Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7]2.[C:22](O)(=[O:26])[C:23](O)=[O:24]>Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH2:5][N:6]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:8]=2[C:9]2[NH:13][C:22](=[O:26])[C:23](=[O:24])[NH:12][C:10]=2[CH:11]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Br)c2c(c1N)CN(CCc1ccccc1)CC2
Agent: Cl
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CN(CCc1ccccc1)CC3
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of the product from Example 10 (0.54 g, 1.56 mmol) in 3N HCl (20 mL) was treated with oxalic acid (0.3 b, 2.34 mmol) and refluxed for four hours. When cool to room temperature the precipitate was filtered, suspended in water (70 mL) and basifyed to pH 10. The solids were filtered, and dried to give the title compound (0.37 g, 60%) as a brown solid, mp=290-295° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[C:17](=[O:16])[CH2:18][N:19]([CH3:20])[C:11]1=[S:12])[CH3:2]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C)c1N1C(=O)CN(C)C1=S
Yield: 60 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 8.9 g of 2-ethyl-6-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.5 g of triethyl amine, and 250 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.45 g) as a peach solid, m.p. 106°-108° C. Anal. Calcd. for C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.52; H, 6.61; N, 11.29. Mass spectrum (+ESI, [M+H]+) m/z 269/271.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), benzoyl chloride (0.20 ml), triethylamine and dichloromethane (20 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from ethanol to give 1-{4-[2-(6-benzoylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.71 g) as white powder, m.p. 178°-178.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)=[CH:32][CH:31]=4)=[O:35])=[CH:43][CH:42]=3)[NH:18][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCc4ccccc4)cc3[nH]2)cc1

Procedure:
Compound 639 was prepared according to the procedure similar to that described in Scheme III from 1-benzyloxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C27H28N4O4: 473.21; found: 473.08.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[OH-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1I.O>CN(C)C=O>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1[O:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Reactant: COc1ccc(O)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Temperature: 5 °C

