Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:28][CH:25]4[CH2:26][CH2:27][O:23][CH2:24]4)=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC1CCOC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOC1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (55 mg) was reacted with tetrahydro-furan-3-ylamine similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-tetrahydrofuran-3-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 26.1 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-tetrahydrofuran-3-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 443 (M)+. 1H NMR (400 MHz, DMSO) δ 11.60 (d, J=6.1 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 5.06-4.92 (m, 2H), 4.60-4.48 (m, 2H), 4.47-4.33 (m, 1H), 3.89-3.80 (m, 2H), 3.79-3.71 (m, 1H), 3.57 (dd, J=9.0, 3.4 Hz, 1H), 2.25-2.14 (m, 1H), 1.87-1.76 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:26])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:26])[N:17]=2)[C:3]=1[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11]
Reactant: Fc1cccc2nc(Cl)cnc12
Reactant: CC(=O)C(C)(C)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C(C)(C)c1c(F)cccc1Oc1cnc2c(F)cccc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
0.32 g of 3-(2-fluoro-6-hydroxy-phenyl)-3-methyl-butan-2-one and 0.28 g of 2-chloro-5-fluoro-quinoxaline were dissolved in 3 ml of dimethylformamide. 0.25 g of potassium carbonate were added thereto followed by stirring for 2 hours at 100° C. Subsequently, the reaction mixture was purified by silica gel column chromatography to obtain 0.14 g of 3-[2-fluoro-6-(5-fluoro-quinoxalin-2-yloxy)-phenyl]-3-methyl-butan-2-one.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.C[O:20][C:21]1(OC)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[O:20]=[C:21]1[CH2:26][CH2:25][N:24]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)[CH2:23][CH2:22]1
Reactant: COC1(OC)CCNCC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
Benzyl 4-oxopiperidine-1-carboxylate (29.5 g, 126 mmol), 4,4-dimethoxypiperidine hydrochloride (20 g, 110 mmol), and trietylamine (16.9 mL, 1121 mmol) were stirred in 1,2-dichloroethane (600 mL). Sodium triacetoxyborohydride (30.4, 143 mmol) was added at 0° C. (over 30 minutes) followed by acetic acid (8.2 mL, 143 mmol) and the solution was stirred at room temperature for 24 h. 1N NaOH (100 mL) was added to the mixture and the solution was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in acetone (300 mL) and HCl (50 mL, 5N to 6N in 2-propanol) was added and was heated at reflux overnight. The mixture was concentrated in vacuo, diluted with dichloromethane (100 ml) and extracted with HCl 1N (4×100 ml). The aqueous extracts were combined and basified with NaOH pallets. The solution was then extracted with dichloromethane (3×100 mL), combined organic extracts were dried with anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the titled compound (23 g, 66%) 1H-NMR (300 MHz, CD3OD): δ 7.30 (5H, m), 5.10 (2H, s) 4.21 (2H, d, J=13.5 Hz) 2.87 (4H, t, J=6.2 Hz), 2.77-2.70 (1H, m) 2.62-2.58 (2H, m), 2.40 (2H, t, J=6.2 Hz) 1.86 (2H, d, J=12.0 Hz), 1.75 (2H, t, J=5.6 Hz) 1.42 (2H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccco2)cc1
Yield: 46 %

