Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7]>O1CCCC1>[CH3:1][NH:2][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[I:3]
Reactant: CN
Reactant: O=C(Cl)c1ccccc1I
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1I

Procedure:
A total of 40 ml of a 40% by weight aqueous solution of methylamine was reacted with a solution of 16 g of o-iodobenzoyl chloride in 25 ml of tetrahydrofuran for 10 minutes. The excess solvent was evaporated in a hot water bath at 65°. The mixture was allowed to cool and 40 ml of water was added to precipitate the crude product which was recovered and washed with 1 N NaOH, 1 N HCl, and then water until the washings were neutral. The crude product was dried under vacuum and purified by recrystallization from toluene to yield 12.6 g of N-methyl-o-iodobenzamide as white crystals, m.p. 153°-154°, Rf 0.75 on thin layer chromatography using silica gel 60 and methanolchloroform-acetic acid (15:85:1) mixture.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH:21]=[O:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][C:21]([OH:31])=[O:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CC=O)c3o2)cc1OC1CCCC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(Cc2nc3cc(Cl)cc(CC(=O)O)c3o2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chlorobenzoxazole-7-ethanal (2.0 g, 0.005 mol) in 50 ml of acetone was treated with 20 ml of 1 N Jones reagent and stirred for 1 hour at room temperature. Excess Jones reagent was destroyed by the addition of 50 ml of 2-propanol and the low boiling solvents were stripped under reduced pressure. Water (50 ml) and saturated sodium chloride (50 ml) were added and the aqueous residue was extracted with 2×75 ml of ethyl acetate. After drying, the ethyl acetate was evaporated to give 2.1 g of a brown foam. Solution of this material in CH2Cl2 and flash chromatography on silica gel afforded 0.72 g of the title acid as a yellow foam after elution with 500 ml of 0.5% CH3OH in CH2Cl2. The foam was dissolved in 3 ml of CH3OH and allowed to crystallize for 1 hour at freezer temperatures. After filtration, a total of 0.27 g of yellow title compound, mp 131-133° C., was isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][NH:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH2:12][N:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][O:5]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)CONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CON(Cc2ccc(F)cc2Cl)C1=O
Yield: 107.5 %

Procedure:
By the method of Example 6, Step B, 95.6 g (0.83 mole) of 4,4-dimethyl-3-isoxazolidinone, 186 g (0.83 mole) of 2-chloro-4-fluorobenzyl bromide, 114.7 g (0.83 mole) of potassium carbonate, and 2.2 g (0.008 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane were reacted at room temperature in 1500 ml of acetonitrile, yielding 230 g of impure 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere, 45.0 g (0.209 mole) of 2-amino-3'-fluorobenzophenone was added in four portions at 15 min intervals to a stirred melt (120°-125° C.) of 38.2 g (0.241 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 120°-125° C. for one hr. and then at 145°-150° C. for 45 min. The mixture was cooled to 130° C. and 100 ml of toluene was added. The cooled mixture (room temperature) was diluted with 100 ml of ethyl acetate and extracted with 100 ml of 10% potassium hydroxide. The organic layer was extracted with three 100 ml portions of 3N hydrochloric acid, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 35.5 g (50%) solid. The solid was dissolved in 200 ml of methylene chloride and the solution stirred with 50 g of fluorisil for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo. A 5 g portion of the residue was recrystallized from ethyl acetate-isopropyl ether to give 4.1 g of yellow-orange solid, m.p. 98°-101° C.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][CH:6]=1
Reactant: CCCc1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1nc(I)c[nH]1
Yield: 88.2 %

Procedure:
[step 1] 2-Propylimidazole (3.0 g, 27.3 mmol) was dissolved in dioxane/water (55 mL/55 mL), sodium hydrogen carbonate (8.67 g, 81.8 mmol) and iodine (15.0 g, 59.9 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4,5-diiodo-2-propylimidazole (7.09 g, 72%). [step 2] 4,5-Diiodo-2-propylimidazole (3.0 g, 8.31 mmol) obtained in Reference Example A16, step 1 was dissolved in ethanol/water (60 mL/60 mL), sodium sulfite (8.40 g, 66.5 mmol) was added, and the mixture was heated under reflux overnight. After completion of the reaction, the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-iodo-2-propylimidazole (1.73 g, 88%).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: NNc1ccc(Br)cc1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(-c3ccc(Br)cc3)c3c(C(F)(F)F)cccc23)cc1

Procedure:
Prepared according to Method C step A from (2-fluoro-3-trifluoromethyl-phenyl)-(4-methoxyphenyl)-methanone (0.149 g, 0.5 mmol), 4-bromophenylhydrazine hydrochloride (0.134 g, 0.6 mmol) and DMAP (0.061 g, 0.5 mmol) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:22])([CH3:21])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10].[H][H]>CO.[Ni]>[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]([CH3:21])([CH3:22])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:2]=2[CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(N)c2)c1

