Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1.C(N(CC)CC)C.CS([Cl:25])(=O)=O>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([CH2:7][Cl:25])=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)(C)n1cc(CO)c(Br)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(C)(C)n1cc(CCl)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of (3-bromo-1-tert-pentyl-1H-pyrazol-4-yl)methanol (675 mg, 2.73 mmol) in dichloromethane (10 mL) was cooled to 0° C. Triethylamine (0.53 mL, 3.8 mmol) and methanesulfonyl chloride (0.28 mL, 3.6 mmol) were added. The reaction was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (725 mg, 100%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.48 (s, 1H), 4.47 (s, 2H), 1.86 (q, J=7.48 Hz, 2H), 1.52 (s, 6H), 0.69 (m, 3H).
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].C(S[CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1)C.CO.[CH3:43][C:44](C)=O.O>O>[CH2:43]([S:3]([CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1)(=[O:5])=[O:4])[CH3:44]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSCC
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CS(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Oxone (123 mg, 0.2 mmol) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH/acetone/water (15:5:3) (2 ml) at 0-4° C. The solution was allowed to warm to ambient temperature and stirred for 2 hr. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5) and the purified product triturated with ether to give the title compound (44 mg, 59%). NMR: 0.65 (t, 3H), 1.03 (t, 3H), 1.27 (t, 3H), 1.52 (m, 2H), 2.85 (q, 2H), 3.30 (m, 6H), 4.64 (t, 2H), 4 81 (s, 2H), 7.25 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.79 (s, 1H), 7.97 (d, 2H), 8.50 (d, 1H), 9.91 (s, 1H); m/z 537.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:20]2[CH3:29])=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:18].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:20]2[CH3:29])=[N:13][C:14]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@@H]2C)c1C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3[C@@H]2C)n1
Product: Cl
Yield: 45.4 %

Procedure:
After 2-methyl-4-fluoroaniline(1.1 ml, 9.9 mmol) was added to a mixture solution of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) obtained in the above Step 1 and dimethylformamide (10 ml), 0.90 g of the title compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [OH-:1].[K+].[CH3:3][S:4]([NH:7][C:8]1[S:9][C:10](CC(OCC)=O)=[CH:11][N:12]=1)(=[O:6])=[O:5].Cl.[CH2:20]([OH:22])[CH3:21]>>[CH3:3][S:4]([NH:7][C:8]1([CH2:21][C:20]([OH:1])=[O:22])[NH:12][CH:11]=[CH:10][S:9]1)(=[O:5])=[O:6]
Reactant: CCO
Reactant: CCOC(=O)Cc1cnc(NS(C)(=O)=O)s1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CS(=O)(=O)NC1(CC(=O)O)NC=CS1

Procedure:
To a solution of 1 N potassium hydroxide aqueous solution (246 ml.) in ethanol (52 ml.) was added ethyl 2-methanesulfonamidothiazol-5-ylacetate (26 g.) over 1 minutes under ice-cooling and stirring, and the mixture was stirred for about 5 minutes to produce a homogeneous solution. The solution was further stirred for 5 minutes and adjusted to pH 2 with 10% hydrochloric acid under ice-cooling and then stirred for 20 minutes at the same temperature. The precipitated crystals were collected by filtration, air-dried overnight and then dried over phosphorus pentoxide to give colorless crystals of 2-methanesulfonamidothiazol-2-ylacetic acid (16.6 g.), mp 232° to 234° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH2:16]([NH:18][C:19](=[O:36])[NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:19]([NH:18][CH2:16][CH3:17])=[O:36])=[CH:26][CH:25]=2)[CH:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
(S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (Intermediate 1B) (992 mg, 4.0 mmol), 4-(3-ethylureido)phenyl boronic acid pinacol ester (1.05 g, 3.6 mmol), cesium carbonate (3.9 g, 12.0 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (163 mg, 0.2 mmol) in dioxane/water (1:3, 2.4 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, the residue suspended in water (150 mL) and the pH adjusted from 10 to 7 with HCl (2M aq solution). EtOAc (150 mL) was added and aqueous layer removed. The organic layer was washed with brine (70 mL) and then concentrated in vacuo to leave a brown solid which was purified by flash chromatography (0-5% MeOH in DCM over 30 min) to yield an orange solid, 630 mg, 42%.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([NH:17][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Reactant: Nc1ccc2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(CC)CCOc1ccc(CNc2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of 1.0 gram (0.0045 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde and 0.65 gram (0.0045 mole) of 6-aminoquinoline (available from Aldrich Chemical Company) in 25 mL of 1,2-dichloroethane (DCE, available from Aldrich Chemical Company)was added 0.3 mL (0.0045 mole) of glacial acetic acid (available from J. T. Baker Inc.) followed by 1.4 grams (0.0068 mole) of sodium triacetoxyborohydride (available from Aldrich Chemical Company). Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide was added dropwise. The resulting solution was extracted with three 25 mL portions of diethyl ether. The extracts were combined, washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.25 grams of a dark brown paste. The dark brown paste was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 15. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].C(O[C:8](=[O:20])[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH3:19])[CH:13]=1)[CH3:10])C.CC(O)=O>CCO.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[CH:9]([CH3:10])[C:8](=[O:20])[NH:4][C:3]2=[O:1])=[CH:13][C:14]=1[CH3:19]
Reactant: CCOC(=O)C(C)Nc1ccc(Br)c(C)c1
Reactant: N#CO[K]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(N2C(=O)NC(=O)C2C)ccc1Br
Temperature: 60 °C
Reaction time: 11 h

