Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:5]=[CH:4][N:3]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCn1c2ccccc2c2cc(Nc3ccnc(Cl)n3)ccc21

Procedure:
Briefly, 2,4-dichloropyrimidine (1) was reacted with 3-amino-9-ethylcarbazole (2) by heating in iso-propanol in the presence of N,N-diisopropylethylamine. Separation of the regioisomers provided the pure 4-substituted pyrimidine derivative (3), which was reacted with 4-(3-Aminopropyl)morpholine (4) in sec-butanol under microwave heating in the presence of N,N-diisopropylethylamine to provide EHop-016 (5).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 36.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.7 mg) was obtained.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[C:10]([S:24][CH2:25][CH3:26])=[N:11][C:12]2[C:17]([C:18]=1[CH3:19])=[CH:16][CH:15]=[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=2)=[O:8])C.C1COCC1.CO>O>[C:20]([C:14]1[CH:13]=[C:12]2[C:17]([C:18]([CH3:19])=[C:9]([C:7]([OH:8])=[O:6])[C:10]([S:24][CH2:25][CH3:26])=[N:11]2)=[CH:16][CH:15]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(C)(C)C)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCSc1nc2cc(C(C)(C)C)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A solution of 600 mg (14.36 mmol) lithium hydroxide monohydrate in water (30 ml) was added to a solution of 1.7 g (5.1 mmol) 7-tert-butyl-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid ethyl ester in a THF/methanol blend (2:1 vv, 30 ml) and then the reaction solution was stirred for 16 h at 60° C. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and washed with EE. The aqueous phase was adjusted to pH 2 with 1M hydrochloric acid and then extracted with EE. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 420 mg (1.38 mmol, 27%) 7-tert-butyl-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:23]1(/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:6][CH:7]=2)=[C:12](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:13]([F:16])([F:15])[F:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: C1COCCN1
Product: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 3.34 g (7.5 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, and 13 g of morpholine is boiled for one hour. The reaction mixture is processed as described in Example 1, and the crude product is crystallized from hexane. 2.80 g (82.4%) of the aimed compound are obtained; m.p.: 84°-89° C.
Reaction SMILES: CO.C(OC([NH:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:19][C:18]=1[Cl:34])[CH2:12][OH:13])=O)(C)(C)C>C(OCC)(=O)C>[ClH:34].[NH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)=[CH:19][C:18]=1[Cl:34])[CH2:12][OH:13]
Reactant: CC(C)(C)OC(=O)NC(CO)CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: NC(CO)CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.3 %

Procedure:
To a methanol solution (5 mL) of the compound of Example 39 (0.27 g), ethyl acetate containing 3 mol/L hydrochloric acid (5 mL) was added and the mixture was stirred in an ice bath. The mixture was allowed to warm to room temperature and was left overnight. Subsequently, the solvent was removed under reduced pressure to give the desired product as a colorless powder (0.22 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([OH:11])[CH:6]2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:10]1[CH2:9][O:8][CH:7]2[CH:3]([O:2][CH3:1])[CH2:4][O:5][CH:6]12)(=[O:22])=[O:21]
Reactant: COC1COC2C(O)COC12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COC2C(OS(C)(=O)=O)COC12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-ol (1.03 g, 6.43 mmol) in anhydrous DCM (30 mL) were added N,N-diethylethanamine (1.3 mL, 9.4 mmol) and methanesulfonyl chloride (0.58 mL, 7.5 mmol). The reaction was stirred at rt for 6 h. The reaction was quenched with NaHCO3 (sat, 50 mL), and then extracted with EtOAc (80 mL×3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as colorless oil (1.1 g, 71.9%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([N+:11]([O-])=O)=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:14]>CO.[Ni]>[NH2:11][C:7]1[C:6]2[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Cn1c(=O)[nH]c2ccnc([N+](=O)[O-])c21
Agent: [Ni]
Solvent: CO
Product: Cn1c(=O)[nH]c2ccnc(N)c21
Reaction time: 1 h

