Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:21]([C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[CH3:22]
Reactant: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g), bis(tricyclohexylphosphine)palladium(II)dichloride (332 mg), tripotassium phosphate (11 g) and vinylboronic acid pinacol ester (3 g) were added toluene (27 mL) and water (1.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). The obtained 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in ethanol (20 mL), 5% palladium carbon-ethylenediamine complex (600 mg) was added, and the mixture was stirred at room temperature for 8 hr under hydrogen atmosphere. The mixture was filtered through celite, and the solvent was evaporated from the filtrate to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg). The obtained 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg) was dissolved in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (7 ml), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (441 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:30])([CH3:29])[CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](O)=[O:21].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:20](=[O:21])[CH:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18]([CH3:30])([CH3:29])[CH3:17])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)(C)C(C(=O)O)c1ccccc1
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 3,3-dimethyl-2-phenylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.53 (dd, J=7.4, 10.9, 1H), 7.73 (dd, J=3.3, 5.3, 2H), 7.44 (d, J=7.0, 1H), 7.41-7.24 (m, 7H), 4.41-4.30 (m, 1H), 3.62 (d, J=13.1, 0.5H), 3.53 (d, J=13.1, 0.5H), 3.45 (d, J=15.0, 0.5H), 3.35 (d, J=13.1, 0.5H), 2.90 (dd, J=3.1, 8.9, 0.5H), 2.63-2.45 (m, 2.5H), 2.44-2.36 (m, 0.5H), 2.31 (d, J=6.5, 1H), 2.28 (d, J=5.3, 1H), 2.23 (d, J=5.8, 1H), 2.15 (dd, J=5.9, 12.3, 0.5H), 1.92 (dd, J=6.1, 12.2, 0.5H), 1.84 (dd, J=8.1, 12.6, 0.5H), 1.72 (ddd, J=6.5, 12.5, 18.9, 1H), 1.46-1.25 (m, 2H), 1.14 (d, J=1.8, 9H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5].Cl.[CH3:12][C:13]1[N:14]=[C:15]([C:24](Cl)=[O:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH:5][C:24]([C:15]1[S:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([CH3:12])[N:14]=1)=[O:25]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1nc(C(=O)Cl)sc1-c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)c1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
2,6-Dimethyl aniline hydrochloride (230 mg) was added to a stirred suspension of 4-methyl-5-(4-pyridinyl)-thiazole-2-carbonylchloride hydrochloride (230 mg) in dry toluene (4 ml) at room temperature, and triethylamine (1.8 ml) was added to the mixture, and was stirred at room temperature for overnight. The mixture was diluted with chloroform, washed with water, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from iso-propanol to give 2',6'-dimethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (180 mg, yield 31%) as colorless plates.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9]I)[CH2:7][S:8][C@H:3]12.[CH:16]1[C:17]2[N:18]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:20][N:21]=1.O>C(#N)C>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][N+:21]3[CH:20]=[CH:19][N:18]4[CH:22]=[CH:23][CH:24]=[C:17]4[CH:16]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)[O-])=C(CI)CS[C@H]12
Reactant: c1cc2cnccn2c1
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccn4cccc4c3)CS[C@H]12
Temperature: 0 °C
Yield: 93 %

Procedure:
2.5 g of 7-amino-3-iodomethyl-3-cephem-4-carboxylate was suspended in 30 ml of acetonitrile; and 2 ml bistrimethyl-silylacetamide was added thereto. To the mixture was added 2 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1. The reaction mixture was reacted at 10° C. for 1 hour and then cooled to 0° C. To this solution was added 0.6 ml of water; and the resulting mixture was filtered and then washed with 30 ml of cold acetonitrile to obtain 2.4 g of light yellow title compound (yield: 93%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[CH:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([SH:27])[CH:23]=[CH:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH:21]1[C:20]2[C:25](=[CH:26][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:23][C:22]=1[S:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: Sc1ccc2ccccc2c1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1CSc1ccc2ccccc2c1

