Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CC(O)=O>[C:14]([O:17][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (6.5 g; 21 mmol; 1 eq.) in AcOH (32.5 mL) was added sodium acetate (3.46 g; 42 mmol; 2 eq.) and the reaction mixture was stirred at 100° C. for 12 hours. After concentration in vacuo, the residue was partitioned between Ethyl acetate and water. The organic layer was washed with 5% aq. NaHCO3 then brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 5/1) afforded the title compound (4.78 g, 79%) as a white solid.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:61])[CH2:31][C:32]1[C:33](=[O:60])[N:34]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:61])[CH2:31][C:32]1[C:33](=[O:60])[N:34]([CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][NH2:45])[CH:36]=2
Reactant: COC(=O)Cc1cc2ccc(OCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: COC(=O)Cc1cc2ccc(OCCN)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester is replaced with [7-(2-tert-butoxycarbonylaminoethoxy)-1-benzyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:31][S:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25][CH2:31][S:32][CH3:33])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CSCCl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3CC(=O)O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
A mixture of compound 38 (0.2 g, 0.471 mmol), chloromethylmethylsulfane (0182 g, 1.89 mmol) and potassium carbonate (0.324 g, 2.36 mmol) in DMF (5 mL) was stirred at room temperature for 1 h, then heated to 100° C. for 10 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over sodium sulphate and concentrated. The crude reaction mixture was purificated by prep HPLC to afford 41 (15 mg, 7%). LCMS: 485.20 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 8.06 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8 Hz), 7.93 (d, 2H, J=8.4 Hz), 7.8-7.6 (m, 3H), 6.75 (s, 1H), 5.10-5.25 (m, 2H), 3.45-3.3 (m, 2H), 3.30 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Mg]Cl)C=CC=CC=1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)C=O
Reactant: O=[N+]([O-])c1cc(I)ccc1I
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1,4-diiodo-2-nitrobenzene (3.0 g, 8.0 mmol) in anhydrous THF (20 mL) was cooled to minus 40° C., and then a solution of phenylmagnesium chloride (2 M in THF, 4.8 mL, 9.6 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for ten minutes, followed by addition of trimethylacetaldehyde (1.2 mL, 11.2 mmol), and the mixture was stirred for 30 minutes at minus 40° C. The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (60 mL), poured into water (120 mL), and extracted with ethyl acetate twice (60 mL each). The combined organic phase was washed with water (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 81%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1 H, J=1.6 Hz, Ph-H), 7.88 (dd, 1 H, J=1.6 and 8.4 Hz, Ph-H), 7.51 (d, 1 H, J=8.4 Hz, Ph-H), 5.28 (d, 1 H, J=3.6 Hz, Ph-CH), 2.29 (d, 1 H, J=3.6 Hz, OH), 0.85 (s, 9 H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ 149.87 (C), 141.0 (CH), 136.2 (C), 132.3 (CH), 131.63 (CH), 91.85 (C), 74.33 (CH), 36.81 (C), 25.6 (CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:28]([C@@H:30]2[CH2:32][C@H:31]2[CH2:33][C:34]([O:36]CC2C=CC=CC=2)=[O:35])=[O:29])=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:28]([C@@H:30]2[CH2:32][C@H:31]2[CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@@H]1C[C@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C(=O)[C@@H]1C[C@H]1CC(=O)O)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of benzyl 2-((1S,2R)-2-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)acetate (63 mg, 0.10 mmol) and 10% palladium-carbon (11.1 mg, 0.10 mmol, 50%, wet) in MeOH (20 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (40.0 mg, 0.077 mmol, 74.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:7]([CH2:8][Cl:13])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(CO)c1
Reactant: O=S(Cl)Cl
Product: Cc1cnc(Cl)c(CCl)c1

Procedure:
