Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].I.CS[C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[NH:25]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CSC(=N)c1cccs1
Reactant: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (60) (0.1 g, 0.368 mmol) in dry ethanol (5 mL) was treated with 10% Pd—C (0.02 g), purged with hydrogen gas and stirred for 4 h under hydrogen atm. (balloon pressure). The solid was filtered off using celite bed and washed with dry ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.21 g, 0.737 mmol) and stirred for 24 h at room temperature. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was filtered and dissolved into sat. NaHCO3 sol.: CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain N-(3-(1-ethylpiperidin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (61) (0.085 g, 66%) as a solid. mp 150-152° C.; 1H NMR (DMSO-d6) δ 1.01 (t, 3H, J=6.9 Hz), 1.59-1.75 (m, 2H), 1.90-2.05 (m, 4H), 2.35 (q, 2H), 2.65-2.73 (m, 1H), 2.94-2.97 (m, 2H), 6.23 (brs, 1H), 6.62 (dd, 1H, J=1.2, 8.4 Hz), 6.97 (s, 1H), 7.02 (d, 1H, J=2.1 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz), 10.59 (s, 1H); ESI-MS m/z (%): 353 (M+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1)([O-])=O.C(Cl)(Cl)Cl>C(O)C.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccc([N+](=O)[O-])cc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Agent: [Ni]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-5-nitro-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.50 g) obtained in Example 404 is suspended in ethanol/tetrahydrofuran (1:1, 400 ml), and thereto is added Raney nickel, and the mixture is stirred at room temperature under atmospheric hydrogen pressure for 12 hours. To the resulting yellow suspension is poured chloroform (200 ml), and the mixture is stirred at room temperature for 0.5 hour. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform to chloroform/methanol=4/1), suspended in ethyl acetate/diethyl ether. The precipitates are collected by filtration, washed with diethyl ether, and dried to give trans-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.94 g). This product (150 mg) is suspended in methanol, and the mixture is treated with 4N hydrogen chloride in dioxane to give the title compound (158 mg).
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].CN(C)C=O>O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][N:29]2[C:28](=[O:30])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:35])=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2cccc(CCOS(=O)(=O)c3ccccc3)c2c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
The compound IV (14 g, 0.041 mol) produced as described above and potassium phthalimide (12.3 g, 0.0656 mol) were added into a reaction vessel, and dimethylformamide (200 ml) was added. The mixture was heated and refluxed for 2 hours. After cooling it to room temperature, 200 ml of water was added, and the mixture was stirred and filtered. The filter cake formed was washed with water and dried, to produce 12.3 g of N-[2-(7-methoxy-1-naphthyl)ethyl]phthalimide (II). The yield was 92.3%. The melting point was 160-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH:38]([CH3:40])[CH3:39])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[ClH:22].[CH:38]([O:37][CH2:36][CH2:35][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)([CH3:40])[CH3:39]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Solvent: Cc1ccccc1
Product: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl

Procedure:
3.4 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 2.6 g of 2-isopropyloxyethyl p-toluenesulfonate are suspended in 30 ml of toluene and heated to boiling point. The clear solution so obtained is boiled under reflux for 17 hours and then concentrated by evaporation. Water is added to the residue, and the mixture is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with methylene chloride. The crude oil is chromatographed over silica gel and crystallised in the form of the hydrochloride from acetone, yielding 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 184°-185°.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH:34]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:39][C@H:40]1[C@H:49]([O:50]C(=O)C)[C@@H:48]([CH2:54][O:55]C(=O)C)[O:47][C@@H:42]([O:43][CH2:44][CH2:45][NH2:46])[C@@H:41]1[NH:59][C:60](=[O:62])[CH3:61])(=O)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O(C)[Na]>C(Cl)Cl.CO>[C:60]([NH:59][C@@H:41]1[C@@H:40]([OH:39])[C@H:49]([OH:50])[C@@H:48]([CH2:54][OH:55])[O:47][C@H:42]1[O:43][CH2:44][CH2:45][NH:46][CH2:34][CH2:33][CH2:32][C@@H:10]1[O:11][C@@H:12]([CH3:31])[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:62])[CH3:61]
