Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ncc(Cl)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=429.2 [M+H]+and 431.1 [M+2+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CCNCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccccc2C(C)C)C1=S
Yield: 42.9 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20 % ethyl acetate in hexane) Crystallization from ethanol afforded the title compound (9.8 g) as a white solid, m.p. 125°-127° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4](Cl)=[O:5].[CH:22]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24][C:23]2=[O:31].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C[Si](C#N)(C)C>[CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4]([CH:24]1[C:25](=[O:30])[CH:26]2[CH2:29][CH:22]([CH2:28][CH2:27]2)[C:23]1=[O:31])=[O:5]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen and at 0-5° C., 0.7 g (2 mmol) of 2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl-sulfonylbenzoyl chloride in 40 ml of acetonitrile was added dropwise to 0.28 g (2 mmol) of bicyclo[3.2.1]octane-2,4-dione and 0.4 g (4 mmol) of triethylamine in 40 ml of acetonitrile, and the mixture was stirred at room temperature for 4 hours. 1 drop of trimethylsilyl cyanide and 0.05 g of potassium carbonate were then added, and the mixture was stirred at 40° C. for 2 hours and then at room temperature for 12 hours. Following this, the solvent was removed, the residue was taken up in ethyl acetate and the solution was extracted repeatedly with 5% strength potassium carbonate solution. The combined extracts were then adjusted to pH 2-3 using 10% strength hydrochloric acid and extracted repeatedly with methylene chloride. These combined organic extracts were then washed with water and dried, and the solvent was removed. The oily yellow residue was chromatographed over silica gel (mobile phase: methylene chloride/methanol=99/1 to 97/3). This gave 0.4 g (44% of theory) of the title compound of melting point 98-103° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:33]>>[OH:24][C:21]([CH3:22])([CH3:23])[C:20]#[C:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][CH2:9][CH:8]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:7]3[S:6][C:5]([C:3]([NH2:33])=[O:2])=[N:14][C:13]=3[C:12]=2[CH:15]=1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(N1CCOCC1)CO2
Yield: 64 %

Procedure:
A solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (130 mg, 0.30 mmol) in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the reaction mixture was concentrated to afford crude compound which was triturated with EtOAc to afford compound 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (80 mg, 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=1.88 Hz, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.27 (dd, J1=8.4 Hz, J2=1.92 Hz, 1H), 7.02 (d, J=8.32 Hz, 1H), 5.43 (s, 1H), 4.40 (m, 3H), 3.54 (m, 4H), 2.65 (m, 4H), 1.46 (s, 6H); LC-MS (ESI & APCI): 414.6 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:10]([O:4][CH2:3][CH2:2][Br:1])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCBr
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Product: BrCCOC(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
To 2-bromoethanol (40.7 g, 326 mmol) was added conc. sulfuric acid (9.96 g, 102 mmol) under ice-cooling while stirring. Thereto was added benzhydrol (12.0 g, 65.1 mmol), and the mixture was heated at 100° C. for 15 minutes. The reaction mixture was allowed to stand for cooling, poured into ice-cold water and extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained liquid was distilled under reduced pressure to give the title compound (3). Yield 13.9 g (73%). b.p. 125°-165° C./2.5 mmHg.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])CCC.[Cl:17][C:18]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>O1CCCC1>[CH2:11]([O:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:18]=1[Cl:17])[CH2:12][CH2:13][CH3:14]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCCCOc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O
Yield: 76.1 %

Procedure:
A solution of 3,4-dibutoxy-3-cyclobutene-1,2-dione (2.263 g, 10 mmol) and 2-chloro-4-cyanobenzylamine (1.666 g, 10 mmol, Example 2, Step 3) in tetrahydrofuran (25 mL) was stirred at room temperature for 22 hours. The residue remaining after removal of solvent was dissolved in chloroform and was chromatographed (flash, ethyl acetate/hexane) on silica. The solid isolated from the appropriate fractions was recrystallized from ethyl acetate to provide 2.427 g of a white solid: mp 147.5°-149° C. MS (m/z) 318 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[C:18]([F:28])[CH:17]=3)[CH2:11][C:10]([OH:12])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C:31]1[CH:32]=[N:33][C:34]2[N:35]([N:37]=[C:38]([CH:40]=O)[N:39]=2)[CH:36]=1)[CH3:30]>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([C:23]([CH3:26])([CH3:27])[C:24]#[N:25])=[C:18]([F:28])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:40][C:38]3[N:39]=[C:34]4[N:33]=[CH:32][C:31]([CH2:29][CH3:30])=[CH:36][N:35]4[N:37]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1c(F)cc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Reactant: CCc1cnc2nc(C=O)nn2c1
Solvent: CO
Product: CCc1cnc2nc(CC3=C(O)CC(CCc4cc(F)c(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Reaction time: 12 h

