Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:13]([OH:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([CH3:21])([C:18]([OH:20])=[O:19])[O:9]2)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:35]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[S:40][C:39]2[C:50]3[C:55]([CH:56]=[CH:57][C:38]=2[N:37]([CH2:58][CH2:59][N:60]([CH3:62])[CH3:61])[C:36]1=[O:63])=[CH:54][CH:53]=[CH:52][CH:51]=3>O1CCCC1.CN(C)C1C=CN=CC=1>[OH:14][C:13]1[C:12]([CH:15]([CH3:16])[CH3:17])=[CH:11][C:10]2[O:9][C:8]([C:18]([O:20][CH:35]3[CH:41]([C:42]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=4)[S:40][C:39]4[C:50]5[C:55]([CH:56]=[CH:57][C:38]=4[N:37]([CH2:58][CH2:59][N:60]([CH3:62])[CH3:61])[C:36]3=[O:63])=[CH:54][CH:53]=[CH:52][CH:51]=5)=[O:19])([CH3:21])[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(C)c1cc2c(c(C(C)C)c1O)CCC(C)(C(=O)O)O2
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)C2OC(=O)C2(C)CCc3c(cc(C(C)C)c(O)c3C(C)C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.4 g (0.0048 mol) of (±)-5,7-diisopropyl-6-hydroxy-2-methylchroman-2-carboxylic acid in 25 ml dry tetrahydrofuran was added 0.09 g (0.0055 mol) of 1,1'-carbonyldiimidazol. After stirring at room temperature for 30 minutes, 2.0 g (0.0047 mol) (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one and 20 mg of 4-dimethylaminopyridine were added. The reaction mixture was stirred at room temperature for 17 hours, concentrated to dryness and the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and chromatographed on 70 g silica gel. The column was eluted with 75 ml portions of acetonitrile. Fractions 5-8 were combined and the solvent removed to give 1.3 g (40%) of isomer "A" as an amorphous solid, [α]D25 -74.31° (C 1.03, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22].[C:24](Cl)(Cl)=[O:25].ClC(Cl)C>ClCCCl>[Cl:22][C:21]1[C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[C:3]([Cl:23])[C:2]=1[N:1]=[C:24]=[O:25]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N)c2Cl
Reactant: O=C(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N=C=O)c2Cl
Temperature: 0 °C

Procedure:
5 g (14.25 mmol) of 7-amino-6,8-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 325 ml of 1,2-dichloroethane under reflux. The still hot solution is subsequently added dropwise while stirring and cooling with ice to 3.73 g (37.65 mmol) of phosgene in 50 ml of ice-cold 1,2-dichloroethane, the addition being carried out in such a manner that the temperature of the mixture does not exceed 20° C. The mixture is heated under reflux for 1 hour, 80 ml of dichloroethane are allowed to distill off and 80 ml of fresh dichloroethane are added thereto. While cooling with ice, argon is conducted directly into the solution until it has reached a temperature of 10° C. There is thus obtained a 1,2-dichloroethane solution of [6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)C.O.Cl>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CC(O)Cn1c(N)cc(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)Cn1c(N)c(N=O)c(=O)n(C)c1=O