Reactant: C[C@@H]1O[C@@H](CCC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(=O)N[C@H]1[C@H](OCCN)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CO[Na]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N[C@H]1[C@H](OCCNCCC[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)propanal (800 mg, 1.69 mmol) and 2-aminoethyl 3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-β-D-glucopyranoside (987 mg, 2.53 mmol) in CH2Cl2 (15 mL) was added acetic acid (29 μL, 0.506 mmol) and sodium triacetoxyborohydride (893 mg, 4.21 mmol). After stirring at rt overnight, the reaction mixture was concentrated and the residue was taken up in EtOAc (70 mL), washed with sat'd NaHCO3 (2×100 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was taken up in CH3OH (8 mL), to which NaOCH3 (27 mg, 0.506 mmol) was added. After stirring at rt for 2 hr, the resulting mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (120 g), eluting with 5-100% AcCN in water to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.30 (d, J=6.6, 3H), 1.50 (m, 1H), 1.60 (m, 1H), 1.68 (m, 1H), 2.02 (s, 3H), 2.64 (m, 2H), 2.81 (m, 2H), 3.39 (m, 1H), 3.57 (m, 2H), 3.69 (m, 1H), 3.78-3.85 (m, 4H), 3.92 (m, 2H), 4.00 (m, 2H), 4.45 (d, J=7.7, 1H), 4.52 (d, J=11.9, 1H), 4.62 (d, J=11.8, 1H), 4.68 (d, J=12.1, 1H), 4.79 (d, J=12.0, 2H), 7.28-7.38 (m, 15H), 7.65 (s, 1H); [M+H/e]+=723.3925.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=O)[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[S:43])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=S)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.25 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disufide; 0.21 g) in xylene (10 mL) was refluxed overnight. The mixture was cooled to about 50° C. and water (15 mL) was added and refluxed for 2 h. The mixture was stirred at room temperature overnight and evaporated. The residue was partitioned between EtOAc and water. The EtOAc layer was washed with water, dried and evaporated to yield 0.25 g of N-(2,6-dichlorothiobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 504 (MH+).
Reaction SMILES: [NH2:1][C:2](=[N:31]O)[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1.O1CCCC1.Cl.[H][H]>C(O)C.[Pd].O>[NH2:31][C:2](=[NH:1])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccc(C(N)=NO)cc2NC(=O)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C(=N)N)cc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 12 h
Yield: 35.8 %

Procedure:
To a stirred solution 4-[(amino)(hydroxyimino)methyl]-N1,N2-bis(4-methoxybenzoyl)-1,2-benzenediamine (0.50 g, 1.2 mmol), tetrahydrofuran (5 mL), water (25 mL), and 1 N aqueous hydrochloric acid (1.4 mL) in ethanol (50 mL) was added 10% palladium-on-carbon (250 mg). The vessel was placed under vacuum and the atmosphere was replaced with hydrogen (1 bar). After 12 h, the balloon was removed and the mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 180 mg (35%) of the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]=[N+:7]=[N-:8].[Na+].[Cl-].[NH4+].C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:19]([N:8]1[N:7]=[N:6][C:3]([CH2:2][C:1]#[N:5])=[N:4]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [N-]=[N+]=[N-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Malononitrile (37.6 g, 0.57 mol), sodium azide (37.0 g, 0.57 mol), ammonium chloride (30.2 g, 0.57 mol), and DMF (400 mL) were charged to a reaction vessel. The vessel was placed under a nitrogen gas purge, equipped with a thermocouple, and stirred with a mechanical stirrer at room temperature for 30 minutes. The thick slurry was heated to 80° C. and stirred at that temperature for 2 h. 1H NMR analysis of a sample showed the reaction to be complete. The mixture was cooled to ambient temperature, at which time triethylamine (159 mL, 1.14 mol) and trityl chloride (159 g, 0.57 mol) were added. The mixture was stirred for 16 hours at ambient temperature. TLC analysis showed that the reaction had gone to completion. The reaction mixture was filtered through a fritted funnel and the solids (NH4Cl salts) were washed with ethyl acetate (1.5L×2). The organic layer was washed with H2O (1L×3) and the aqueous portions were combined and extracted with another part of ethyl acetate (1L). The two organic portions were combined and washed with water (1L), brine, and dried with MgSO4. The sample was concentrated in vacuo to a brown solid. A crude 145 grams of material was added to 400 mL of ethyl acetate and heated to reflux. n-Hexanes (400 mL) was added to the hot solution dropwise over 15 min with continued refluxing. The solution became cloudy and was then cooled slowly to ambient temperature as a granular solid precipitated from the solution. The granular solid was collected with a fritted funnel and dried in a vacuum oven for 16 h. Low yields for this reaction prompted us to reexamine the NH4Cl salts that were filtered away during the first step of purification. The salts were slurried with ethyl acetate (600 mL) for several minutes. The solids were filtered once again, washed with ethyl acetate, and the organic mother liquor was concentrated in vacuo to a white solid. The two batches of clean product were combined to give 135 grams (0.38 mol, 69% yield) of (2-trityl-2H-tetrazol-5-yl)-acetonitrile. 1H NMR (CDCl3): 4.06 (s, 2H), 7.09 (m, 6H), 7.36 (m, 9H). Anal. Caldc. for C22H17N5: C, 75.19; H, 4.83; N, 19.93. Found: C, 75.11; H, 4.98; N, 20.06.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C1CSCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCSCC2)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=537.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one, thiomorpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:12][N:13]([CH3:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C>[CH3:32][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:46]([NH2:49])=[N:45][C:43]([C:36]1[C:35]([NH2:34])=[N:40][C:39]([NH2:41])=[C:38]([Cl:42])[N:37]=1)=[O:44]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCCN
