered. After drying in vacuo the solid is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][O:18][C:16](=[O:17])[CH2:15][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)n1c(=O)n(CC(=O)OC)c2ccccc21
Yield: 99 %

Procedure:
N-isopropenyl-2-benzimidazolone (15.0 g, 86.10 mmol), methyl bromoacetate (13.2 g, 86.1 mmol) and potassium carbonate (14.25 g, 103.26 mmol) were stirred in acetonitrile (300 ml) at room temperature overnight. The next day the reaction mixture was filtered and concentrated to give 21.0 g (99% yield) of (3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid methyl ester as a clear oil:
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:53])([F:54])[F:55])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 456.4 (MH+).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:52][CH:53]=[CH:54][N:55]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:46]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:55][CH:54]=[CH:53][N:52]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59][C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=2)[N:46]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
N-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro-2-pyridyl}acetamide was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and N-(6-chloro-3-nitro-2-pyridyl)acetamide in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.