Procedure:
To 79 g (0.4 mol) of 6-amino-1-(2-hydroxypropyl)-3-methyl- 2,4-(1H, 3H)-pyrimidinedione (IV), dissolved in 500 ml of ethanol, was added 30 g NaNO2 (0.43 mol) which was dissolved in water, whereafter 36 ml conc. hydrochloric acid was added. The red crystals were dissolved through boiling and the sodium chloride was filtered off. The red filtrate was used for synthetizing 5,6-diamino-1-(2-hydroxypropyl)-3-methyl-2,4-(1H, 3H)-pyrimidinedione (VI) NMR.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([OH:17])[C:6]=2[CH:7]=1)[CH3:2].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:25]3[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CC)oc2c1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.80 g, 3.4 mmol), 4-fluorophenyl methyl sulfone (0.60 g, 3.4 mmol) and Cs2CO3 (1.12 g, 3.4 mmol) in DMF (40 mL) was heated to 100° C. overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The mixture was poured into water (50 mL) and extracted with EtOAc (90 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with petroleum ether/EtOAc (20:1) to afford the desired compound (0.80 g, 60%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:25]([C:32](=[O:48])[C:33]3[CH:38]=[C:37]([I:39])[C:36]([CH2:40][CH3:41])=[C:35]([I:42])[C:34]=3[O:43][CH2:44][C:45]([OH:47])=[O:46])[C:24]=2[CH:49]=1>C(Cl)Cl>[CH2:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:8](=[O:17])[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)=[CH:49][C:24]=2[C:25]=1[C:32](=[O:48])[C:33]1[CH:38]=[C:37]([I:39])[C:36]([CH2:40][CH3:41])=[C:35]([I:42])[C:34]=1[O:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1oc2ccc(NC(=O)c3ccc(OC)cc3)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Triethylamine (28 mg, 0.28 mmol) and anisoyl chloride (47 mg, 0.28 mmol) were added to a solution of 5-amino-2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-benzofuran (prepared as in Example 1(g) (150 mg, 0.23 mmol) in methylene chloride (5 ml) . The resulting mixture was stirred at room temperature overnight, then washed with brine, dried using MgSO4 and concentrated to produce 172 mg (95%) of 2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:12])(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH2:14][C:15]#[N:16]>C1COCC1.CCOCC>[C:4]([S:11][CH2:14][C:15]#[N:16])(=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCl
Reactant: OC(=S)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Sodium methoxide (5.13 g; 0.095 mol) is added with stirring to an ice cold solution of thiobenzoic acid (13.8 g; 0.095 mol) in THF (100 ml). A yellow slurry forms. Next, chloroacetonitrile (6.45 ml; 0.10 mol) is added, and the reaction mixture stirred overnight at room temperature. It is then filtered, and the filtrate concentrated in vacuo to yield a yellow oil. This oil is dissolved in ether, the solution washed with saturated sodium bicarbonate solution, saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The residual oil is distilled (boiling point 105°-106° C. at 10.5 mm) to afford 12.8 g (76%) of title product, a yellow oil.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH2:9][C:10](Cl)=[O:11]>>[Br:8][CH2:9][C:10]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)CBr
Reactant: OC1CCCCC1
Product: O=C(CBr)OC1CCCCC1

Procedure:
The sub-title compound was prepared analogously to the procedure described in Example 32(i) above from cyclohexanol (1 g; 10 mmol) and bromacetylchloride (1 mL; 12 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Product: CC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 99 above, with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and acetyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:24]([F:34])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:24]([F:34])[CH:23]=1
Reactant: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1F
Yield: 100 %

Procedure:
Use a method similar to the General Procedure 14 to deprotect 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.406 g, 0.83 mmol) in 1,4-dioxane (12.8 mL). Purify by SCX chromatography eluting with dichloromethane and dichloromethane/2M ammonia in methanol (1:1) followed by chromatography on silica gel (40 g RediSep column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 over 30 min) and then dichloromethane/2M ammonia in methanol (90:10 over 30 min; 35 mL/min) to afford 7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (0.3237 g). MS (ES+) m/z: 390.1 (M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.301 g, 0.772 mmol) to provide the title compound as a beige solid (0.328 g, 84%). MS (ES+) m/z: 390.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:23][CH2:24][CH:25]=[C:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[N:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]2=3)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: NCCNc1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of N-(4-chloro-phenyl)-ethane-1,2-diamine (0.68 g, 3.96 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.31 mL, 2.64 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound. 1H-NMR (DMSO) δ: 1.40 (6H, s), 2.20–2.40 (2H, m), 2.70–2.90(3H, m), 3.10–3.30 (3H,m), 5.20 (2H, br, s), 5.80 (1H, m), 6.15 (1H, t), 6.60–6.70 (1H, m), 7.10–7.30 (4H, m) 7.50 (2H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 464 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CCOCC>[CH2:9]([N:11]([CH2:12][CH3:13])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: CCNCC
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: CCN(CC)Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 11.9 ml of benzyl bromide in 100 ml of ether was added dropwise to a mixture of 30.9 ml of diethylamine in 100 ml of ether. This mixture was stirred overnight then filtered and washed with ether. The combined filtrate and wash was washed with water, dried and concentrated to an oil. This oil was distilled through a Kugelrohr and the fraction boiling at <70° C., 1.5 mm collected, giving 10.6 g of N,N-diethylbenzenemethanamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][C:27]1[C:34]([F:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([S:24][CH2:26][C:27]3[C:28]([F:36])=[CH:29][C:30]([C:31]#[N:32])=[CH:33][C:34]=3[F:35])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(F)c(CBr)c(F)c1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2c(F)cc(C#N)cc2F)n1-c1ccc(F)cc1
Temperature: 56 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
A mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (760 mg, 2 mmol), 4-(bromomethyl)-3,5-difluorobenzonitrile (464 mg, 2 mmol) and K2CO3 (414 mg, 3 mmol) in acetone (10 mL) was stirred at 56° C. for 4 h. After cooling, the solids were removed by filtration and rinsed with acetone. The combined filtrates were concentrated and purified by flash chromatography, eluting with EtOAc-Hexane (1:1) to afford the title compound (89 mg). 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J=4.2, 2H), 7.17 (d, J=6.5, 2H), 7.03 (d, J=2.2, 1H), 6.88-6.79 (m, 3H), 6.50-6.44 (m, 2H), 4.08 (d, J=9.1, 2H), 2.04 (s, 1H), 1.49 (s, 7H); MS (EI) m/z 432 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:17]([F:19])[F:18])[C:3]=1[C:20]#[N:21].[CH3:22][C@H:23]1[O:28][C@@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1.[F-].[K+].O>CS(C)=O>[F:18][CH:17]([F:19])[C:4]1[C:3]([C:20]#[N:21])=[C:2]([N:25]2[CH2:24][C@H:23]([CH3:22])[O:28][C@H:27]([CH3:29])[CH2:26]2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)F)c(C#N)c2Cl)nc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1CN(c2c(C#N)c(C(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)C[C@H](C)O1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
5-Chloro-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile (1.24 g, 3.7 mmol) and 2,6-cis-dimethylmorpholine (0.86 g, 7.4 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (13 ml) and potassium fluoride (0.43 g, 7.4 mmol) was added to the clear solution. The resulting mixture was stirred at 20° for a period of 2 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml). The organic extract was dried over sodium sulfate and concentrated with a rotary evaporator. The desired product (1.3 g, 85%) was isolated by triturating the residue with ether (10 ml) containing 3 drops of methanol, stirring the suspension overnight, filtering, and drying under high vacuum. MS: 412.5, r.t.: 2.2, 1HNMR: (in d6-DMSO solvent) 9.02(1H, d, J=2.4), 8.52(1H, dd, J=8.8, 2.8), 7.98(1H, d, J=8.8), 7.12(1H, t, J=52.8), 3.68(2H, m), 3.36(3H, s), 3.28(2H, m), 2.80(2H, m), 0.99 (6H, d, J=6.4) ppm, 13C-NMR: (in d6-DMSO solvent) 155.9, 154.2, 148.2, 139.6, 119.2, 113.2, 113.1, 112.0, 109.9, 79.0, 71.6, 55.9, 44.3, 18.9 ppm.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C.CCOCC>[Br:20][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 3 h