Procedure:
8 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate, 4.5 g of 2-thionaphthol, 4.4 g of potassium carbonate and 100 mg of potassium iodide are refluxed for 20 hours in 200 ml of acetone. 200 ml of water is then added and extraction is carried out three times with methylene chloride. The organic phases are dried over Na2SO4 and evaporated down. The oil which remains is chromatographed on silica gel using a mixture of n-hexane and ethyl acetate. There is obtained 8.19 g of slightly yellow crystals of melting point 52°-58° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1.O.C1COCC1.ClCCl>[CH3:4][C:3]([CH3:7])([CH2:5][O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH2:2][OH:1]
Reactant: CC(C)(CO)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)COC1CCCCO1
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of neopentyl glycol (6.0 g, 57.6 mmol) and 3,4-dihydro-2H-pyran (2.64 mL, 28.94 mmol) in 2:1 THF/dichloromethane (135 mL) was added p-TsOH.H2O (100 mg, 0.53 mmol) and the reaction stirred overnight. Solid NaHCO3 was then added and after rapid stirring for 15 min the reaction was filtered and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.21 g, 59%) as a pale liquid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.FC(F)(F)S(OCC(F)F)(=O)=O>C(Cl)Cl>[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:3][CH:2]([F:7])[F:1])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:10]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(CC(F)F)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an appropriate sized vial the trifluoroacetic acid salt of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.42 (25 mg, 0.044 mmol) and triethylamine (27 mg, 0.27 mmol) were dissolved in DCM (1.5 mL). To this mixture 2,2-difluoroethyl trifluoromethanesulfonate (11 mg, 0.051 mmol) was added and mixture was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure and the residue was purified via prep HPLC (2-65% acetonitrile in water, 0.1% trifluoroacteic acid) to isolate (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.46 as a trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C(OCC)(=O)C>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCCCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-diaminobutane (8.8 g) in ethanol (100 ml) at room temperature was added a solution of 4-chloro-3-nitropyridine in ethanol (50 ml). The mixture was stirred at room temperature for 30 minutes, poured into ethyl acetate (400 ml), and then washed with water (3×150 ml). The aqueous phases were back-extracted with methylene chloride (3×120 ml) and all the organic phases were combined, dried over Na2SO4, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol containing 1% ammonium hydroxide. The fractions containing the product were combined and evaporated under vacuum to give the title compound, (4.2 g), which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(Br)n1
Product: CN(C)CCNC(=O)c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and N,N-dimethylethylenediamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.Cl.C(C1C=CC(NCCN[C@@H]2CN[C@H:49]([C:52](N3CCSC3)=[O:53])C2)=NC=1)#N.C(Cl)(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:52]([N:13]([C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:25]([N:27]2[CH2:31][CH2:30][S:29][CH2:28]2)=[O:26])[CH2:10]1)[CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)(=[O:53])[CH3:49]
Reactant: N#Cc1ccc(NCCN[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NCCNc2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCNc1ccc(C#N)cn1)[C@H]1C[C@@H](C(=O)N2CCSC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 319 (1), 800 mg] and triethylamine (0.42 mL) were dissolved in dichloromethane (20 mL), and acetyl chloride (0.18 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 5 hr. The reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with chloroform. The extract was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (786 mg) as a white solid.
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)(=O)C.[CH2:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20]>C(O)C>[CH2:22]([N:21]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:19][CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Solvent: CCO
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1

Procedure:
4-Methanesulphonamidophenethyl mesylate (10 g, 34 mmole) and N-ethylbenzylamine (10 ml, 67 mmole) were heated at reflux temperature in ethanol (80 ml) for 3 hours. The solvent was evaporated, the residue taken up in 2M hydrochloric acid and washed twice with methylene chloride. The aqueous layer was basified with sodium bicarbonate (to pH~12) and extracted with methylene chloride. The latter organic extract was dried (MgSO4) and evaporated to give an oil which solidified when triturated with diisopropyl ether. The solid was filtered off and discarded and the filtrate was evaporated in vacuo to give the title compound as an oil, yield 4.4 g.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]([CH3:12])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.O>C1C=CC=CC=1>[CH3:12][C:10]1[O:11][CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=1
Reactant: CCOC(=O)C(C=O)CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1coc(C)c1

Procedure:
The abovementioned mixture of ethyl 2-formyllevulinate and its diethyl ketal was dissolved in benzene, the catalyst was added, and the resulting solution was refluxed with a Dean-Stark trap for 3-3.5 h until the water was completely removed. The reaction mixture was then distilled under reduced pressure, resulting in 15 g (97 mmol) of ethyl 5-methylfuran-3-carboxylate, boiling point 97° C./15 mm Hg.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][Cl:27])=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.O.CO>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:16]2[S:17][C:13]3[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:11][CH:10]=[C:9]([OH:8])[C:14]=3[N:15]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Nc1nc2c(OCc3ccccc3)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1nc2c(O)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
N-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide (1.0 g, 2.0 mmol) were dissolved in CH2Cl2 (10 ml) and treated at −78° C. with tetrabutyl ammonium iodide (0.95 g, 2.6 mmol) and a solution of boron trichloride in CH2Cl2 (1M, 7.4 ml). After subsequent warming to 0° and stirring for additional 2 h, ice (2 g) and then water (10 ml) and methanol (2 ml) were added and the phases separated. The aqueous phases were extracted twice with CH2Cl2/MeOH, the combined organic layers were dried with Na2SO4 and evaporated to dryness. Recrystallization from CH2Cl2/MeOH afforded the title compound as an off-white solid (18%). MS: m/e=403 ([M−H+]−).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(Cl)Cl>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(OCCCOC2CCCCO2)cc(C(=O)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Methyl 3-tert-butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoate (O5.059; 5.37 g) was dissolved in methanol (80 ml) and THF (160 ml), and lithium hydroxide solution (61.28 ml, 1 M in water) was added. After stirring at 40° C. for 2 h, the mixture was dried, and the residue was taken up with water and freeze-dried. The product obtained was stirred with DCM, filtered and dried. 4.9 g of product were obtained.
Reaction SMILES: ClC1N=CC(C(Cl)=O)=CN=1.C(O)C.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=1.[NH2:26][NH2:27]>>[NH:26]([C:17]1[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=[CH:15][N:16]=1)[NH2:27]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: NN
Agent: O=C(Cl)c1cnc(Cl)nc1
Solvent: CCO
Product: CCOC(=O)c1cncnc1NN
Yield: 44 %