comprising reacting 2-chloro-3-hydroxymethyl-5-methylpyridine with thionyl chloride to give 2-chloro-3-chloromethyl-5-methylpyridine, followed by reacting the 2-chloro-3-chloromethyl-5-methylpyridine thus obtained with 2-nitroimino-1,3-diazacyclopentane in the presence of a base and an organic solvent, to give 1-(2-chloro-5-methyl-3-pyridylmethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(=O)(O)O.[CH3:15][CH:16]([CH3:29])[CH2:17][CH2:18][C:19](=O)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].BrC(CCC(C)C)C(C1C=CC=CC=1)=O.[ClH:45]>CO.CCO.[Zn]>[ClH:45].[ClH:45].[CH3:15][CH:16]([CH3:29])[CH2:17][CH2:18][CH:19]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:21]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)CCC(=O)C(=O)c1ccccc1
Agent: CC(C)CCC(Br)C(=O)c1ccccc1
Agent: Cl
Agent: O=S(O)O
Solvent: CO
Solvent: CCO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 31 %

Procedure:
To a refluxing mixture of 1-(3-aminopropyl)piperidine (284 mg, 2 mmol), sulfurous acid (6% SO2 aqueous solution) (1.1 ml) and zinc dust (200 mg) in methanol (2.5 ml) was added dropwise over a period of 1 hour a solution of 5-methyl-1-phenylhexane-1,2-dione [bp: 104°-107° C./2 mmHg; prepared from 2-bromo-5-methyl-1-phenylhexan-1-one by a known method {N. Kornblum and H. W. Frazier: J. Am. Chem. Soc., 88, 865 (1966)}] (275 mg, 1.35 mmol) in methanol (1.0 ml). Thereafter, 200 mg of zinc dust and 1.8 ml of sulfurous acid were freshly added to the mixture and the resulting mixture was refluxed for further 2 hours. After cooling, methanol was added to the mixture and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in 2N-HCl. The resulting solution was washed three times with ether and then basified with an aqueous sodium hydroxide solution, followed by extraction with ether. The combined ethereal extract was washed twice with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 0.43 g of oily matter. To an ethanol solution of the matter was added 6N-HCl in EtOH (0.64 ml) and the solution was allowed to stand. Precipitated crystals were collected by filtration and washed with ethanol to obtain 170 mg of the title compound as white crystals (yield: 31%).
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([CH3:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH3:18][CH:12]1[C:11]2[C:10]3[CH2:19][CH2:20][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)CC3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1CCc2ccc3c(c21)CCNCC3
Temperature: 60 °C

Procedure:
Into a glass vial, the product from step (c) dissolved in CHCl3 (3 ml) was placed. To this solution, TMSI (0.31 ml, 2.3 mmol) was added. The reaction mixture was heated to 60° C. for 4 h and then allowed to cool to room temperature. The reaction mixture was quenched by addition of 2N HCl (5 ml) and further diluted with water (25 ml). The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was basified by addition of 5N KOH to pH 10. The basic solution was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title product. 1H NMR (CDCl3) δ 6.95 (d, J=7.5 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 3.36-3.27 (m, 1H), 3.08-2.90 (m, 7H), 2.82-2.74 (m, 1H), 2.27-2.16 (m, 1H), 1.89 (bs, 1H), 1.80-1.73 (m, 1H), 1.33-1.22 (m, 2H), 1.12 (d, J=6.9 Hz, 3H); MS: ESI (positive): 202 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:22](OC)(OC)OC.C(OC)(OC)(OC)CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[N:12]1([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:22]1
Reactant: COC(OC)OC
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)C(C)(C)Cn1cnc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Ethyl 3-(3-aminoquinolin-4-ylamino)-2,2-dimethylpropanoate (see Example 26 Parts A through D, 5.3 g, 18 mmol) was treated according to a modification of the method described in Part B of Example 8 using trimethyl orthoformate in lieu of trimethyl orthobutyrate. Prior to the addition of trimethyl orthoformate (3.0 mL, 27 mmol) and pyridinium p-toluenesulfonate (0.050 g), the reaction was heated at reflux for 15 minutes. The reaction was heated at reflux overnight, allowed to cool to ambient temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL), and extracted with water (45 mL) containing 10% hydrochloric acid (5 mL). The acidic extract was made basic with the addition of potassium carbonate and then extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 4.3 g of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as an oil.