Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([Cl:22])=[O:18])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccncc3)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2[nH]c(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 mL) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:26][CH2:25][CH2:24][S:21](=[O:23])(=[O:22])[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:12])[CH3:13])[CH2:15][CH2:16]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)cc2)CC1

Procedure:
4-Chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide was prepared by an analogous procedure as described in example 9 starting from 104 mg (1.1 equiv.) 4-chloro-benzoic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 4-chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C(O)(=O)C>C1(Cl)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][Br:12])([O-:3])=[O:2]
Reactant: Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1CBr
Temperature: 40 °C
Yield: 60 %

Procedure:
2-Nitro-5-chlorotoluene (6.0 g, 35.0 mmol), 1,3-dibromo-5,5-dimethyl hydantoin (10.6 g, 37.1 mmol), and 1,1-azobis-(cyclohexanecarbonitrile) (VAZO 88, 400 mg, 16 μmol) were combined in 275 mL of C6H5Cl and stirred. Glacial acetic acid (200 μL) was added and the reaction was heated to 40° C. for 120 h. The reaction was washed with 150 mL of warm saturated bicarbonate, extracted with warm bicarbonate (4×150 mL) and washed with water (150 mL). The organic layer was dried over MgSO4 and the solvent was removed to yield a pink-red oily solid that consists of 2-nitro-5-chlorotoluene (˜40%) and the desired product (˜60%) and can be carried on to the next reaction without further purification. Flash chromatography on silica gel (25:1 hexanes:EtOAc) yields the pure brominated product as a brown solid (38%). 1H NMR (CDCl3, 300 MHz) δ 8.0 (1H, dd), 7.56 (1H, d), 7.45 (1H, dd), 4.79 (2H, s). 13C NMR (CDCl3, 300 MHz) δ 28.43, 127.02, 129.61, 132.37, 134.64, 139.91, 145.96. FTIR (KBr, cm−1) 1604, 1569, 1522, 1474, 1443, 1338, 1306, 1227, 1202, 1109, 1064, 908, 827, 757, 706.93, 827, 757, 707, 685, 524. HRMS (EI) calcd M+, 248.9187; found, 248.9186.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:20][O-:21].[Na+]>>[OH:19][CH:16]([CH2:17][OH:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([O:21][CH3:20])[C:11]=2[N:12]=[CH:13]1
Reactant: C[O-]
Reactant: OCC(O)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Product: COc1nc2ccccc2c2c1ncn2CC(O)CO

Procedure:
Using the method of Example 157, 4-chloro-1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]quinoline (from Example 124, Part D) was reacted with sodium methoxide to provide 1-(2,3-dihydroxypropyl)-4-methoxy-1H-imidazo[4,5-c]quinoline, m.p. 214°-216° C. after recrystallization from isopropanol. Analysis: Calculated for C14H15N3O3 : %C, 61.5; %H, 5.5; N, 15.4; Found: %C, 61.3; %H, 5.5; %N, 15.4.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH:34][CH3:35].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:32][CH:33]=[CH:34][CH3:35])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCBr
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (6.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.30 g). To the solution was added 60% sodium hydride (61 mg) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the mixture was added crotyl bromide (0.31 ml), and the mixture was stirred at 60° C. for 4 days. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.23 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([OH:24])=[O:23])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:23])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Yield: 102.2 %

Procedure:
(cis)-4-Phenyl-1-phenylmethoxycarbonyl-L-proline (3.52 g), dissolved in 25 ml of dry dimethylformamide, is treated with 1.61 g of anhydrous potassium fluoride and 2.0 g of chloromethyl pivalate under argon at room temperature for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with water (three times), saturated sodium bicarbonate and saturated brine. The aqueous layers are backwashed with fresh ethyl acetate. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give 4.86 g of an oil.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]([N:32]1[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]1[C:38]#[N:39])=[O:31]>C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:29][C:30]([N:32]3[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]3[C:38]#[N:39])=[O:31])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (62.9 mg) was suspended in acetonitrile (1 mL). To this solution, diisopropylethylamine (47 μL) was added and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) in acetonitrile (0.8 mL) was added while the mixture was chilled in an ice bath. The mixture was stirred for 4 hours and concentrated. To the resulting residue, ethyl acetate and water were added, followed by an aqueous sodium bicarbonate solution to make the pH basic. The solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][NH:48][CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:57][S:58](Cl)(=[O:60])=[O:59].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][N:48]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCNCC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2Cl2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:30]C(C)(C)C(C1C=CC(C(NC)=O)=CC=1)=O>>[CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]([CH3:30])[C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)c2ccc(C(=O)C(C)(C)C)cc2)cc1
Product: CN(C(=O)c1ccc(C(=O)C(C)(C)C)cc1)C(=O)c1ccc(C(=O)C(C)(C)C)cc1

