Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+].CC(C)=O>O>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [I-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCCI

Procedure:
11-Iodo undecanoic acid was synthesized according to Bergbreiter, J. Org. Chem., 40 (6), (1975) 779-782. Briefly, 250 g 11-Bromo undecanoic acid, 325 g Sodium iodide and 2 liter acetone were refluxed under N2 atmosphere for 24 hours. The mixture was divided and added to 4 liter H2O each. The mixtures were fritted and the crude product recrystallized from methanol and finally characterized by the melting point.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:1]([N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:22]([Cl:21])=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 279 %

Procedure:
The crude oil was dissolved in 140 ml of ethanol, treated with a solution of 10 g of potassium hydroxide in 20 ml of water and stirred at room temperature for 2 hours. The reaction mixture was poured on ice water, extracted with ether, dried (Na2SO4) and the solvent evaporated. The oily residue was filtered through silica gel (eluent hexane/10% ethyl acetate) to give 9.8 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine as a slightly yellow oil. A solution of 1 g of this amine in 20 ml of tetrahydrofuran was treated with 380 mg of triphosgene, heated to reflux for 3 hours, then poured on ice water and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and the solvent evaporated. The oily residue was crystallized in pentane to give 1.2 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride in white crystals, m.p. 79-81° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[C@@H:3]1[C@H:4]([C:9](Br)([Br:11])[Br:10])[O:5][C:6]2=[O:8].CC1(C)[C@H]2[C@@H]1[C@@H](C(Br)(Br)Br)OC2=O.C(=O)([O-])O.[Na+].C([O-])=O.[Na+].Cl>CO>[Br:10][C:9]([Br:11])=[CH:4][C@H:3]1[C@@H:7]([C:6]([OH:8])=[O:5])[C:2]1([CH3:1])[CH3:13]
Reactant: CC1(C)[C@H]2[C@H](C(Br)(Br)Br)OC(=O)[C@H]21
Agent: CC1(C)[C@@H]2[C@H]1C(=O)O[C@@H]2C(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Br)Br

Procedure:
A mixture of (1R,4R,5S)-6,6-dimethyl-4-(tribromomethyl)-3-oxabicyclo[3.1.0]hexan-2-one (I, R1=X1=X2=Br) and (1R,4S,5S)-6,6-dimethyl-4-(tribromomethyl)-3-oxabicyclo[3.1.0]hexan-2-one (I, R1=X1=X2=Br), 0.38 g (0.001 mol), is stirred with sodium hydrogen carbonate, 0.126 g (0.0015 mol), sodium formate, 0.27 g (0.004 mol), and Pt(C) 5%, 0.03 g, in about 4 ml of methanol at 50° C. for 5.5 hours. The reaction mixture is acidified with aqueous hydrochloric acid and extracted twice with methyl t-butyl ether which is dried and evaporated. There is obtained 0.28 g of purity 61% (GC, area-%). The retention time is identical to that of II prepared according to Ref.6, and MS (Mass (intensity in % of base peak): 296 (5) M+, 298 (9) (M+2)+, 300 (4) (M+4)+, 255 (24), 253 (45), 251 (23), 219 (100), 217 (98), 201 (18), 199 (22), 197 (13), 174 (29), 172 (33)) is identical to MS of II prepared according to Ref.6.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-methoxyaniline (30 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methoxyphenyl)benzamide as a white solid. Yield: 47 mg (46%). 1H-NMR: 10.33 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.66-7.61 (m, 3H), 7.24-7.18 (m, 1H), 7.11-7.08 (m, 2H), 6.93 (d, J=9.0, 2 Hz, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=6.5 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH:9]=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][CH:13]([Cl:18])[C:14]([F:17])([F:16])[F:15].O1CCCC1.CC(C)([O-])C.[Na+]>CN(C)C=O>[Cl:12][C:13]([Cl:18])([C:14]([F:17])([F:16])[F:15])[CH:9]([OH:10])[CH2:8][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)CC=O
Reactant: FC(F)(F)C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(C)CC(O)C(Cl)(Cl)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To an agitated mixture of methyl 3,3-dimethyl-5-oxopentanoate (1.0 g), 1,1-dichloro-2,2,2-trifluoroethane (1.06 g) and dry tetrahydrofuran (10 cm3), maintained at -78° C., was added, over a period of 5 minutes, sodium t-butoxide (1.66 cm3 of a 42% w/w solution in dimethylformamide) after which the mixture continued to be agitated at -78° C. for a further 60 minutes. The reaction was quenched with saturated ammonium chloride at low temperature and the mixture allowed to warm to the ambient temperature. After addition of water (20 cm3) and separation of the organic phase, the aqueous phase was extracted with di-isopropyl ether (3×30 cm3) and the extracts combined with the organic phase, which was washed with brine (2×10 cm3) and dried over anhydrous magnesium sulphate. After removal of the volatile components by evaporation under reduced pressure the residual oil was purified by column chromatography (silica gel column eluted with a 9:1 mixture (by volume) of hexane and ethyl acetate) to give methyl 6,6-dichloro-3,3-dimethyl-5-hydroxy-7,7,7-trifluoroheptanoate as a colourless oil (yield 56%).
Reaction SMILES: O=[O+][O-].[CH2:4]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1)[CH:5]=C.Cl.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([CH2:5][CH2:4][C:7]3[CH:16]=[CH:15][C:10]4[C:11](=[O:14])[O:12][CH2:13][C:9]=4[CH:8]=3)[CH2:33][CH2:34]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=[O+][O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc([N+](=O)[O-])cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ozone was bubbled through a solution of 5-allyl-2-benzofuran-1(3H)-one (125 mg, 0.72 mmol) in DCM until the color changed to orange. Removed excess ozone by bubbling nitrogen through solution for a minute. Added a solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (65 mg, 0.24 mmol) and triethylamine (0.033 mL, 0.24 mmol) in DCM (2 mL), followed by NaB(OAc)3H (250 mg, 1.2 mmol). The mixture was allowed to stir at RT for 16 hours. HPLC-MS shows product but reaction is not clean. The product was urified by prep-TLC to afford 5-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)-2-benzofuran-1(3H)-one as a white solid. LC-MS (IE, m/z): 396 [M+1]+. (0.089 μM)
Reaction SMILES: [O:1]1[C:7]23[CH2:8][CH:4]([CH2:5][CH:6]2C=C)[CH2:3][CH:2]13.C1[CH:15]2[CH:16]3[CH:20]=[CH:19][CH:18]([CH:14]2C=C1)[CH2:17]3>>[C:16]12([C:2]34[O:1][C:7]53[CH2:8][CH:4]([CH2:3]4)[CH2:5][CH2:6]5)[CH2:17][CH:18]([CH2:19][CH2:20]1)[CH:14]=[CH:15]2
Reactant: C=CC1CC2CC3OC13C2
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: C1=CC2(C34CC5CCC3(C5)O4)CCC1C2
Temperature: 180 °C
Reaction time: 4 h
Yield: 329.6 %