Procedure:
3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 11.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1F>>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccccc1Br
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccccc2Br)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 1-bromo-2-fluoro-benzene were converted to yield {4-[1-(2-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]([C:15]4[CH:16]=[C:17]([OH:26])[CH:18]=[CH:19][C:20]=4[N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40].O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:13]([C:15]4[CH:16]=[C:17]([O:26][C:43](=[O:44])[NH:42][CH:39]([CH3:41])[CH3:40])[CH:18]=[CH:19][C:20]=4[N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[N:14][C:10]=3[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)n1c(-c2cc(O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a stirred solution of 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-phenol (100 mg, 0.23 mmol) in THF (3 mL) is added potassium carbonate (65 mg, 0.47 mmol) followed by isopropyl isocyanate (25 ul, 0.26 mmol). The resulting mixture is stirred at room temperature for 3 hours and then is warmed to 60° C. for 18 hours. The reaction is cooled to room temperature, poured into water and the product extracted into EtOAc (2×10 mL). The combined organics are dried with MgSO4 (500 mg), filtered, and concentrated. The remaining residue is purified by silica gel flash column chromatography (12 g silica gel, 0-5% MeOH/DCM). Product-containing fractions are combined and concentrated to give the title compound (15 mg, 13%). LCMS (ESMS): m/z 512.5 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:8][CH2:7]1>[Pd].C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-4-(2-nitro-phenyl)-piperazine (1.19 g) in 50 mL of 4/1 ethyl acetate/methanol was treated with 5% palladium on carbon (55 mg) and placed under a hydrogen atmosphere. After stirring at ambient temperature overnight, the reaction was filtered using a pad of silica and the pad was washed with 17% ethyl acetate in hexanes, then 33% ethyl acetate in hexanes. Removal of solvent afforded 0.75 g of the product as a solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Br:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2>>[Br:5][C:6]1[N:7]([CH2:3][CH2:2][C:1]#[N:4])[C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC#N)c2c1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
Acrylonitrile (10 mL of 1.52 M in 1,4-dioxane, 30.4 mmol) was added to methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (840 mg, 2.5 mmol) in a microwave vial. The vial was sealed and Triton® B (500 μL 1.1 μmol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was cooled and poured to precipitate the crude product. The granular solid was collected, washed with water and dried. Recrystallization from ethanol gave the product as a colorless solid (696 mg, 74%). MS m/z 390 (MS+); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.27-1.49 (m, 3 H) 1.60-2.01 (m, 7 H) 2.77-2.90 (m, 1 H) 2.98 (t, J=6.40 Hz, 2 H) 3.87 (s, 3 H) 4.62 (t, J=6.59 Hz, 2 H) 7.67 (dd, J=8.42, 1.46 Hz, 1H) 7.83 (d, J=8.42 Hz, 1 H) 8.25 (s, 1 H).
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10](Cl)[C:11]#[CH:12]>[Br-].[Zn+2].[Br-].C(Cl)C#C.O1CCCC1>[OH:8][CH:7]([C:6]1[O:9][C:3]([CH3:2])=[CH:4][CH:5]=1)[CH2:12][C:11]#[CH:10]
Reactant: C#CCCl
Reactant: Cc1ccc(C=O)o1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C#CCC(O)c1ccc(C)o1
Temperature: 10 °C
Yield: 80.3 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (24.3 g), dry zinc bromide (16.9 g) and dry tetrahydrofuran (110 g). Propargyl chloride (0.55 g) was added thereto at 10° C. while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the heat generation stopped, a mixture of 5-methylfurfural (55.06 g), propargyl chloride (47.9 g) and tetrahydrofuran (110 g) was dropwise added to the reaction mixture at 35° C. in 2 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to give 2-(1-hydroxy-3-butynyl)-5-methylfuran (60.3 g) in a yield of 81% (based on the starting 5-methylfurfural).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=[C:3]1[CH3:15].[Li+].[OH-]>C1COCC1.CO>[CH3:14][O:13][C:11]([C:5]1[N:4]=[C:3]([CH3:15])[N:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(C)n(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
To a solution of dimethyl 1,2-dimethyl-1H-imidazole-4,5-dicarboxylate (1.89 g, 8.91 mmol) in THF (35 mL) and MeOH (15 mL) was added at 0-5° C. LiOH (1M; 9.35 mL, 9.35 mmol). The reaction mixture was stirred at RT for 7 h and the solvents were evaporated in vacuo. The residue was poured into water (20 mL) and ethyl acetate (30 mL). The ethyl acetate phase was washed with water (10 mL). The combined aqueous phases were acidified with hydrochloric acid (1M, 10 mL) and extracted with dichloromethane/MeOH (95:5, 8×60 mL). The dichloromethane/MeOH phases were dried over MgSO4, filtered and evaporated to give the product as colorless solid (1.29 g, 6.51 mmol, 73.1%). MS: M=199.1 (M+H)+
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>CS(C)=O>[CH2:21]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
This example illustrates a synthesis of 1-(4,5-Oxipentyl)-3,7- dimethylxanthine. Sodium hydride (95%) (1.38 g, 55 mmol) was added to a solution of theobromine (9.0 g, 50 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, 1-bromo-4-pentene(7.45 g, 50 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% petroleum ether/ethyl acetate eluant to yield 9.67 g (92% yield) 1-(4-pentenyl)-3,7-dimethylxanthine (inventive compound no. 1575).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: O=C1C=CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4 mmol) in tetrahydrofuran (24 mL) is treated with 3,4-dihydro-2H-pyran (2 mL) and pyridinium p-toluenesulfonate (500 mg, PPTS). The reaction is stirred at room temperature for 18 hours. The reaction mixture is then diluted with ethyl acetate (25 mL) and washed with 50% saturated brine (2×30 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting crude brown oil is purified by filtration through a plug of silica gel (25 g, 33% ethyl acetate/hexane) to provide the title compound as a yellow oil (2.00 g, 76%); 1H NMR (CDCl3) δ 7.46 (2×dd, 1 H, J=16.3, 5.7 Hz), 6.2 (m, 1H), 4.9 (m, 1 H), 4.80 (d appt, 1 H, J=23.8, 2.9 Hz), 3.9 (m, 1 H), 3.6 (m, 1 H), 2.73 (2×dd, 1 H, J=18.4, 6.2 Hz), 2.35 (2×d, 1 H, J=18.4 Hz), 1.8 (m, 1 H), 1.6 (m, 4 H); IR (neat) νmax 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm-1 ; MS (CI) m/e (% relative intensity) 183 (M+H+, 28), 85(100).
Reaction SMILES: [O:1]1[C@H:10]2[C:5](=[CH:6][CH2:7][CH2:8][C@H:9]2[CH:11]=[O:12])[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C@H:10]2[C:5](=[CH:6][CH2:7][CH2:8][C@H:9]2[CH2:11][OH:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@@H]1CCC=C2CCCO[C@@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC[C@@H]1CCC=C2CCCO[C@@H]21
Temperature: 0 °C

Procedure:
202 mg (8R,8aR)-3,4,6,7,8,8a-hexahydro-2H-chromene-8-carbaldehyde was dissolved in 8 mL MeOH and the solution was cooled to 0° C. and 52 mg sodium borohydride was added slowly. The reaction was stirred for several hours and gradually warmed to RT. The methanol was removed using a rotovap and the residue was diluted with CH2Cl2 and added to sat. NH4Cl. The mixture was separated, and the aqueous was extracted with CH2Cl2. The crude extract was dried over Na2SO4, filtered, concentrated, then purified on silica gel to provide the title compound. 1H NMR (400 MHz, CDCl3) δ=1.46-1.80 (m, 4H), 1.84-2.10 (m, 3H), 2.13-2.38 (m, 2H), 2.78-2.86 (m, 1H), 3.52-3.62 (m, 1H), 3.66-3.76 (m, 1H), 3.76-3.87 (m, 1H), 3.94-3.47 (m, 2H), 5.52 (s, 1H) ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][C:11]=1[CH3:12].[OH-].[Na+].CN([CH:18]=[O:19])C>O>[CH3:12][C:11]1[CH:10]=[C:9]([CH:18]=[O:19])[O:8][C:7]=1[CH3:6]
Reactant: CN(C)C=O
Reactant: Cc1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)oc1C
Reaction time: 3 h
Yield: 76 %