Procedure:
5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(3-nitrophenyl)pentanamide (Example 1i), 22.39 g (0.0604 mol), is dissolved in 400 ml of methanol, 1.5 g of Raney nickel is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue solidifes to afford 19.8 g of N-(3-aminophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide after recrystallization from isopropyl ether; mp 93°-94° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1>[F:13][C:14]1[C:19]([B:23]([OH:24])[OH:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)nc1F

Procedure:
0,6 M of n-butyllithium are added at -10° to 0,6 M of diisopropylamin in 600 ml THF. The mixture is cooled to -70°, 0,6 M of 2,6-difluoropyridin are added and after stirring for 15 minutes 0,6 M of trimethylborate are added at the same temperature. The mixture is allowed to warm up to -30°. Then the borate ester is hydrolysed with dilute HCl, the product extracted with ether, washed, dried and the solvent removed. Thus, 2,6-difluoro-pyridine-3-boronic acid is obtained.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:57])[CH2:21][C:22]1([CH2:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:36][CH2:35]2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:38][CH2:39]3)=[C:27]([C:24]3[CH2:23][C:22]([CH2:49][C:50]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:56])([CH2:21][C:20](=[O:57])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CC(C)(C)OC(=O)CCN1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OC(=O)c3ccc(NC(=N)N)cc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was added to a mixture of tert-butyl 3-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)propanoate (60.7 mg), pyridine (0.2 mL), and NMP (0.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (42.7 mg).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[CH3:10])[CH:7]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH3:10])[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 40.2 %

Procedure:
5-Fluoro-N-(1-(3,5-dimethoxyphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C25H34N4O6: 486.25; Observed: 509.3 (M++Na).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C@@H:20]3[CH2:22][C@H:21]3[CH2:23][OH:24])[C:14]=2[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C@@H:20]3[CH2:22][C@H:21]3[CH:23]=[O:24])[C:14]=2[CH2:13][CH2:12]1
Reactant: OC[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH2Cl2 (7.4 mL of 2M solution, 14.8 mmole) at -78° C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH2Cl2 (15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH2Cl2 and washed with water, 1N HCl, and then 1N NaOH. The organic layer was dried and concentrated in vacuo to give the aldehyde product (1.98 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([Cl:20])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(CC(=O)Cl)cc1OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3,4-diethoxy-phenyl)-acetic acid (2.0 g, 8.9 mmol) in DCM (6 ml) were successively added oxalylchloride (1.13 ml, 13.4 mmol) and a catalytic amount of DMF (0.069 ml, 0.89 mmol) at 0° C. (ice bath). The reaction mixture was stirred at 0° C. for 1 h then evaporated to dryness under vacuum to yield the crude (3,4-diethoxy-phenyl)-acetyl chloride (2.2 g, 8.9 mmol, quant.) as a brownish oil which was used in the next step without further purification.
Reaction SMILES: C(Br)CC.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:30][C:31]1[C:41]2[N:40](CCC)[C:39](=[O:45])[C:38]([CH3:47])([CH3:46])[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:35]=2[CH:34]=[C:33]([N+:55]([O-:57])=[O:56])[CH:32]=1>CCOCC.CCCCCC>[Cl:30][C:31]1[C:41]2[NH:40][C:39](=[O:45])[C:38]([CH3:47])([CH3:46])[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:35]=2[CH:34]=[C:33]([N+:55]([O-:57])=[O:56])[CH:32]=1
Reactant: CCCN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCBr
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 32 g (0.088 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and propyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 3 days, 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-1-propyl-2H-1,4-benzodiazepin-2-one of melting point 142°-143° (ether/n-hexane).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[S:8][CH:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCCC>[C:12]([NH:1][C:2]1[C:7]2[S:8][CH:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cccc(N)c2S1
Solvent: CCCCCl
Product: CC(=O)Nc1cccc2c1SC(C)C2