Procedure:
A solution of 2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile (272 mg, 0.7 mmol) in anhydrous MeOH (1.5 mL) was treated with 6-ethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0 mmol), followed by borane-dimethylamine complex (191.7 mg, 1.05 mmol) at room temperature. The reaction was stirred for 12 hours. The precipitate was removed by filtration, and the filtrate was concentrated to a crude oil. The crude oil was purified by flash chromatography (25 g SiO2, 1:3:1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid):(81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give product as an oil. It was further purified by preparatory HPLC. Yield: 19.0 mg, 8.0%. 1H NMR (CDCl3) δ: 1.37 (t, J=3.75 Hz, 3H)), 1.48-1.75 (m, 8H), 1.84 (s, 6H), 1.91-2.02 (m, 2H), 2.32-2.49 (m, 3H), 2.61-2.70 (m, 2H), 2.79-2.86 (m, 2H), 4.10 (s, 2H), 6.69 (d, J=10.86 Hz, 2H), 8.62 (s, 1H), 8.73 (s, 1H). MS (ESI): 548 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>CN(C=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]([CH2:2][NH:1][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[N:7][N:6]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
A solution of 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg, 0.17 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vessel containing PS-DIEA (2.5 eq, 150 mg) and butane-1-sulfonyl chloride (1.1 eq, 0.19 mmol) suspended in anhydrous DMF (3 mL). The reaction mixture was stirred at ambient temperature under argon for approximately 16 hours before it was filtered, washed with DMF (3×5 mL) and concentrated under reduced pressure. The resulting yellow residue was recrystallized from ether to yield 13 mg (22%) of the title compound as a yellow powder. MS (m/z, ES+): 355 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]3[N:12]([CH:14]=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:17][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH:1][C:18](=[O:20])[CH3:19])=[N:13][N:12]2[CH:14]=[N:15][N:16]=[C:11]2[CH:10]=1
Reactant: Cc1cc2nncn2nc1-c1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nn3cnnc3cc2C)c1

Procedure:
A 1.5 g. portion of 6-(m-aminophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 6) is dissolved in 30 ml. of pyridine at room temperature. To the solution is added 6.0 ml. of acetic anhydride and the reaction mixture is heated on a steam bath for 1 hour. The reaction mixture is cooled in an ice bath and is filtered. The filter cake is washed with petroleum ether and is dried to afford the product of the example as cream colored crystals, m.p. 298°-301° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:43]([C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[CH:51][NH:52]2)=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[CH2:14][C:15]([N:52]1[C:53]2[C:49](=[CH:48][CH:47]=[C:46]([N+:43]([O-:45])=[O:44])[CH:54]=2)[CH:50]=[CH:51]1)=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)n1ccc2ccc([N+](=O)[O-])cc21)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino }-acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL) was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60° C. for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (×3), dried over Na2SO4 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (6.42 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 9H), 2.78 (m, 3H), 2.95 (d, J=1.5 Hz, 1H), 3.12 (d, J=2.1 Hz, 2H), 4.01 (d, J=13.8 Hz, 0.6H), 4.18 (d, J=12.0 Hz, 1.4H), 4.92 (d, J=3.4 Hz, 1.4H), 5.08 (d, J=11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d, J=3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min, 10-99% CH3CN, 5 min run; ESI-MS 405.5 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Solvent: c1ccncc1
Product: C=CCN(CC=C)c1nc(NC(C)=O)n2oc(=O)nc2n1

Procedure:
6 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are stirred at room temperature for 18 hours with 60 ml. of absolute pyridine and 8 ml. of acetic acid anhydride. The solvents are distilled off at 40° C. and the residue is dissolved in 220 ml. of methylene chloride. The solution obtained is washed with 1-N hydrochloric acid, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}acetamide having a melting point of 164°-165° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:33][OH:34]>N1C=CC=CC=1>[OH:34][N:33]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NO
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCCC(=NO)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Yield: 48.4 %

