Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]([CH3:36])[C:16](=[O:35])[CH2:17][O:18][C:19]3[N:24]=[C:23]([CH3:25])[C:22]([NH:26]C(=O)OC(C)(C)C)=[C:21]([CH3:34])[N:20]=3)[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:26][C:22]1[C:23]([CH3:25])=[N:24][C:19]([O:18][CH2:17][C:16]([N:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:10][CH2:11]2)[CH3:36])=[O:35])=[N:20][C:21]=1[CH3:34]
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(CC3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CCCCC3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
6N HCl (0.7 mL) was added to a chloroform (0.5 mL) solution of Compound 32 (39 mg) and the mixture was stirred at room temperature for 1 hour. While the reaction mixture was cooled with ice, a 4N aqueous sodium hydroxide solution was added to neutralize the mixture. The resulting product was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd., NH-DM1020) column chromatography (ethyl acetate) to give 23 mg (76% yield) of the title compound.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12>CN(C)C=O>[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([CH2:5][CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of N-(2-chloroethyl)pyrrolidine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which crystallizes on trituration with ether. Recrystallization from ethyl acetate-hexane gives white crystals, m.p. 139°-141°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:8][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=2)=[O:27])=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2.33 g (11.8 mmol) of 3,5-dinitrobenzylalcohol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 6.9 g of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [CH2:1]([P:4](=[O:10])([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CCOCC>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH2:5][P:4]([CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH3:3])=[O:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCP(=O)(CO)CCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCP(=O)(CCC)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To dipropyl hydroxymethylphosphine-oxide (Ref. U.S. Pat. No. 5,272,128) (16.4 g, 0.1 mol) in anhydrous ether (200 mL) at 0° C., was added p-toluenesulfonyl chloride (19.1 g, 0.1 mol), triethyl amine (27.8 mL, 0.2 mol). The reaction was stirred at room temperature over night. The ether solution was decanted, and the precipitate was washed in a filter funnel with ˜1 L ether until HPLC found no product. Combined ether layer were concentrated. The crude product was purified on silica gel chromatography with 8% MeOH/DCM.
Reaction SMILES: Cl[CH:2]([C:6]1[C:15]([C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])=[C:14]([OH:24])[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[CH:11][CH:12]=2)[N:7]=1)[CH2:3][O:4][CH3:5]>O1CCCC1>[CH3:5][O:4][CH2:3][CH:2]1[C:6]2=[N:7][C:8]3[CH:9]=[C:10]([Cl:25])[CH:11]=[CH:12][C:13]=3[C:14]([OH:24])=[C:15]2[C:16](=[N:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:17]1
Reactant: COCC(Cl)c1nc2cc(Cl)ccc2c(O)c1C(=O)Nc1nccs1
Solvent: C1CCOC1
Product: COCC1OC(=Nc2nccs2)c2c1nc1cc(Cl)ccc1c2O
Yield: 65 %

Procedure:
Using the procedure of Step C of Example 1, the product of Step B was reacted at reflux for 24 hours in tetrahydrofuran to obtain a 65% yield of 1,3-dihydro-3-methoxymethyl-1-[(2-thiazolyl)-imino]-6-chloro-furo[3,4-b]-quinoline-9-ol melting at >270° C.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([OH:8])[CH:6]=[CH2:7].C([O:11][C:12]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)=O)C>>[CH2:5]([O:8][C:12]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)=[O:11])[CH:6]=[CH2:7]
Reactant: C=CCO
Reactant: CCOC(=O)Cc1csc2cncn12
Agent: CC[O-]
Agent: [Na+]
Product: C=CCOC(=O)Cc1csc2cncn12

Procedure:
A 30 mg potion of a sodium ethoxide powder was added to 6.2 ml of an allyl alcohol solution containing 314.2 mg of 3-ethoxycarbonylmethylimidazo[5,1-b]thiazole, and the mixture was then was then heated under reflux for 7 hours. After cooled, the reaction solution was concentrated under reduced pressure, and the organic layer extracted with dichloromethane (10 ml×4) was dried over anhydrous magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 240.4 mg of the title compound as a colorless solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28]1[C:29](=[O:64])[NH:30][C:31](=[O:63])[C:32]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=1>C1COCC1>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28]1[C:29](=[O:64])[NH:30][C:31](=[O:63])[C:32]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH2:44][OH:45])[CH:34]=1
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cc4ccccc4o3)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cc2ccccc2o1
Reaction time: 18 h
Yield: 89 %