Procedure:
2-Fluoro-3-trifluoromethylaniline (28.8 g, 161 mmol) is dissolved in DMF (100 mL). A solution of NBS (28.6 g, 161 mmol) in DMF (100 mL) is added dropwise at room temperature. After 3 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([NH2:35])[C:28]=1[NH2:36].[I-].ClC1C=CC=C[N+]=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:16](=[O:17])[NH:36][C:28]2[C:29]([NH2:35])=[CH:30][C:31]([F:34])=[C:32]([F:33])[C:27]=2[F:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OC(C(=O)O)c2cccc(Br)c2)CC1
Reactant: Nc1cc(F)c(F)c(F)c1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(OC(C(=O)Nc2c(N)cc(F)c(F)c2F)c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butyl ester (general procedure 165D+saponification)(1 g) in acetonitrile (10 mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg), 2-chloro-1-methylpyridinium iodide (802 mg) and dropwise diisopropylethylamine (1.1 mL). The reaction mixture is stirred at room temperature for 2 hours. Solvent is removed under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to get 4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3-bromophenyl)methoxy]piperidine-1-carboxylic acid tert-butyl ester. This intermediate is dissolved in acetic acid (15 mL) and the reaction mixture is refluxed for 3 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium hydrogencarbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to yield 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.
Reaction SMILES: [CH:1](OC(Cl)(Cl)Cl)=[O:2].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([NH:29][NH2:30])=[O:28])[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>O1CCOCC1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[C:26]([C:27]4[O:28][C:1](=[O:2])[NH:30][N:29]=4)[CH:25]=3)[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: NNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Reactant: O=COC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)o1

Procedure:
7.2 A solution of 131 mg (0.65 mmol) of trichloromethyl formate in 3 ml of dioxane is added to a suspension of 178 mg (0.50 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzohydrazide in 1 ml of dioxane, and the mixture is heated at the boil for 4 hours. The reaction mixture is allowed to cool, and water is added. The resultant precipitate is filtered off with suction, washed with water and dried. The residue is chromatographed on a silica gel column with dichloromethane/methanol, giving 6-(3,5-difluorophenyl)-2-[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl]-2H-pyridazin-3-one (“A15”) as colourless crystals; ESI 383;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[O:20]=[C:19]1[C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[N:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([S:9]([OH:12])(=[O:10])=[O:11])[CH:3]=2)[NH:8]1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzenesulfonic acid and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-sulfonic acid.