Procedure:
To a nitrogen inerted slurry of 2.24 g (11.5 mmol) of 3-methyl-4-nitro-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 25 mL of methanol was added 0.5 mL of Raney nickel (50% slurry in water). The reaction slurry was purged with hydrogen and then stirred under balloon pressure hydrogen for 1 h. To the reaction slurry was added 20 mL of methanol and the reaction slurry was purged with hydrogen and then stirred under balloon pressure hydrogen for 2 h.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[C:33]([SH:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:34][C:33]3[N:25]=[CH:26][N:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[N:29]4)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncnc4nc[nH]c34)s2)c(C(=O)C2CCCC2)c1
Yield: 25.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(7H-purin-6-ylsulfanyl)-thiazol-2-yl]-urea (124 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 7H-purine-6-thiol (304 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:26]([CH2:40][O:41]C(=O)C)=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[CH2:40][OH:41]
Reactant: CC(=O)OCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(CO)c(Cl)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 169.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and acetic acid 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (Stage 238.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.27 min (Method A); M+H=435 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.65-8.62 (m, 1H), 8.18-8.11 (m, 2H), 8.05-8.00 (m, 1H), 7.97-7.94 (m, 1H), 7.58-7.55 (m, 1H), 5.30 (t, 1H), 4.67 (d, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[K+:13]>C(O)C>[CH:9]1[CH:10]=[C:2]2[C:1]([N-:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=1)=[O:11].[K+:13]
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1[N-]C(=O)c2ccccc21
Temperature: 0 °C

Procedure:
In a 1-liter three-neck round bottom flask, phthalimide (50 g) was suspended in ethyl alcohol (500 ml) and cooled to about 0° C. under stirring. A solution of alcoholic KOH (19 gm in 150 ml alcohol) was added slowly over a period of 15-20 mins., while keeping the mass temperature at 0°-5° C. After the addition was complete, the reaction mixture was stirred for 1/2 hour at 0°-5° C. and then filtered.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN1C(=O)N(C)CCC1.O>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:7]=[C:6]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)[N:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1cc(C)cc(-c2cc(-c3cc(C)cc(C)c3)ncn2)c1
Reaction time: 1 h

Procedure:
First, 5.97 g of 4,6-dichloropyrimidine, 12.04 g of 3,5-dimethylphenylboronic acid, 8.48 g of sodium carbonate, 0.34 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (abbreviation: DMPU) were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.58 g of 3,5-dimethylphenylboronic acid, 1.78 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of DMPU, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=O.Cl.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.[CH2:22](O)[CH3:23].S(=O)(=O)(O)O>O>[CH2:22]([O:8][C:1](=[O:7])[CH2:2][C:3]1[C:16]2[C:15](=[CH:14][CH:13]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:17]=2)[NH:18][C:4]=1[CH3:6])[CH3:23]
Reactant: CCO
Reactant: CC(=O)CCC(=O)O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(C(F)(F)F)cc12

Procedure:
A stirred mixture of 11.6 g. of levulinic acid, 21.3 g. of 4-trifluoromethylphenylhydrazine hydrochloride, 125 ml. of ethanol and 10 ml. of concentrated sulfuric acid is heated under reflux for 24 hours. The reaction mixture is poured onto chopped ice and water. A precipitate forms and is collected by filtration to give ethyl-2-methyl-5-trifluoromethyl-3-indoleacetate.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([OH:15])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([NH:29][NH2:30])=[O:15])=[CH:5][N:4]=1
Reactant: CCCNc1nc(SC)ncc1C(=O)O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(SC)ncc1C(=O)NN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
2-Methylthio-4-n-propylaminopyrimidine-5-carboxylic acid (22.6 g) obtained in Step 1 was dissolved in THF (360 mL), then carbonyldiimidazole (16.9 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, a THF (100 mL) solution of hydrazine monohydrate (14.5 mL) was added dropwise to the reaction mixture over 30 minutes, followed by stirring at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture. Precipitated crystals were collected by filtration and the resulting crystals were washed with water and dried thoroughly under reduced pressure to give 2-methylthio-4-n-propylaminopyrimidine-5-carbohydrazide (20.1 g, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH3:49])[N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:43][C:44]1[S:45][CH:46]=[C:47]([CH3:49])[N:48]=1)=[O:41]
Reactant: Cc1csc(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)cs4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-4-methylthiazole (60 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 15 mg of the title compound.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([C:17]3([OH:21])[CH2:20][CH2:19][CH2:18]3)=[N:14][CH:13]=2)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:9][C:7]1[CH:6]=[C:5]([C:12]2[S:16][C:15]([C:17]3([OH:21])[CH2:20][CH2:19][CH2:18]3)=[N:14][CH:13]=2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)cc(-c2cnc(C3(O)CCC3)s2)c1
Yield: 83.5 %