Procedure:
In a manner similar to that described in Example 3, furoyl chloride (0.044 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.033 g of 4-[4-(2-furoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+288.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([NH:24][CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][O:27]3)[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
(R)-N2-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (56 mg, 0.14 mmol) was dissolved in methanol (3 mL). Acetic acid (7.91 μL, 0.14 mmol) was added followed by formaldehyde (10.28 μL, 0.14 mmol) and sodium cyanoborohydride (8.68 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was purified by preparative HPLC yielding (R)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (18.70 mg, 32.3%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)[N:17]=3)[CH2:9]1)[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([C@@H:8]1[N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:18]([C:29]2[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=2)[N:17]=3)[CH2:9]1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1S(C)(=O)=O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (0.022 ml, 0.28 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (107 mg, 0.22 mmol) and triethylamine (0.061 ml, 0.44 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 2 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (86 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH3:13]>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: N
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (reagent preparation 25) (95.5 mg, 0.35 mmol) was treated with 0.5M ammonia in dioxane solution (7 mL) and the mixture was stirred for 1 h at room temperature. Concentrated aqueous ammonia (2 mL) was then added to the mixture then stirred an additional 12 h. The mixture was then concentrated and the residue suspended in water (5 mL). The solid was collected by filtration and dried to give 2-amino-5-bromopyridine-3-sulfonamide (55.7 mg, 89%).
Reaction SMILES: [CH:1](=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH:2]=[CH:3][CH3:4].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:16](=[O:17])[CH2:15][Cl:14])=[CH:2][CH:3]=[CH2:4]
Reactant: O=C(Cl)CCl
Reactant: CC=CC=Nc1c(C)cccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC=CN(C(=O)CCl)c1c(C)cccc1C
Temperature: 20 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
17.3 g (0.1 mol) of N-but-2-enylidene-2,6-dimethylaniline were added dropwise to a solution of 11.3 g (0.1 mol) of chloroacetyl chloride in 10 ml of toluene at 20° C. The mixture was further stirred at 20° C. for 1 hour and 10.1 g (0.1 mol) of triethylamine were then added dropwise. The mixture was further stirred at 20° C. for 1 hour and the precipitate which separated off was filtered off under suction. The filtrate was washed with dilute aqueous bicarbonate solution and then with water, and was subsequently concentrated in vacuo. The residue was recrystallized from hexane. 12.4 g (49.7% of theory) of N-(1,3-butadienyl)-N-(2,6-dimethylphenyl)chloroacetamide were obtained in the form of colorless crystals of melting point 88° C.
Reaction SMILES: [C:1]12([S:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1>>[C:22]1([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][S@:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])[CH2:16]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=[S@](NC1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfinyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanesulfinamide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Reactant: NCCCO
Solvent: CO
Product: O=c1ccc2cc(OCCCNCCCO)ccc2[nH]1

Procedure:
A solution of 6-(3-chloropropoxy)carbostyril (5.0 g) and 3-amino-1-propanol (24 ml) in methanol (25 ml) is heated at 100° C. for 4 hours in an autoclave. The mixture is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol:aqueous ammonia=70:10:1), and recrystallized from methanol-diethyl ether to give 6-[3-(3-hydroxypropyl)aminopropoxy]carbostyril(4.4 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13]([CH3:20])=[N:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[C:21](O)=[O:22])=[C:4]([Cl:24])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:42]([O:44][CH2:45][CH2:46][O:47][NH2:48])=[CH2:43].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:42]([O:44][CH2:45][CH2:46][O:47][NH:48][C:21]([C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([F:19])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:24])[N:16]=[CH:15][N:14]=[C:13]2[CH3:20])=[O:22])=[CH2:43]
Reactant: C=COCCON
Reactant: Cc1ncnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 168 h
Yield: 44 %

Procedure:
To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (47 mg, 0.11 mmol) in DMF (2 mL) was added HOBt (26.0 mg, 0.170 mmol), Et3N (0.060 mL, 0.044 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (15 mg, 0.15 mmol), and EDCI (30 mg, 0.16 mmol) at room temperature. The resulting solution was stirred for 7 days at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (1.5 to 2% MeOH in CH2Cl2) to afford 24 mg (42%) of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. To a solution of the vinyl ether (24.0 mg, 0.048 mmol) in EtOH (2 mL) was added 1 N aqueous HCl (0.21 mL) at room temperature. After stirring for 3 hours at room temperature, pH of the reaction mixture was adjusted to 6 to 7 with 1 N aqueous NaOH, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (5 to 10 to 20% MeOH in CH2Cl2 with 1% Et3N) to afford 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-hydroxyethoxy)-amide (5 mg, 22%). MS APCI (−) m/z 467, 469 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.38 (s, 1H), 7.60 (d, 1H), 7.35 (dd, 1H), 6.86 (dd, 1H), 4.10 (t, 2H), 3.81 (t, 2H), 2.99 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][NH:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CN
Product: CNC[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.50 g, 1.9 mmol) and methylamine (10 mL, 8 M solution in ethanol, mmol; used as solvent) gives the title compound.
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:11].Cl.[NH2:39][OH:40].C(N(CC)CC)C>ClCCl.CO>[F:37][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][C:15](=[N:39][OH:40])[CH2:14][CH2:13]1)=[O:11]
Reactant: NO
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=O)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 29.6 %