Procedure:
To a mixture of 5-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (4 g) and pyridine (50 ml) is added hydroxylamine hydrochloride (1.84 g) and the mixture is refluxed for 2.5 hours. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from dioxane/water to give 5-hydroxyimino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2 g) as white powder, m.p. 272-273° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:19]([CH2:21][C:22](OCC)=[O:23])=O)([F:18])([F:17])[F:16].CS(O)(=O)=O>>[CH2:1]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:14][C:22](=[O:23])[CH:21]=[C:19]2[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: CS(=O)(=O)O
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccccc3)ccc2o1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
A stirred suspension of 4-benzylphenol (4.67 g, 25.4 mmol), CF3COCH2CO2Et (7.00 g, 38.0 mmol), & MeSO3H (8.5 mL, 130.9 mmol) was heated at 65° C. for 9 h. On cooling, the mixture was partitioned between Et2O (200 mL) and H2O (50 mL), then the aqueous phase was basicified with 2 M NaOH. The organic layer was separated and washed with H2O and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (4:1 PE-Et2O) furnished 6-benzyl-4-trifluoromethylchromen-2-one (3.42 g, 44%): δH (CDCl3)=4.10 (s, 2H), 6.85 (s, 1H), 7.20–7.40 (m, 5H), 7.45 (dd, 1H), 7.60 (d, 1H). This compound (2.00 g, 6.6 mmol) was dissolved in H2SO4 (20 mL), then the whole was stirred for 15 minutes. The mixture was carefully treated with crushed ice (80 g), then the resulting white precipitate was collected by filtration. The precipitate was air-dried, before being treated with hot THF (100 mL). After filtration, the filtrate was concentrated to yield 4-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)benzenesulfonic acid (2.20 g, 87%): δH ((CD3)2SO)=4.05 (s, 2H), 7.00 (s, 1H), 7.20 (d, 2H), 7.45 (d, 1H), 7.50–7.60 (m, 4H). This compound was reacted with (COCl)2, as described above in Preparation 2, to give a solid which was dissolved in EtOAc, before being filtered and concentrated to produce the title compound (2.30 g, 87%): Rf (2:1 PE-EtOAc)=0.60.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and pyrrolidin-2-one (80 μL) and by the reaction and treatment in the same manner as in Example 1, the title compound (244 mg) was obtained.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CBr)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution prepared with t-butyl 3-(6-hydroxymethyl-pyridin-2-yl)-trans-acrylate (trans form, 2 g) described in Reference Example 10-(1) and carbon tetrabromide (4.23 g) in methylene chloride (20 mL) at ice temperature, triphenylphosphine (2.68 g) was added in small portions, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was transferred to a separating funnel, diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 2.23 g of t-butyl 3-(6-bromomethylpyridin-2-yl)-trans-acrylate as a light yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:9]1=[O:24].[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:25]([O-:27])=[O:26])=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:9]1=[O:24]
Reactant: O=c1nc(-c2ccccc2)c2ccccc2n1Cc1ccccn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.13 g of 1-(2-pyridylmethyl)-4-phenyl-2(1H)-quinazolinone in 10 ml of concentrated sulfuric acid was added dropwise a solution of 1 g of potassium nitrate in 3 ml of concentrated sulfuric acid with cooling by an ice bath. The resulting mixture was stirred at room temperature for 3 hours and then poured onto cracked ice. The precipitate was collected by filtration, washed successively with water and ammonia water and dried to give 1-(2-pyridylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone. Recrystallization from chloroform gave colorless fine crystals, m.p. 175°-176° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].CO[C:20](=[O:23])[O:21][CH3:22].CC(C)([O-])C.[K+]>COC>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:1](=[O:4])[CH:2]([CH3:3])[C:20](=[O:23])[O:21][CH3:22])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: COC
Agent: [K+]
Product: COC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.51 g (2.1 mmol) of 4-propionyl-1-(tert-butoxycarbonyl)piperidine (from Step A) and 0.35 mL (17.6 mmol) of dimethylcarbonate in 5 mL of tert-butyl, methylether at 0° C. was treated with 0.45 g (4.0 mmol) of potassium tert-butoxide. After 10 minutes at 0° C., the reaction was stirred at rt for 17 hours and refluxed for 3 hours. The reaction was quenched with 1 N HCl and partitioned between 100 mL of Et2O and 100 mL of 1 N HCl. After separating phases, the organic layer was washed with 100 mL of brine, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 9:1 v/v of hexanes/acetone as the eluant to afford the title compound as a straw colored oil: RF: 0.32 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.35 (d, J=7.1, 3H), 1.42–1.66 (m, 11H), 1.79–1.80 (m, 2H), 2.68–2.79 (m, 3H), 3.71 (q, J=7.1, 1H), 3.73, 3.77 (2s, 3H), 4.12 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)[C:2]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[C:3]([C:22]#[N:23])[C:4]2=[O:21])=[CH:15][CH:16]=1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Yield: 70.5 %

Procedure:
A solution of Compound 22 (1.6 g, 4.9 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (2.2 g, 24.5 mmol) in CH2Cl2 at room temperature and further stirred overnight. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.30 g (72%) of yellow solids. M.P. 121° C. 1H NMR (DMSO-d6): δ 2.35 (s, 3H), 2.96 (m, 4H), 3.54 (m, 4H), 5.42 (s, 2H), 7.11-7.17 (m, 2H), 7.23-7.26 (m, 2H), 7.44 (dd, J=1.2, 8.6 Hz, 1H), 7.64 (s, 1H). EIMS m/z 377 (M+1).