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.31 mmol) was added to a suspension of 12-amino-dodecanoic acid (3-dimethylaminopropyl)amide dihydrochloride (5) (0.081 g, 0.22 mmol) in absolute ethanol (5 mL). The mixture became homogeneous. It was stirred at 70° C. (oil bath) for 5 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.093 g, 0.24 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 3 hours and cooled to room temperature. The solvent was then removed by rotary evaporation, the residue dissolved in small volume of methanol, and this solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with a gradient of 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane, to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (3-dimethylaminopropyl)amide 6 (0.070 g, 63%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 6H), 2.01 (t, 2H), 2.11 (s, 6H), 2.20 (t, 2H), 3.02 (m, 2H), 3.12 (t, 2H), 6.80 (br, 3H), 7.75 (m, 1H). m/z (ESI) 512 [C23H42ClN9O2+H]+. mp 82-84° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10](O)[N:9]([CH3:13])[C:5]2=[N:6][C:7]=1C.[OH:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.[CH2:48](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([CH2:48][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:21]4=[O:45])=[CH:46][CH:47]=3)[N:9]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCP(CCCC)CCCC
Reactant: Cc1nc2c(cc1Br)nc(O)n2C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxy-methyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl) dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97-100° C. (softening)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([CH2:12]P(=O)(OC)OC)([OH:11])=[O:10].[CH3:19][O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][CH:29]2[C:34](N(CC1C=CC=CC=1)CC1C=CC=CC=1)=O.Cl>O1CCCC1>[C:9](/[CH:12]=[CH:34]/[CH:29]1[C:30]2[C:25](=[C:24]([O:23][CH2:22][C:21]([O:20][CH3:19])=[O:51])[CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:27][CH2:28]1)([OH:11])=[O:10]
Reactant: COC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: COP(=O)(CC(=O)O)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)COc1cccc2c1CCCC2/C=C/C(=O)O
Reaction time: 0.17 h
Yield: 118.5 %

Procedure:
To a solution of isopropylamine (1.87 ml) in dry tetrahydrofuran (50 ml) was added dropwise 1.15M n-butyllithium in hexane solution (10.6 ml) at -78° C. The mixture was stirred for 20 min at -78° C. to give lithium diisopropylamide. To the obtained lithium diisopropylamide solution was added a solution of dimethyl carboxymethylphosphonate (1.02 g) in dry tetrahydrofuran (3 ml) at -78° C. After stirred for 10 min, to the mixture was added the aldehyde compound (prepared in reference example 1, 1.38 g) at room temperature. The mixture was stirred for 1 h at room temperature. After acidified by adding 1N hydrochloric acid until pH 3, the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from ethyl acetate-hexane (3:7) to give the title compound (1.07 g) as white powder having the following physical data.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:12]=3[C:11]=2[CH:10]([CH2:25][Cl:26])[CH2:9]1)=O)(C)(C)C.[N+:27]([O-])([O-:29])=[O:28].[K+].N>OS(O)(=O)=O>[Cl:26][CH2:25][CH:10]1[C:11]2[C:12]3[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][C:13]=3[CH:14]=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: COC(=O)c1ccc2c3c(ccc2c1)N(C(=O)OC(C)(C)C)CC3CCl
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c2c3c(ccc2c1)NCC3CCl
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 13.3 %

Procedure:
Powdered 150 (900 mg, 2.39 mmol) was added to stirred conc. H2SO4 (6 mL) at 0° C. and the mixture was warned to room temperature for 15 nm. The resulting solution was cooled to −5° C. and treated dropwise with a solution of KNO3 (266 mg, 2.63 mmol) in conc. H2SO4 (1.5 mL). The mixture was stirred at −5° C. for a further 5 min, then poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was chromatographed on silica gel, eluting with CH2Cl2 to give crude methyl 1-(chloromethyl)-9-nitro-1,2-dihydro-3H-benzo[e]indole-7-carboxylate (151) (102 mg, 13%) as an orange-brown solid; 1H NMR [(CD3)2SO] δ 8.66 (d, J=1.7 Hz, 1H), 8.30 (d, J=1.7 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), δ 3.92-3.83 (m, 4H), 3.74-3.67 (m, 1H), 3.63 (dd, J=10.6, 2.3 Hz, 1H), 3.39-3.28 (m, 2 H).