Procedure:
Following the above procedure, but using in place of the 4-(2,2-dimethyl-1-oxopropyl)-benzamide an equivalent amount of 4-(2,2-dimethyl-1-oxopropyl)-N-methylbenzamide, there is obtained 4-(2,2-dimethyl-1-oxopropyl)-N-methyl-N-[4-(2,2-dimethyl-1-oxopropyl)-benzoyl]-benzamide (m.p. 121.5°-122.5° C.).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:19]([NH2:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:20][C:19]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)=[O:48])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([OH:48])([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)[C:2]([F:4])([F:3])[F:1])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M solution of (trifluoromethyl)trimethylsilane in THF (0.23 ml) and a 0.1M solution of tetrabutylammonium fluoride trihydrate in THF (0.42 ml) were added to 4-{3-chloro-4-[1-methyl-2-(2-methyl-pyridin-4-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile (80 mg) in THF (1 ml). The mixture was stirred for 1 h at room temperature and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:1) to give the title compound (60 mg) as a light yellow solid. MS (m/e)=447.1 [M+H+].
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=1[CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:3][C:4]2[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=2[CH3:12])[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ncn(C(C)C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2c(C)ncn2C(C)C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1-(propan-2-yl)-1H-imidazole hydrochloride (824 g, 3.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (970 mg, 7.0 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in acetone (30 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-8% MeOH/DCM), affording 6-methyl-2-({[4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}-sulfanyl)pyrimidin-4-ol (215 mg, 28% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.36 (d, 3H, J=6.7 Hz), 2.09 (s, 3H), 2.19 (s, 3H), 4.31 (m, 1H), 4.45 (s, 2H), 6.00 (s, 1H), 7.66 (s, 1H); M+279. The product was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CS(C)=O.O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCOc1ccc(I)cc1
Yield: 88.3 %

Procedure:
To 34.0 g of p-iodo-phenol dissolved in 350 ml of DMSO, were added 7.4 g of sodium hydroxide dissolved in 50 ml of water and stirred to obtain a homogeneous solution. Then, 32.4 g of n-decyl bromide were added and stirred at room temperature for 3 days. The resulting solution was introduced into 1 l of iced water, and extracted three times with hexane. The hexane phase was washed with water, followed by distilling off the hexane to obtain 46.6 g of oily p-n-decyloxy-iodobenzene.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[Cu]=O.CN(C)C=O>[CH2:11]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1O
Agent: O=[Cu]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCO2
Yield: 79.9 %

Procedure:
138.0 g (1.0 mol) of 2,3-dihydroxybenzaldehyde, 415.0 g (3.0 mol) of potassium carbonate, 4.7 g of copper oxide, 255.0 g (3.0 mol) of methylene chloride and 1500 ml of distilled dimethylformamide are boiled for 7 hours, while stirring intensively.. The reaction mixture is evaporated to dryness in vacuo and, after addition of 1000 ml of ice-water to the residue, the mixture is extracted four times by shaking with 300 ml of methyl tert-butyl ether each time. The combined ether extracts are washed with 5% strength sodium hydroxide solution and water and dried over sodium sulphate. The methyl tert-butyl ether is then stripped off (and can be reused) and the residue is distilled in vacuo at 92°-93° C./1 mbar. 120 g (80% of theory) of 2,3-methylenedioxybenzaldehyde having a melting point of 32°-33° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: CCI
Reactant: O=C(O)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
2-Bromobenzoic acid (2.005 g, 9.47 mmol, 1.0 eq.) was combined with iodoethane (1.60 ml, 19.9 mmol, 2.0 eq.)and sodium bicarbonate (1.68 g, 19.9 mmol, 2.0 eq.) in dimethylformamide (10 ml, 1M) and stirred at room temperature for a total of 4 days. The reaction was then diluted with water (20 ml) and extracted with ether:hexane (1:1, 3×20 ml). The combined organic extracts were washed with aqueous 10% sodium hydrogen sulfite (20 ml), water (20 ml), and aqueous saturated sodium chloride (20 ml). Next, the organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (50 g) eluting with ether:hexane (1:6) to furnish the title C compound (2.17 g).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.13 g, 0.33 mmol) was added to a solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide 26 (0.09 g, 0.3 mmol), triethylamine (0.12 mL), and ethanol (1.7 mL). The reaction mixture was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The residue was triturated with water and then purified by flash chromatography (silica gel, 20–10:1:0–0.2 CH2Cl2/methanol/concentrated ammonium hydroxide, v/v) to provide 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide 27 (0.1 g, 64%) as a yellow solid. mp 114–116° C. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.60 (m, 2H), 3.32 (m, 2H), 3.50 (m, 4H), 3.70 (m, 4H), 4.81 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H). m/z (ESI): 523 [C22H31ClN8O5+H]+.
Reaction SMILES: [N:1](CCC(OCC)=O)=[C:2]=[O:3].[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16]N)[CH3:12].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:1]([CH:15]([CH3:16])[C:14]([O:13][CH2:11][CH3:12])=[O:18])=[C:2]=[O:3]
Reactant: CCOC(=O)CCN=C=O
Reactant: CCOC(=O)CCN
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N=C=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The solution of ethyl 3-isocyanatopropionate in toluene used in the above process can be prepared as follows: A mixture of 15.36 g of β-alanine ethyl ester in 600 ml of toluene is dissolved by heating to 90° C. Then 63 ml of a 20% solution of phosgene in toluene are added over 10 minutes under argon and at a temperature of 90°-95° C. Stirring at ca. 90° C. for 16 hours gives the desired solution of ethyl isocyanatopropionate, which is used direct in the above reaction.