Procedure:
To a solution of 18.0 g of 7-amino-2,3-dihydro-2-methylbenzo[b]thiophene (Example 7) in 100 ml of 1-chlorobutane was added a solution of 13.0 ml of acetic anhydride in 20 ml of 1-chlorobutane. After the exothermic reaction subsided, the mixture was refluxed for 0.3 hour, cooled in an ice-bath and filtered. The isolated solid was washed with 1-chlorobutane to yield 15.2 g of the title compound; m.p. 125°-127° C.
Reaction SMILES: Cl.[CH:2]([C@H:5]1[NH:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH:2]([C@H:5]1[N:10]([C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)[C@H]1NCCNC1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1C(=O)NCCN1c1nccc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of (R)-3-isopropylpiperazin-2-one hydrochloride (2.61 g, 14.62 mmol) and iPr2NEt (7.60 mL, 43.86 mmol) in DMF (20 mL) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (3.47 g, 19.00 mmol) in DMF (2 mL). The resulting solution was stirred at 100° C. under N2 for 3 h at which point the reaction was deemed complete by LC-MS. Sat. aq. NH4Cl (30 mL) was added to quench the reaction, followed by addition of EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give nearly pure crude product. Purification on a silica cartridge using ISCO FCC eluting with 100% EtOAc gave 4.03 grams of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (96%) as a slightly orange thick oil. LC-MS m/z 289.17 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 6.82 (d, J=4.4 Hz, 1H), 6.56 (br, 1H), 5.20 (d, J=6.8 Hz, 1H), 4.83-4.77 (m, 1H), 3.55-3.37 (m, 3H), 2.49-2.41 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][CH3:15])[N:8]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:7]1[CH:12]=[C:11]([O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=2)[N:10]=[C:9]([S:14][CH3:15])[N:8]=1)[CH3:2]
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCO
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1cc(Oc2cccc(C(F)(F)F)c2)nc(SC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanol (1.18 g, 0.0256×1.0 mol) and NaH (1.02 g, (ca.60% in mineral oil), 0.0256×1.0 mol) were dissolved in THF and 4,6-dichloro-2-methylthiopyrimidine (Compound No. VII-23)(5.0 g, 0.0256 mol) was added thereto. The resulting solution was stirred for about 30 minutes at room temperature. To this reaction solution, m-trifluoromethyl-phenol (6.23 g, 0.0256×1.5 mol), NaH (1.54 g, (ca.60% in mineral oil), 0.0256×1.5 mol), and KI (2.12 g, 0.0256×0.5 mol) dissolved in DMF were added. The resulting solution was refluxed for about 7 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, and thereafter purified on a silica gel column.
Reaction SMILES: [Zn+2:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[C:11]2[NH:15][C:14]([C:16]([C:50]3[CH:55]=[CH:54][C:53]([C:56]#[C:57][Si](C)(C)C)=[CH:52][CH:51]=3)=[C:17]3[N:49]=[C:20]([C:21]([C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])=[C:22]4[NH:40][C:25](=[C:26]([C:32]5[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=5[F:39])[C:27]5[CH:28]=[CH:29][C:30]=1[N:31]=5)[CH:24]=[CH:23]4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1COCC1.CO>[Zn+2:1].[C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:16]2[C:17]3[NH:49][C:20](=[CH:19][CH:18]=3)[C:21]([C:41]3[C:42]([F:48])=[CH:43][CH:44]=[CH:45][C:46]=3[F:47])=[C:22]3[N:40]=[C:25]([CH:24]=[CH:23]3)[C:26]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])=[C:27]3[NH:31][C:30]([CH:29]=[CH:28]3)=[C:10]([C:4]3[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[C:11]3=[N:15][C:14]=2[CH:13]=[CH:12]3)=[CH:51][CH:52]=1)#[CH:57]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2c3nc(c(-c4c(F)cccc4F)c4ccc([nH]4)c(-c4c(F)cccc4F)c4nc(c(-c5c(F)cccc5F)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(-c2c3nc(c(-c4c(F)cccc4F)c4ccc([nH]4)c(-c4c(F)cccc4F)c4nc(c(-c5c(F)cccc5F)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of Zn-3 (82 mg, 93.2 μmol) in THF (9 mL) was added a suspension of K2CO3 (30 mg, 217 μmol) in methanol (3 mL). The mixture was stirred for 1 h at room temperature in the dark. Then CH2Cl2 (20 mL) was added. The mixture was washed with aqueous 5% NaHCO3 solution (20 niL) and dried (Na2SO4). Purification by column chromatography (silica, CH2Cl2/hexanes 1:2) afforded 58 mg (71.6 μmol, 77%) of the title compound as a red-purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:7]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[N:20]=[CH:19][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:15][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:20]=[CH:19][N:18]=2)=[CH:7][C:6]=1[NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10]
Reactant: CCCS(=O)(=O)Nc1cc(N)ccc1C
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cl)ncn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(Nc2cc(-c3cccc([N+](=O)[O-])c3)ncn2)ccc1C
Temperature: 80 °C

Procedure:
A mixture of propane-1-sulfonic acid (5-amino-2-methyl-phenyl)-amide (5.5 g, 24 mmol) and 4-chloro-6-(3-nitro-phenyl)-pyrimidine (5.52 g, 23.4 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control), the reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The formed precipitate was filtered out, washed with water (2×200 mL), dried, washed with chloroform (2×50 ml), dried to yield propane-1-sulfonic acid {2-methyl-5-[6-(3-nitro-phenyl)-pyrimidin-4-ylamino]-phenyl}-amide as yellow powder.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[C:16]([C:6]2[S:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(Br)s1
Product: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
1-(5-(3-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from 2-acetyl-5-bromothiophene acid and 3-trifluoromethylbenzeneboronic acid according to general procedure A.