Procedure:
TBAF (0.1 mL, 0.1 mmol; 1 M solution in THF) was added dropwise to a solution of 3-benzofuran-2-yl-4-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dione Compound 17a (0.04 g, 0.064 mmol) in THF (1 mL) under nitrogen. After 18 hours, the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 25 (0.022 g, 89%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.32 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (s, 1H), 7.77 (m, 1H), 7.65 (s, 1H), 7.57 (dd, J=7.9, 1.3 Hz, 1H), 7.29 (m, 3H), 7.02 (dd, J=7.9, 4.5 Hz, 1H), 4.47 (t, J=6.9 Hz, 2H), 3.5 (t, J=6.0 Hz, 2H), 2.05 (m, 2H); MS (ES) m/z: 388 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH2:16][CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:31][CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH:16]([CH2:31][CH:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Reactant: ICC1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(CC2CCOC2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (285 mg, 0.89 mmol) in anhydrous tetrahydrofuran (6 ml) at −78° C. under an atmosphere of nitrogen is added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.55 ml, 1.0 mmol) dropwise over a period of 5 minutes and the reaction allowed to stir at −78° C. for 30 minutes. A solution of 3-iodomethyl tetrahydrofuran (212 mg, 1 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-5-(tetrahydro-furan-3-ylmethyl)-cyclopent-2-enone (150 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 134.3 %

Procedure:
To a mixture of 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (246 mg) and aminoguanidine hydrochloride (98 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 1.5 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 161) (215 mg) as gray white crystals.
Reaction SMILES: C([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[O:33]1C[CH2:36][CH2:35][CH2:34]1>>[CH:4]1([C:6]([O:8][CH2:9][CH2:10][CH:36]=[CH:35][CH:34]=[O:33])=[O:7])[CH2:3][CH2:5]1
Reactant: CCOC(=O)C1CC1C=O
Reactant: C1CCOC1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=CC=CCCOC(=O)C1CC1
Yield: 80 %

Procedure:
A mixture of ethyl 2-formyl-1-cyclopropanecarboxylate (55 g, 0.39 moles) and formylmethylenetriphenylphosphorane (117.7 g, 0.39 moles) in tetrahydrofuran (600 ml) is refluxed for 40 hours. The solvent is removed under reduced pressure. The residue is triturated with ether/hexane (1:1) and filtered. The filtrate is evaporated, dissolved in ether/petroleum ether and filtered through a column of silica gel. The solvent is stripped from the filtrate to give a dark oil. The oil is distilled under reduced pressure to give the product as a clear colorless oil (52.1 g, 80%), b.p. 105°-113° C. (2.0 mm).
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:1][CH3:2])[CH:11]=[CH:12][CH:13]=1
Reactant: CCBr
Reactant: O=Cc1cccc(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)c1cccc(F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
18 L ethyl bromide were dissolved in 30 L of THF and added dropwise to a suspension of 6 kg of magnesium in 30 L of THF. The reaction solution was next stirred for two hours at 65° to 75° C. and then cooled to 0 to 10° C. 15 kg of 3-fluorobenzaldehyde in 60 L of THF were added while cooling with ice over a period of 6 hr and the reaction solution was stirred overnight at room temp. The reaction solution was quenched with saturated ammonium chloride solution at 0°-10° C. The reaction solution was stirred for one hour, organic layer separated and concentrated. The concentrate was extracted with 40 L of DCM and washed with 30 L of 5% HCl solution. The solvent was removed in vacuo. After drying, 20 kg of 1-(3-Fluoro -phenyl)-propan-1-ol were obtained as a brown oil and taken as such to the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[C:22]1([CH:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[K+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:30]([CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29])[CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: CCOC(=O)CCCNC(C)c1ccccc1
Reactant: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)N(CCCC(=O)O)C(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2-furoyl)-2-(p-anisidino)propionic acid and ethyl 4-(1-phenylethylamino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(1-phenylethylamino)butyric acid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[N:10]=1>CN(C=O)C>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[N:10]=1
Reactant: COCCO
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Sodium hydride (60 wt % dispersion in mineral oil, 2.51 g, 62.8 mmol) (Aldrich) was added to a stirred mixture of anhydrous 2-methoxyethanol (Aldrich, 2.87 mL, 36.4 mmol) and DMF (30 mL) at 0° C. After 30 min of stirring at 0° C. the reaction mixture turned into a white solid. It was then treated with 2,6-difluoropyridine (3.00 mL, 33.1 mmol) (Aldrich) and allowed to warm to room temperature over 1.5 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 and stirred for 1 h, partitioned between EtOAc and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (40 g column, 0-5% EtOAc in hexanes) to give 2-fluoro-6-(2-methoxyethoxy)pyridine (3.0769 g, 17.98 mmol, 54% yield) as a viscous, clear colorless oil. m/z (ESI, +ve ion) 172.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.64 (1H, q, J=8.2 Hz); 6.67 (1H, dd, J=8.0, 1.0 Hz); 6.46 (1H, dd, J=7.8, 2.3 Hz); 4.41-4.47 (2H, m); 3.70-3.76 (2H, m); 3.44 (3H, s).
Reaction SMILES: CCOCC.[C:6]1([CH3:16])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH:13]([CH3:15])[CH3:14].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C.O>[CH:13]([O:12][C:7]1[CH:8]=[CH:9][C:10]([N+:24]([O-:26])=[O:25])=[CH:11][C:6]=1[CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccccc1OC(C)C
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1OC(C)C
Temperature: 6 °C
Reaction time: 12 h