Procedure:
According to the procedure of S. F. Martin, et al. J. Org. Chem. 1984, 49, 2512-2516, phosphorus oxychloride (10.7 mL, 114.4 mmol) was added dropwise to a stirred, ambient temperature solution of 2,3-dimethylfuran (10 g, 104 mmol) in DMF (150 mL) under a dry nitrogen atmosphere over a period of 30 min. After 3 h., the reaction mixture was hydrolized with 2.5 N aq. sodium hydroxide and further diluted with water (50 mL). Aqueous mixture was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were washed with water, dried with brine and purified by silica gel flash chromatography (eluent: ethyl acetate) to provide a yellow oil (9.8 g, 76%); MS (ESI): [M+H]+, 125.1.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:11][NH:12][CH:13]1[CH2:17][C:16]2([O:21][CH2:20][CH2:19][O:18]2)[CH:15]=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:27][C:28]#[N:29].[K+].Cl>C(O)C.O>[CH2:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:11][N:12]([CH:13]1[CH2:17][C:16]2([O:18][CH2:19][CH2:20][O:21]2)[CH:15]=[CH:14]1)[C:28]([NH2:29])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(CCNC1C=CC2(C1)OCCO2)OCc1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCC(CCN(C(N)=O)C1C=CC2(C1)OCCO2)OCc1ccccc1
Reaction time: 18 h

Procedure:
N-(3-Benzyloxyoctyl)-4,4-ethylenedioxycyclopent-2-enamine (972 mg) in ethanol (60 ml) was treated with potassium cyanate (360 mg) in water (4.0 ml) then 1.0N aqueous hydrochloric acid (3.0 ml) at room temperature. After 18 hours, the mixture was diluted with water and extracted with chloroform. The extract was dried then decolourised and the solvent was removed in vacuo to give crude N-(3-benzyloxyoctyl)-N-(4,4-ethylenedioxycyclopent-2-enyl)urea as a yellow glass. This material was dissolved in tetrahydrofuran (11.0 ml) and 2.0N aqueous hydrochloric acid (11.0 ml) and the solution set aside at room temperature for 1.25 hours. After dilution with water, the product was extracted into chloroform, and the solvent removed from the dried extract to give the mixture of diastereomers of 2-(3-benzyloxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione as a colourless glass, δ (CDCl3) 0.95 (3H, bt, --CH3), 2.41 (4H, m, ##STR13## 3.40 (2H, m, --N--CH2 --), 4.24 (2H, m, 1-H, 5-H), 4.48 and 4.50 (total 2H, both s, --CH2Ph from each isomer), 7.31 (5H, bs, --Ph).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28]>>[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[N:28]1[CH2:20][CH2:19][N:4]([C:5]2[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Reactant: Cn1ccnc1N
Product: Cc1c(C)c(N2CCN(c3nccn3C)CC2)c(C)c2c1OC(C)(C)C2
Yield: 51.9 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (330 mg, 1.0 mmol) synthesized in Reference Example 146 and 1-methyl-1H-imidazole-2-amine (146 mg, 1.5 mmol), the reaction was carried out in the same manner as Example 117 to obtain 184 mg of the title compound as an oily product (yield 52%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:20][CH:21]=1)=[CH:12]2
Reactant: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1

Procedure:
Cyclopentyl-[2-(4-aminophenyl)-5-chloro-1H-indol-7-yl]-amine prepared in Example 82 and methanesulfonylchloride were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([N:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[C:13](=[O:19])[NH:12]/[C:11]/1=[N:20]\[NH2:21])[CH2:6][CH2:7][CH2:8][CH3:9].C([O-])(O)=O.[Na+]>Cl>[CH2:5]([N:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[C:13](=[O:19])[N:12]2[N:1]=[N:21][N:20]=[C:11]12)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCn1c2nc[nH]c2c(=O)n2nnnc12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A saturated aqueous NaNO2 (130 mg, 1.89 mmol) solution was added dropwise to a solution of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (150 mg, 0.63 mmol) in 5% aqueous HCl solution (3 ml) under stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was neutralized by saturated NaHCO3 solution and extracted by ethyl acetate (3×). The combined organic phases were washed by brine and dried over MgSO4. The filtration and evaporation of solvent gave the desired product (94.6 mg, 60.7%) as white solid. LCMS calculated for C10H14N7O(M+H): 248.1; found: 248.0.