Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][Cl:24])=[CH:17][CH:16]=3)=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[S:11][C:10]=2[CH:37]=1)(=[O:4])=[O:3].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[K+]>CN(C)C=O>[ClH:24].[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:17][CH:16]=3)=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[S:11][C:10]=2[CH:37]=1)(=[O:4])=[O:3]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCCl)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Product: Cl
Reaction time: 2 h

Procedure:
An 0.58 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-chloroethoxy)benzoyl]benzo[b]thiophene was combined with 20 ml. of dimethylformamide, 4.8 ml. of piperidine and 100 mg. of potassium iodide, and the mixture was stirred overnight at 40° and then at 50° for two hours. The mixture was evaporated to a brown oil under vacuum, and the oil was worked up by pouring it into 50 ml. of saturated aqueous sodium bicarbonate and extracting the mixture twice with 40 ml. portions of ethyl acetate. The organic layers were combined, washed twice with 100 ml. portions of saturated aqueous sodium chloride and concentrated under vacuum to an oil. To the oily residue was added 50 ml. of 3% hydrogen chloride in methanol, and the acidic mixture was concentrated again to an oil, which was dissolved in hot denatured ethanol and crystallized. The first crop of purified crystals amounted to 0.4 g. and had a melting point and infrared and ultraviolet spectra identical to those of the products of Examples 12 and 31.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]2[N:21]([CH2:22][C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[N:18]=2)[CH2:11][CH2:10]1.[C:33](=[O:36])([O-:35])[O-].[Na+].[Na+]>CO>[C:4]([OH:6])(=[O:5])[C:33]([OH:35])=[O:36].[CH3:28][C:25]1[O:24][C:23]([CH2:22][N:21]2[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[N:18]=[C:17]2[NH:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:9]([CH2:3][CH2:4][OH:5])[CH2:10][CH2:11]2)=[CH:27][CH:26]=1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cn2c(NC3CCCNCC3)nc3ccccc32)o1
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCCN(CCO)CC3)nc3ccccc32)o1
Product: O=C(O)C(=O)O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 6.3 %

Procedure:
A mixture of 11.3 parts of N-(hexahydro-1H-azepin-4-yl)-1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-amine (E)-2-butenedioate(2:3), hemihydrate, 10.6 parts of sodium carbonate and 120 parts of methanol was stirred for 30 minutes at reflux temperature. After cooling to 30° C., gaseous oxirane was bubbled during 2 hours through the mixture. The reaction mixture was evaporated and the residue was stirred in dichloromethane. The precipitate was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 2-propanone. The salt was filtered off and crystallized from a mixture of 2-propanone and ethanol. The product was filtered off and dried, yielding 0.7 parts (6.3%) of hexahydro-4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1H-azepine-1-ethanol ethanedioate(1:2); mp. 155.8° C. (compound 211).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].Cl.[CH3:9][NH:10][OH:11].[CH2:12]=O>O.C(=O)(O)[O-].[Na+]>[OH:11][N:10]([CH2:12][C:5]1[O:1][C:2]([CH2:6][OH:7])=[CH:3][CH:4]=1)[CH3:9]
Reactant: OCc1ccco1
Reactant: C=O
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(O)Cc1ccc(CO)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-furanmethanol (14.7 g), N-methylhydroxylamine hydrochloride (13.8 g) and aqueous formaldehyde (36%, 18 ml) was stirred at 0° for 1 hr and at room temperature for 4 hr. The solution was diluted with water (100 ml), excess sodium bicarbonate added and the solution extracted with ethyl acetate (4×100 ml). The combined ethyl acetate extracts were dried (sodium sulphate), filtered and the filtrate evaporated to give an oil which was distilled (6×10-1 mm/200°-210°) to give the title compound (9.1 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH:8]=2)=[O:10])[S:13][C:14]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(Cn2ccnc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
Compound 107 (150 mg, 0.387 mmol) was dissolved in DMF (2 ml), and imidazole (129 mg, 1.89 mmol) was added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 108 (120 mg, 74%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCc2cc(S(=O)(=O)N3CC(c4ccccc4)NC3=O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.20 g, 0.58 mmol) prepared in Preparation 5 was dissolved in 12 m of dichloromethane. Pyridine (0.1 m, 0.58 mmol) and benzoyl chloride (0.1 g, 0.58 mmol) were added dropwise one after another at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 hours and further stirred at room temperature for 3 hours. The reaction mixture was diluted with 20 m of dichloromethane, washed twice with 10 m of water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2/1, v/v) to afford the title compound.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:20](Cl)=[N:19][S:18][N:17]=1>CN(C=O)C>[C:11]([O:10][C:8]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:20]2[C:16]([Cl:15])=[N:17][S:18][N:19]=2)[CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Clc1nsnc1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of t-butyl 1-homopiperazine carboxylate (45 mmol, 9 g) and DMF (50 ml) was heated to 100° C. 3,4-dichloro-1,2,5-thiadiazole (23 mmol, 2.2 ml) was added dropwise to the mixture with stirring. The resulting mixture was stirred at 100° C. for 2 days. Mixture was quenched with ice/water and extracted with ethyl acetate (3×). The combined organic layer was washed with water (2×) and Sat. sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude was purified on a silica column using 20% ethyl acetate/hexanes to give 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (5.8 g). The material thus obtained was converted into the title compound by following the same procedures as in Example 1. 1H NMR (CDCl3) 9.52 (s, 2H), 7.838 (s, 2H), 7.508 (s, 1H), 7.321-7.307 (d, 2H), 6.769 (br. s, 1H), 5.464 (s, 2H), 3.925-3.851 (m, 4H), 3.820-3.790 (t, 2H), 3.612-3.582 (t, 2H), 1.987-1.959 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[O-:20][CH2:21][CH3:22].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:20][CH2:21][CH3:22])=[N:4][CH:5]=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CC[O-]
Reactant: CCN1CCN(S(=O)(=O)c2cnc(Cl)c(Br)c2)CC1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1Br