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:31][CH2:32][CH2:33][O:34]C)=[N:18][C:19]3[C:24]([C:25]=2[CH3:26])=[CH:23][CH:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[O:15])[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:31][CH2:32][CH2:33][OH:34])=[N:18][C:19]3[C:24]([C:25]=2[CH3:26])=[CH:23][CH:22]=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=3)=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(OCCO)nc2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
9.2 ml (9.2 mmol, 1M in DCM) boron tribromide was added in drops at −50° C. to a solution of 399 mg (0.9 mmol) N-[(3-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-7-(trifluoro-methyl)-quinoline-3-carboxylic acid amide (Example 7) in DCM (8 ml). The mixture was subsequently heated to 0° C. within 2 h and stirred for 1 h at 0° C. The mixture was then stirred for 1 h at 10° C. It was thereafter quenched with a 0.5 M aq. NaHCO3 sol. and diluted with MeOH and DCM. The organic phase was separated and washed with a 10%-strength aq. Na2S2O3 sol., dried over MgSO4 and concentrated in a vacuum. After crystallisation (EtOAc/hexane 1:1) of the residue, 109 mg (0.3 mmol, 29%) N-[(3-fluorophenyl)-methyl]-2-(2-hydroxy-ethoxy)-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 9) was obtained. MS: m/z 423.1 [M+H]+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)C.[CH2:34]([NH2:36])[CH3:35].O1CCCC1>>[CH2:34]([NH:36][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)[CH3:35]
Reactant: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4nc(C)ns4)c3c2)nc1)OCC
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCOc1ccc(Oc2ccc3ncnc(Nc4nc(C)ns4)c3c2)nc1

Procedure:
Using 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)quinazoline-4-amine obtained in Example 47 and 2 M ethylamine/tetrahydrofuran solution, and in the same manner as in Example 47 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (24 mg) was obtained as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCCCCCNC(=O)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCNC(=O)N(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.6 g (17.6 mmol) 3-(3-pyridyl)-acrylic acid, 1.8 ml (20.8 mmol) oxalyl chloride and 5.0 g (16.0 mmol) 6-(3,3-diphenyl-ureido)-hexylamine.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]2[CH2:9][O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>ClCCl>[OH:16][CH2:1][C:2]1[N:7]=[C:6]2[CH2:9][O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c([n+]1[O-])COC2=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCc2nc(CO)ccc21
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one N-oxide (122 mg, 0.74 mmol) in dichloromethane (2 mL) is heated at reflux. Trifluoroacetic anhydride (1.5 mL, 10 mmol) is added dropwise and heating is continued for approximately 30 min. The reaction mixture is cooled and concentrated. The residue is treated with methanol (3 mL) and triethylamine (2 mL) and stirred until no starting material remained. The reaction mixture is concentrated and the residue is purified by chromatography (silica gel). The product containing fractions are concentrated to give the title compound (70 mg, 42%).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(N(CCc2ccc(F)cc2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 4-fluorophenethylbromide (1.38 g, 6.8 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:61]=[CH:62][C:63]([NH2:66])=[N:64][CH:65]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:59][C:60]1[CH:61]=[CH:62][C:63]([NH:66][C:21]([C@@H:20]2[CH2:19][CH2:18][N:17]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[N:16]2[C:14](=[O:15])[C@@H:13]([CH2:12][N:3]([CH:1]=[O:2])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[N:64][CH:65]=1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(F)cn1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1 g, 1.95 mmol) in THF (15 mL) under N2 was added 2,4,6-trichlorobenzoyl chloride (0.572 g, 2.34 mmol) and DIPEA (1.68 mL, 9.75 mmol). The mixture was stirred at rt for 2 h. THF was removed under vacuum and toluene (15 mL) was added. To this mixture was added 5-fluoro-2-pyridinamine (0.262 g, 2.34 mmol) and DMAP (47.5 mg, 0.39 mmol). After being stirred at rt overnight, the mixture was diluted with EtOAc (50 mL) and washed with citric acid and brine. The organic solution was dried and concentrated. The residue was purified by flash column chromatography eluting with EA/PE (1:5) to provide the title compound (0.23 g, 19%) as colorless oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:19].Cl.