Procedure:
KOCN (326 mg, 4.02 mmol) was added to a mixed solution of 2-(4-bromo-3-methyl-phenylamino)-propionic acid ethyl ester (383 mg, 1.34 mmol) in EtOH (5.30 mL) and H2O (2.68 mL). The mixture was stirred at room temperature for three hours and at 60° C. for 11 hours, and AcOH (1 mL) was then added, followed by further stirring for two hours. KOCN (163 mg, 2.01 mmol) was added, followed by further stirring for three hours. The reaction solution was cooled. H2O (50 mL) was added to the reaction solution at room temperature, and this aqueous layer was then extracted with ethyl acetate (20 mL×3). The organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(4-bromo-3-methyl-phenyl)-5-methyl-imidazolidine-2,4-dione as a yellow form (134 mg, 35%).
Reaction SMILES: [CH2:1]([N:3]([CH:6](O)[CH3:7])[CH2:4][CH3:5])[CH3:2].[H-].[Na+].Cl[CH2:12][C:13](=[O:27])[CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:16].Cl.C1C[O:32]CC1>>[CH2:1]([N:3]([CH2:6][CH2:7][O:32][CH2:12][C:13](=[O:27])[CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:16])[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCOC1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Reactant: CCN(CC)C(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCOCC(=O)CC(=O)OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Diethylaminoethanol (7.49 mL, 56.6 mmol) in THF (25 mL) was added dropwise to a suspension of sodium hydride (3.5 g, 87.5 mmol) in THF (100 mL) at 0° C. The mixture was then stirred for 30 minutes at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (11.10 mL, 51.5 mmol) in THF (25 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were washed two times with ethyl acetate and then made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform three times. The combined extracts were washed with brine, dried and evaporated to give the title compound (16.3 g) as an oil. Electrospray MS m/z 336 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:9][C:10]1[CH:11]=[C:12]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>C(OCC)C>[ClH:19].[Br:9][C:10]1[CH:11]=[C:12]([S:16]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCN1CCCC1
Solvent: CCOCC
Product: Cl
Product: O=S(=O)(NCCN1CCCC1)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
N-(2-Aminoethyl)pyrrolidine (1.61 g) was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (3.61 g) in diethyl ether (100 ml) at room temperature. The resulting suspension was stirred for 30 minutes and filtered to afford the sub-title compound as a solid (4.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][CH:14]1[CH2:19][NH:18][CH:17]([CH3:20])[CH2:16][NH:15]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]2[CH2:16][CH:17]([CH3:20])[NH:18][CH2:19][CH:14]2[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC1CNC(C)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C(C)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,4-dichlorobenzene-1-sulfonyl chloride (840 mg, 3.42 mmol) and 2,5-dimethylpiperazine (1.171 g, 10.26 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (1.2 mL, 6.84 mmol). The mixture was stirred overnight at room temperature. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4. After solvent evaporation crude product was treated with ethyl acetate/hexanes. Solid impurity was filtered of and the filtrate was concentrated to afford 1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine in quantitative yield. It was carried to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>C(Cl)Cl>[Br:39][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(CO)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a cooled (0° C.) and stirred solution of DCM (100 mL) containing (2-fluoro-4-nitrophenyl)methanol (9 g, 52.6 mmol, 1 eq), triphenylphosphine (16.5 g, 63.1 mmol, 1.2 eq) was added followed by addition of NBS (11.24 g, 63.1 mmol, 1.2 eq), the mixture was allowed to warm to RT and stirred for 2 h. The DCM was evaporated under reduced pressure and the residue was purified by CC using PE/EtOAc (9:1) as eluent to get 1-(bromomethyl)-2-fluoro-4-nitrobenzene (10.50 g, 85%; TLC system: PE/EtOAc (7:3), Rf: 0.6).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:15]1CC[O:18][CH2:17][CH2:16]1.C(OC(Cl)=O)C(C)C.C(CN)O>C(Cl)Cl>[OH:18][CH2:17][CH2:16][NH:15][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: NCCO
Solvent: ClCCl
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (1.734 g, 10.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (100 mL) and cooled to 0° C. in an ice bath. The flask was then charged with N-methyl morpholine (1.44 mL, 15.0 mmol) and isobutlychloroformate (1.51 mL, 11.5 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 20 min until the solution became cloudy. At which point freshly distilled ethanolamine (695 uL, 11.5 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature to form N-(2-hydroxyethyl)quinoline-2-carboxamide was formed according to the formula
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2)[CH3:2].[CH2:14]([I:18])[CH2:15][CH2:16][CH3:17]>C(#N)C.CCOCC>[I-:18].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N+:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCCCI
Reactant: CCOc1ccc2cnccc2c1
Solvent: CC#N
Solvent: CCOCC
Product: CCCC[n+]1ccc2cc(OCC)ccc2c1
Product: [I-]