Procedure:
To a chilled (6° C.) solution contaning 31.8 g (0.2 mol) of the ether prepared as in (a) above and 28.7 g of acetic anhydride in 200 ml of glacial acetic acid was added dropwise a solution of 13.9 g (0.22 mol) of 90% nitric acid in 100 ml of glacial acetic acid. The reaction mixture was allowed to stand at ambient temperature for 12 hours, poured into water and extracted with methylene chloride. The extract was washed with 5% sodium carbonate, water, dried, and concentrated to give 21.8 g of product as an amber oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1.N1C=CC=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:13]1([CH3:12])[CH:21]=[CH:20][C:16]([C:17]2[O:1][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:15][CH:14]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a suspension of 3-hydroxyanthranilic acid (0.153 g, 1 mmol) in toluene (10 mL) was added 4-methylbenzoylchloride (0.464 g, 3 mmol) followed by pyridine (0.275 g, 3.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes then heated to 80C for 1 hr. After this time the reaction was cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (20 mL). Subsequent separation of the layers, drying the organic over MgSO4 and filtration afforded a solution. After removal of the solvent, the residue was dissolved in xylenes (20 mL) and the solution treated with p-TsOH (0.4 g, 2.1 mmol). The reaction mixture was then heated to reflux overnight. After this time the reaction was cooled and poured into water (100 mL), the organic layer separated then washed with water (100 mL). The organic was dried over MgSO4, filtered and concentrated to a solid. Recrystallization of this solid from ethyl acetate gave a white solid product, 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.15 g, 60% yield). MS (ESI) m/e 254 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C[O:22][C:23](=[O:28])[C:24]([NH2:27])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:27][C:24]([CH3:26])([CH3:25])[C:23]([OH:28])=[O:22])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NC(C)(C)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-1 a) and b) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride; MS-(+)-ion: M+1=367.0 amu.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cnccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cnccc2[nH]1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 1H-imidazo[4,5-c]pyridine-2-thiol (4 g) in acetone (50 mL) were added potassium carbonate (11 g) and MeI (1.8 ml). After stirring for 3 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-70% EtOAc in hexane) to give 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]3[N:26]=[C:22]([C:20]([NH:19][C@@H:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])[S:23][CH:24]=3)=[CH:28][CH:29]=2)=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3F)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chloro-2-fluoro-1-isocyanatobenzene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 9.281 (s, 1H), 8.824-8.796 (d, J=8.4 Hz, 1H), 8.703 (s, 1H), 8.330 (s, 1H), 8.227-8.168 (t, J=8.7, 9 Hz, 1H), 8.069-8.040 (d, J=8.7 Hz, 2H), 7.589-7.560 (s, J=8.7 Hz, 2H), 7.508-7.463 (d, J=2.1, 11.1 Hz, 1H), 7.268-7.238 (d, J=9 Hz, 1H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.341-2.273 (m, 1H), 1.000-0.953 (t, J=6.9, 7.2 Hz, 6H); MS (ESI) m/z 503 (M−H), 505 (M+H)+.
Reaction SMILES: [S:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[Cl:29][C:25]1[N:24]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:7](=[O:9])[CH:6]4[S:1][CH:2]([CH2:3][CH2:4][CH2:5]4)[C:10]3=[O:11])[CH2:22][CH2:21]2)[CH:28]=[N:27][CH:26]=1
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Reactant: O=C1OC(=O)C2CCCC1S2
Solvent: ClCCl
Product: O=C1C2CCCC(S2)C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1

Procedure:
Tetrahydrothiopyran-2,6-dicarboxylic anhydride (3.7 g., 21 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (5.63 g., 21 mmole) were combined in 200 ml. of methylene chloride and stirred for 30 minutes at room temperature. The solvent was removed in vacuum and 200 ml. of toluene added. The mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. Upon cooling, the reaction was concentrated to an oil and this was dissolved in 2% ethanol/chloroform and filtered through silica gel. The fractions which contained the product were concentrated in vacuum and the resulting residue was recrystallized from isopropyl alcohol with the addition of 4N isopropanolic HCl. 0.6 Grams of the title compound was obtained as the hydrochloride, hydrate; m.p. 248°-250° C.