Procedure:
The title compound was prepared by (a) treating 2-chloropyrimidine-5-carbonylchloride (Example 13, 110 mg, 0.62 mmol) with ethanol (200 mg, 4.4 mmol in 1 mL of ethyl acetate) to provide 60% of ethyl 2-chloropyrimidine-5-carboxylate, (b) reaction of ethyl 2-chloropyrimidine-5-carboxylate (70 mg, 0.37 mmol) with hydrazine (100 mg, 3 mmol) to afford 44% of ethyl 4-hydrazinopyrimidine-5-carboxylate as in Example 19, (c) reaction of ethyl 4-hydrazinopyrimidine-5-carboxylate (0.36 g, 2.0 mmol) with citraconic anhydride (0.34 g, 3.0 mmol) in analogy to Example 21 to afford 10% (0.05 g) of the title compound; m.p. 95-98° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH3:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH2:27]=O.[ClH:29].[CH3:30][NH:31][CH3:32]>C(O)C>[ClH:29].[ClH:29].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][C:15]([CH2:30][N:31]([CH3:27])[CH3:32])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH3:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(CC)c3)cs2)cc1OCC
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3ccc(O)c(CC)c3)c(CN(C)C)s2)cc1OCC
Temperature: 100 °C
Reaction time: 4 h
Yield: 8.7 %

Procedure:
A suspension of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)thiazole, 1 g of paraformaldehyde and 1.1 g of dimethylamine hydrochloride in 20 ml of ethanol was stirred at 100° C. for 4 hours with heating. The solvent was distilled off. The residue was mixed with 20 ml of water and 30 ml of ethyl acetate for extraction and phase separation. The ethyl acetate layer was extracted with 10% hydrochloric acid (20 ml×3). The combined aqueous layer was made basic with 10% sodium hydroxide and extracted with dichloromethane. The extract was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=49/1). The product was dissolved in acetone, mixed with hydrochloric acid-methanol and heated. The resulting crystals were collected by filtration, dried and recrystallized from acetone to obtain 117 mg of 2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)-5-dimethylaminomethylthiazole dihydrochloride.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:30][N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C>CN(C)C=O>[OH2:3].[ClH:4].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:31]([CH3:39])[CH3:30])=[CH:33][CH:34]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)Nc1ccc(N(C)C)cc1)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Yield: 443.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.41 g, 0.019 mole) was added dropwise, slowly, to a stirred and chilled (10° C.) suspension of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole) in anhydrous dimethylformamide (75 ml). The suspension was stirred at room temperature for 30 minutes and then an additional portion of oxalyl chloride (0.73 g, 0.0057 mole) was added. The resulting solution was stirred at room temperature for 45 minutes and then added slowly to a suspension of N,N-dimethyl-1,4-benzenediamine dihydrochloride (3.97 g, 0.0019 mole) and triethylamine (7.7 g, 0.076 mole) in anhydrous dimethylformamide (150 ml). The reaction mixture was stirred at room temperature overnight under nitrogen and protected from light. The solution was then poured into 400 ml of ice water. The resulting solid was collected by filtration, rinsed with water, dissolved in hot isopropyl alcohol, filtered, and cooled to room temperature. Upon addition of water, solid precipitated. The solid was collected by filtration, dissolved in hot tetrahydrofuran, and made acidic with ethereal hydrogen chloride. The solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 50° C. to give 4.0 g (47%) of title compound, mp 186°-190° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[CH2:36][CH2:35][CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]([O:30]C)=[C:14]3[C:19]([CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:15]3=[O:29])=[C:10]2[C:9]1=[O:37])(C)(C)C.Br>C(O)(=O)C.O1CCOCC1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:16]1[CH2:17][CH2:18][C:19]2[C:14](=[C:13]([OH:30])[C:12](=[O:32])[N:11]3[CH2:33][CH2:34][CH2:35][CH2:36][N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9](=[O:37])[C:10]3=2)[C:15]1=[O:29]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CC(=O)OC(C)(C)C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl[11-(3-chloro-4-fluorobenzyl)-9-methoxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-decahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetate (50 mg, 0.09 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and Iyophilization of appropriate fractions afforded the title compound.