Procedure:
To a solution of 200 mg of (Z)-1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperidin-4-one in a mixture of 6 ml of dichloromethane and 3 ml of methanol were added 29 mg of hydroxylamine monohydrochloride and 59 μl of triethylamine, followed by stirring at room temperature for 22 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluting with chloroform-methanol), followed by crystallizing from diethyl ether to give 61 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxo-ethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CC(=O)CC>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CN(C)CCOc1cccc2[nH]ccc12
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A 100 mL round-bottomed flask equipped with magnetic stirrer and a reflux condenser was charged with 2-butanone (30 mL), 4-hydroxy-1H-indole (1.197 g, 0.009 mol), potassium carbonate (44.71 g, 0.036 mol) and sodium iodide (0.137 g, 0.0009 mol). To this mixture was added 2-chloro-N,N-dimethylethylamine hydrochloride (1.43 g, 0.010 mol). The reaction mixture was brought to reflux and stirred for 24 hours. The solvent was removed in vacuo and the resulting crude residue was dissolved in 60 mL of ethyl acetate and the solution was washed sequentially with water (3×45 mL) and brine (1×45 mL). The aqueous fractions were extracted with ethyl acetate (2×20 mL) and the combined organic fractions were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (95:4.9:0.1 dichloromethane/methanol/ammonium hydroxide) to afford 2-(1H-indol-4-yloxy)ethyl dimethylamine as a transparent pale blue oil (1.322 g, 72%). MS: (M+H)+=205.4.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)C>[CH3:14][N:13]([CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Reactant: CNCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-[3-(4-Nitrophenoxy)propyl]methylamine hydrochloride (3.08 g, 12.49 mmol), 2-(chloromethyl)-6-nitroquinoline (2.78 g, 12.49 mmol), and potassium carbonate (3.45 g, 25.0 mmol) were stirred in 2:1 acetonitrile/ethanol (120 mL) at reflux for 18 hours. The mixture was concentrated and the residue was partitioned between 10% aqueous K2CO3 and 4:1 dichloromethane/isopropanol. The organic phase was dried, decolorized and concentrated to afford crude product which was purified by column chromatography (1:2 hexane/ethyl acetate). Yield: 2.63 g (53%) as a yellow oil.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][C@@H:3]2[CH2:7][C:8]3[C:13]([CH2:14][C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[C:5](=[O:6])[CH2:4][C@@H:3]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][C@H:2]1[OH:1]
Reactant: CNC
Reactant: O=C1C[C@@H]2Cc3ccccc3C[C@H]2O1
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@@H]1Cc2ccccc2C[C@H]1O
Yield: 97 %

Procedure:
A mixture of 18.8 (0.10 mol) of trans-3a, 4,9,9a-tetrahydronaphtho[2,3-b]furan-2(3H)-one, 35 ml of anhydrous dimethylamine, and 35 ml of dry THF is heated in a small Parr bomb at 100° for 3 days. The cooled reaction mixture is then taken to dryness in vacuo, and the residue triturated with ether to give 22.5 g (97%) of crystalline solid after drying in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:17]=1.[CH2:18]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:18]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=3[CH:17]=2)=[CH:30][CH:31]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3)cc1
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A suspension of methyl 8-bromo-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (6.0 g), 4-(2-butoxyethoxy)phenyl boric acid (6.26 g) and potassium carbonate (7.28 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred under argon atmosphere for 1 hour, after which tetrakis(triphenylphosphin)palladium (1.17 g) was added, and the mixture was refluxed for 6 hours. After returning to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate=9:1→hexane:ethyl acetate=4:1), and recrystallized from hexane-ethyl acetate to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (3.33 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH2:39]>C(OCC)(=O)C>[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH:39][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:20][CH:19]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)cc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.63 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid is suspended in 36 ml of ethyl acetate, 2.38 g (20 mmol) of thionylchloride is added and the suspension is heated to boiling temperature. After 15 minutes a clear solution is present, after 1 hour the formation of the acid chloride is complete. The solution is evaporated to dryness under reduced pressure, the residue is concentrated by evaporation in a vacuum twice with 50 ml of dichloromethane each and the dissolved in 36 ml of dioxane. 1.21 g (12 mmol) of triethylamine and 1.93 g (12 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added to this solution and it is stirred for 5 hours at room temperature. The reaction solution is then evaporated to dryness in a vacuum, the residue is extracted with ethyl acetate, the ethyl acetate extract is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 3.19 g (6.3 mmol) =63% of the theoretical yield of the product is obtained as an amorphous solid.