Procedure:
6-Ethoxyisoquinoline (0.5 g.), and butyl iodide (0.5 g.) in acetonitrile (50 ml) were heated under reflux for 24 hours. The solution was cooled and diluted with ether to give pale yellow crystals, m.p. 129°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78.6 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc(CN2CCN[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled mixture of (3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (305 mg) and potassium carbonate (207 mg) in dimethylformamide (1 ml) was added 3,5-dichlorobenzoyl chloride (210 mg). The mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added. The organic layer was washed successively with aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in ethyl ether. After insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was triturated with diisopropyl ether, collected by filtration and dried to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(1H-indol-3-yl-methyl)piperazine.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][CH2:15][O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18]>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2]=1[N:22]1[CH2:21][CH2:20][N:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])[CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A mixture of 1.174 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 1.58 g of ethyl-N-piperazinocarboxylate and 100 ml of absolute ethanol was stirred for 24 hours, then evaporated. The residue was chromatographed on silica gel, eluting with 5% methanol in chloroform, giving 1.0 g of the desired product,, mp 115-118°C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])[CH:8]=2)[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([C:26]2[S:27][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:31]([C:28]4[S:27][C:26]([C:24]5[S:25][C:21]([Cl:20])=[CH:22][CH:23]=5)=[CH:30][CH:29]=4)(=[O:32])=[O:33])[CH2:15][C:14]3=[O:19])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Reactant: Nc1ccc2cc(CN3CCNCC3=O)ccc2n1
Product: Nc1ccc2cc(CN3CCN(S(=O)(=O)c4ccc(-c5ccc(Cl)s5)s4)CC3=O)ccc2n1

Procedure:
The title compound is prepared as described in Example 101 using 1-(2-aminoquinolin-6-ylmethyl)piperazin-2-one, EXAMPLE 67, and 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride, EXAMPLE 2. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ7.82 (d, 1H), 7.68 (d, 1H), 7.42 (m, 3H), 7.36 (d, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 6.70 (d, 1H), 6.43 (bs, 2H), 4.53 (s, 2H), 3.78 (s, 2H), 3.31 (m, 4H). MS (ion spray) m/z 519, 521, (M+H), Cl pattern.
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>C(#N)C>[Cl:37][C:1]1[N:2]=[C:14]([CH3:15])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)NC(C#N)COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}acetamide (1.64 g, 7.5 mmol), triphenylphosphine (4.9 g, 18.8 mmol), and carbon tetrachloride (1.8 mL, 18.8 mmol) in acetonitrile (75 mL) was heated at 45° C. for 6 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (80 mL) and 0.5 N NaOH (70 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-70% EtOAc:hexanes) to give the title compound as a yellow solid, in assumed quantitative yield due to inseparable triphenylphosphine oxide. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.37 (m, 5H), 4.50 (s, 2H), 4.48 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[CH2:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:47]=[CH:46][C:45]([CH:48]([CH3:62])[C:49]([C:55]2[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=2)([OH:54])[C:50]([F:53])([F:52])[F:51])=[C:44]([Cl:63])[CH:43]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:63][C:44]1[CH:43]=[C:42](/[CH:9]=[CH:8]/[C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:47]=[CH:46][C:45]=1[CH:48]([CH3:62])[C:49]([OH:54])([C:55]1[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=1)[C:50]([F:52])([F:53])[F:51]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(C(C)c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Triethyl amine (0.02 ml), 4-vinylbenzoic acid (CAS Reg. No. 1075-49-6, 19 mg), tri-o-tolylphosphine (2 mg) and palladium acetate (1 mg) were added to a solution of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 41 mg) in DMF (1 ml). The mixture was stirred at 100° C. for 3 h. Water was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0->100% EtOAc/heptane) to give the title compound (28 mg) as an orange oil. MS (m/e)=476.1 [M+H+].
Reaction SMILES: C(O)(=O)C.[N:5]([O-:7])=[O:6].[Na+].[F:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[N+]([O-])(O)=O>O>[F:9][C:10]1[CH:25]=[C:24]([N+:5]([O-:7])=[O:6])[C:23]([F:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=S(=O)(Nc1cc(F)ccc1F)c1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(F)c(NS(=O)(=O)c2ccccc2)cc1F
Temperature: 96 °C

Procedure:
To 310 ml of acetic acid diluted with 160 ml of water are added: 1.5 g of sodium nitrite, 0.16 mole (42 g) of 2,5-difluoro-N-benzenesulphonylaniline prepared in the previous stage and 0.94 mole (39 ml) of nitric acid (d=1.52). The reaction mixture is heated to 96° C. for 1 hour. After cooling it is poured onto 1 kg of ice and water. The expected product precipitates. After being filtered off and washed to neutrality it is recrystallized from 250 ml of acetic acid; it melts at 176° C.