[Na+].[Cl-]>O.CO>[NH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:19]
Reactant: COC(=O)c1ccc2c(c1)CCC(N)C(=O)N2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1CCc2cc(C(=O)O)ccc2NC1=O

Procedure:
A solution of NaOH (0.44 g, 11 mmol) in H2O (12 mL) was added to a suspension of 3amino-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 6 (1.72 g, 7.34 mmol) in H2O (100 mL) and MeOH (20 mL). After 5 h the resulting solution was neutralized with HCl (1M, 11 mL) and concentrated to give 7 (2.41 g, theoretically containing approx. 33% NaCl by weight). LRMS (ES), [M+H] m/z=221. ##STR34##
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH:16]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O.C1COCC1.C(Cl)Cl>[CH2:39]([O:38][C:36](=[O:37])[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH:24]([O:25][CH3:26])[O:27][CH3:28])[CH:16]=2)[CH:9]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(OC)c1cc(Oc2cccc(NC3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)c1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
A mixture of cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine (0.00868 mol) and Na2CO3 (0.02083 mol) in H2O (15 mL) and THF (75 mL) was stirred at 5° C. A solution of benzyl chloroformate (0.0104 mol) in THF (25 mL) was added dropwise over 15 min at 5° C. The resultant reaction mixture was stirred for 21 hours at room temperature. This mixture was extracted with diisopropyl ether. The separated organic layer was dried (MgSO4) and filtered, and the solvent was evaporated. The residue (0.00633 mol A) was reacted again with benzyl chloroformate (1.3 g, 0.0076 mol) and TEA (1.53 g, 0.0152 mol) in DCM (70 mL) under the same conditions as above. The residue was purified by column chromatography over silica gel (eluent: 95:5 CH2Cl2:hexane). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 110 °C
Yield: 53.7 %

Procedure:
A mixture of 1.7 g (10 mmol) 2-chloro-1,3-benzothiazole and 2.6 g (10 mmol) 4-chloroaniline in 20 ml acetic acid was heated to 110° C. for 3 h. The reaction mixtures was diluted with 200 ml water and the resulting mixture was extracted with 3×150 ml ethyl acetate. The combined organic phases were washed with 2×100 ml water, dried with MgSO4, filtered and evaporated to dryness. The residue was recrystallysed from a mixture of hexane/ethyl acetate to yield 1.4 g (54%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH:10]O>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3]
Reactant: CCCc1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: CCCc1cccc[n+]1[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 2-n-propylpyridine (187.4 g, 1.505 mol) in 900 ml of acetic acid was added 149 ml of 35% aqueous hydrogen peroxide and the mixture was stirred and heated to 70-80° C. After three hours a further 104 ml of the hydrogen peroxide solution was added, and the mixture was maintained at the same temperature for an additional nine hours. The mixture was concentrated to about 300 ml in volume, 300 ml of water were added, and the mixture again concentrated as far as possible. The residue was made alkaline with anhydrous sodium carbonate, shaken with 750 ml of dichloromethane, and allowed to stand overnight. The resulting deposit of sodium carbonate and sodium acetate was removed by filtration. The filtrate was dried with magnesium sulfate, the solvent removed, and the residue distilled in vacuo. The yield of 2-n-propylpyridine-N-oxide, b.p. 120-140° C./9-15 mbar, was 176 g (81%). 1H-NMR (CDCl3, 200 MHz) δ: 1.05 (t, 3H), 1.80 (sext, 2H), 2.89 (t, 2H), 7.10-7.28 (m, 3H), 8.28 (d, 1H).