Procedure:
A mixture of the product from stage d) (6.60 g, 17.9 mmol) and sodium ethoxide (6.09 g, 89.55 mmol) in ethanol (100 ml) was heated under reflux for 18 hours, then cooled. The reaction mixture was concentrated under reduced pressure, the residue partitioned between water (100 ml) and ethyl acetate (100 ml), and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 ml), the combined organic solutions dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a brown solid, 6.41 g; Found C, 41.27; H, 5.33; N, 11.11. C13H20BrN3O3S requires C, 41.35; H, 5.28; N, 10.99%; δ (CDCl3, 300 MHz) 1.06 (3H, t), 1.48 (3H, t), 2.42 (2H, q), 2.56 (4H, m), 3.09 (4H, m), 4.54 (2H, q), 8.10 (1H, s), 8.46 (1H, s); LRMS: m/z 378, 380 (M+1)+.
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.[F-].[Cs+].[CH3:19][CH:20]1[CH2:24]OC(=O)[O:21]1>CS(C)=O>[C:11]1([N:10]2[CH2:19][CH:20]([CH3:24])[O:21][C:8]2=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: CC1COC(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: CC1CN(c2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 30 h
Yield: 74.3 %

Procedure:
N,N′-Diphenylurea (20.7 g, 98.0 mmol) was dissolved in dimethyl sulfoxide (40 mL), and thereto were added cesium fluoride (1.48 g, 9.80 mmol) and 4-methyl-1,3-dioxolan-2-one (10.0 g, 98.0 mmol), in order. The mixture was stirred for 30 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was recrystallized from ethanol to give the subject 3-phenyl-5-methyloxazolidin-2-one (12.9 g, yield 74.3%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[CH:18]([NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
To a solution of 3,3-diphenylpropan-1-amine 1 (4.22 g, 20.0 mmol) in DCE (100 mL) at room temperature was added acetone (1.19 g, 20.5 mmol, 1.50 mL), acetic acid (1.21 g, 20.1 mmol, 1.15 mL), and NaBH(OAc)3 (5.98 g, 28.2 mmol). The reaction mixture was stirred at room temperature for 5 min, a significant amount of precipitate formed, THF (40 mL) was added, and stirring was continued at room temperature for 3 h. The reaction mixture was quenched with 5 M NaOH, partially concentrated, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2 M NH3) in DCM) gave N-isopropyl-3,3-diphenylpropan-1-amine 2 (4.60 g, 90.9% yield) as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[N:12]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)[N:12]=1)#[N:18]
Reactant: N#Cc1cccc(Cl)n1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccnc1Sc1cccc(C#N)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 263.6 %

Procedure:
2-Mercapto-1-methyl-1H-imidazole (0.91 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were dissolved in DMF (30 ml), and 2-chloro-6-cyanopyridine (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at 70° C. for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.71 g, ca. 100%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:19]\[C:18]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:16]([O:15][CH3:14])[CH:17]=3)/[C:10](=[O:11])/[C:12](=[CH:19]/[C:18]3[CH:17]=[C:16]([O:15][CH3:14])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: COc1cc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC

Procedure:
Calone is reacted with 3,4,5-trimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(3,4,5-tri-methoxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH:27]=O)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][N:32]3[CH2:33][CH2:34][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][CH2:31]3)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCCc1nc(N)c2c(n1)c(CCCC=O)cn2COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc(N)c2c(n1)c(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 125.9 %