Procedure:
Water (2.617 mL) and ethanol (5.235 mL) were added to the product of Step 2 (610 mg, 49.3%), followed by ammonium chloride (52.5 mg, 0.981 mmol) and then iron (548 mg, 9.81 mmol) and the reaction was heated to 80° C. for 1 hour. The reaction mixture was filtered and diluted with ethyl acetate before washing with water, filtering off solids and drying over Na2SO4. Filtration and solvent evaporation gave a residue which was further purified by column chromatography on silica gel, eluting with ethyl acetate/hexane with a gradient 40-50% to afford 1-[5-(3-amino-5-chlorophenyl)-1,3-thiazol-2-yl]cyclobutanol (460 mg, 83%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]#[N:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1N1CCCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with piperidine to obtain 4-piperidino-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 339.3. This compound is reacted with calcium oxide to obtain the corresponding calcium salt, m.w., 716.6.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:18]([CH2:19][CH3:10])[CH2:17][CH3:16])[CH:16]=1)[CH:11]=2)[CH3:27]
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CCCOc1ccc2cc3ccc(OCCCN(CC)CC)cc3nc2c1
Temperature: 100 °C

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and diethylamine as described in Example 15 except that the mixture is heated at 100° C. for 24 hours, giving 1.5 g. of the desired product as yellow crystals, m.p. 235°-236° C.
Reaction SMILES: Cl.C([O:6][C:7](=[O:36])[CH2:8][N:9]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)(C)(C)C.[C:37]([C:41]([OH:43])=[O:42])([F:40])([F:39])[F:38]>C1(C)C=CC=CC=1>[F:38][C:37]([F:40])([F:39])[C:41]([OH:43])=[O:42].[Cl:35][C:25]1[C:24]2[C:29](=[CH:30][C:21]([S:18]([N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH2:8][C:7]([OH:36])=[O:6])(=[O:20])=[O:19])=[CH:22][CH:23]=2)[C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[N:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(Cl)c1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccc(Cl)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine t-butyl ester hydrochloride (60 mg, 0.104 mmol) was dissolved in CF3CO2H (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was dissolved in Et2O and stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with Et2O and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine trifluoroacetate (31 mg, 0.052 mmol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:34][CH3:35])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH:26]([CH3:28])[CH3:27])=[C:24]([CH:29]=O)[NH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:20])[CH3:13]>>[CH2:34]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH:26]([CH3:28])[CH3:27])=[C:24]([CH:29]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:20])[CH3:35]
Reactant: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=O)c1C(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(C)C
Yield: 24.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (90 mg, 0.42 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (140 mg) to give 54 mg (25%) of the title compound as red-brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.Cl.Cl.[CH3:40][N:41]1[CH:46]2[CH2:47][CH2:48][CH:42]1[CH2:43][CH:44]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:45]2>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:52]1[CH2:53][CH2:54][N:49]([CH:44]2[CH2:45][CH:46]3[N:41]([CH3:40])[CH:42]([CH2:48][CH2:47]3)[CH2:43]2)[CH2:50][CH2:51]1)=[O:14])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1C2CCC1CC(N1CCNCC1)C2
Agent: Cl
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 320 mg (1.00 mmol) 8-methyl-3-piperazin-1-yl-8-aza-bicyclo[3.2.1]octane trihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12]O)=[N:8][C:7]([S:17]CC3C=CC=CC=3)=[N:6][C:5]=2[N:25]=1.[Na]>N>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@@H:11]([CH2:14][CH2:15][CH3:16])[CH3:12])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:25]=1
Reactant: CCC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: [Na]
Product: CCC[C@@H](C)Nc1nc(S)nc2nc(N)sc12
Temperature: -33 °C
Reaction time: 0.01 h
Yield: 85.1 %

Procedure:
A round-bottomed flask was equipped with a dry ice-ethanol condenser and immersed in a dry ice-ethanol cooling bath. Ammonia (250 mL) was condensed into the flask followed by the addition of (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}pentan-1-ol (6.8 g, 18.1 mmol). The resulting mixture was allowed to warm to −33° C. and sodium metal was added in small pieces until a blue colour appeared and persisted for 30 seconds. The reaction was then quenched by addition of a spoon of solid ammonium chloride. The ammonia was evaporated off and water (250 mL) was added to the residue. The resulting mixture was neutralized with 1M hydrochloric acid (aq.). The precipitated product was collected by filtration, washed with water and dried in vacuo to yield 4.15 g (80% yield) of the title compound.