Procedure:
A suspension of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butanal (268 mg, 0.704 mmol) and 4 Å molecular sieves in anhydrous dichloromethane (20 mL) was placed under nitrogen and tert-butyl piperazine-1-carboxylate (262 mg, 1.409 mmol) added. The reaction mixture was stirred at ambient temperature for 1 min then sodium triacetoxyborohydride (299 mg, 1.409 mmol) added and the reaction stirred for a further 30 min, Additional 4 Å molecular sieves were added and the reaction mixture stirred at ambient temperature for an additional 16.5 hours, The reaction mixture was filtered through celite and the cake washed with DCM. The solvent was removed in vacuo to give a viscous yellow oil. The oil was redissolved in DCM (50 mL). The organic layer was washed with saturated sodium hydrogen carbonate solution (50 mL), the layers separated and the aqueous layer back-extracted with DCM (2×25 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a yellow gum (488 mg). The sample was dissolved in dichloromethane and purified by chromatography on a silica cartridge (100 g) using a 0-10% MeOH:TBME gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow gum (338 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[O:23]=[S:24]1(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:25]2[CH2:26][CH2:27][CH2:28][S:24]2(=[O:29])=[O:23])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: O=S1(=O)CCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCCS2(=O)=O)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A mixture of 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15.9 mg, 47.2 μmol), 1,1-dioxo-isothiazolidine (11.4 mg, 94.4 μmol) and DBU (14.2 μL, 94.4 μmol) in DMF (250 μL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 75:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.10 mg, 16%). MS (m/e): 387.3 (MH+).
Reaction SMILES: C1(C)C=CC=CC=1.C([Li])CCC.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])[CH:18]=[CH:17]2.CON(C)C(C[C:39]1[N:40]=[CH:41][N:42]([C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=1)=O.C1C[O:67][CH2:66]C1>O>[CH:27]([N:26]([CH:30]([CH3:32])[CH3:31])[C:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:66]([C:39]3[N:40]=[CH:41][N:42]([C:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:43]=3)=[O:67])[CH:15]=2)[CH:20]=1)=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)N(C(=O)c1ccc2cc(Br)ccc2c1)C(C)C
Reactant: CON(C)C(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1)C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Dry toluene (20 ml) was cooled to −70° C. and n-butyl lithium (1.6 M; 2.35 ml) was added dropwise. A solution of 6-bromo-N,N-diisopropyl-2-naphthamide (1.20 g) in dry THF (8 ml) was added dropwise to the reaction mixture. After stirring the mixture at −70° C. for 20 min, a solution of N-methoxy-N-methyl-1-trityl-1H-imidazole-4-carboxyamide (1.09 g) in dry THF (6 ml) was added dropwise to the reaction mixture. The mixture was stirred at −70° C. for 20 min and water was added at the same temperature to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give the title compound (1.40 g) as a colorless powder. The physical and chemical data were identical with those obtained for the compound obtained of Reference Example 13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[OH-].[Na+].Cl>CN1CCCC1=O.O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1])[C:12]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
3-Chloro 4-fluoro nitrobenzene (5.0 g, 28.48 mmol) and dimethyl malonate (3.3 mL, 36.17 mmol) were dissolved in N-methylpyrrolidinone (131.5 mL). Sodium hydroxide (2.4 g, 60 mmol) was added at RT and the solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to 5° C. and 1N HCl solution was added to give a pH of 2. Water (526 mL) was added and the resulting mixture was stirred for 15 minutes during which a pale yellow solid precipitated out. The precipitate was collected by filtration and then washed with water (2×10 mL). The resulting solid mass was dissolved in DCM (50 mL), dried (Na2SO4) and then the volatiles were removed under reduced pressure to afford the title compound (5.5 g, 67%). The product was used as such in the next step without purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]#[N:14])=[CH:7][N:6]=1)#[N:2]>N.CO.[H][H].[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][N:6]=1
Reactant: N#CCCc1ccc(CCC#N)nc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCc1ccc(CCCN)nc1
Yield: 89.5 %

Procedure:
A solution of 2,5-di(2-cyanoethyl)pyridine from Step C (3.16 g) was dissolved in 7N ammonia in methanol solution (45 mL) and hydrogenated under 40 psi of hydrogen gas pressure at 50° C. in the presence of Raney nickel (1.6 g) for 20 h. The catalyst was filtered through solka floc® and washed with methanol. The filtrate and wash were combined and concentrated under reduced pressure to give 2,5-di(3-aminopropyl)pyridine (I)(2.95 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCCCCC.CCO.CO>[NH2:1][CH2:2][C@H:3]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: CO
Solvent: CCCCCC
Solvent: CCO
Product: NC[C@H](NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1

Procedure:
The title compounds were prepared by subjecting the compound of Example 4 to a column chromatography with a chiral stationary phase (Prep HPLC; column: Whelk O 2.5 cm ID×25 cm; mobile phase: hexane/EtOH/MeOH/DEA=50/25/25/0.1; flow rate: 40 ml/min; detector: UV 270 nm; column temp: RT; sample preparation: 10 mg/ml; load: 10 ml (100 mg))