Procedure:
To a 2-liter stainless steel autoclave reactor was charged 0.99 kg (7.26 mol) 3-epoxy-5-vinyl norbornane and 0.06 kg (0.45 mol) dicyclopentadiene. Stirring was started, and the reactor evacuated of air and padded with 5 psig nitrogen. Heating to 180° C. commenced, and upon achieving 180° C., the reactor was held for 4 hours at this temperature. At the end of this time, the reactor was cooled to ambient temperature and discharged. The major identified components of the charge, as measured by GC area, were: 0.6% dicyclopentadiene, 81.6% 3-epoxy-5-vinyl norbornane, 1.3% epoxyethylepoxy norbornane, 13.6% norbornenyl epoxy norbornane. A total of four reactions were completed and distilled to produce 0.3 kg norbornenyl epoxy norbornane with assay greater than 96% (GC area).
Reaction SMILES: [NH4+]=[S:2].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:20][CH:19]=1)[C:15]#[N:16].O1CCCC1.C(OCC)(=O)C>CO.O>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:22][CH:23]=1)[C:15]([NH2:16])=[S:2]
Reactant: COc1cc(F)c(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1OC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Reaction time: 0.25 h

Procedure:
After adding 36.8 ml of a 20% aqueous solution of ammonium sulfide to a solution of 7.97 g of (2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 750 ml of a methanol:tetrahydrofuran (hereinafter, “THF”)=2:1 mixed solvent, the mixture was stirred at room temperature for 22 hours. Next, 1500 ml of ethyl acetate and 1000 ml of water were added to the reaction mixture, stirring was carried out at room temperature for 15 minutes, and the precipitate was filtered off. The organic layer in the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure and combined with the previously obtained precipitate to give the title compound (8.59 g) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][N:11]=[CH:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O-:14][C:15]#[N:16].[K+].Cl[O-].[Na+]>C(O)(=O)C.O>[CH3:13][C:12]1[NH:16][C:15](=[O:14])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:11]=1
Reactant: CC=NNc1cccc([N+](=O)[O-])c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirred, warm (40° C.) solution of 66.2 g (0.37 mole) of acetaldehyde 3-nitrophenylhydrazone (compound 40, FIG. 5) in one liter of acetic acid was added a solution of 30.0 g (0.37 mole) of potassium cyanate in 75 ml of water. The reaction mixture was cooled to 20° C. and stirred for 30 minutes. An aqueous 5% sodium hypochlorite solution (600 ml) was added to the mixture during a 30 minute period while maintaining a temperature of 20° C. A precipitate formed during the addition. After this addition was complete, the mixture was diluted with one liter of water and was filtered; the filtrate was saved for further use. The filter cake was triturated with a solution of ethyl acetate:n-heptane (1:1) and was filtered. The solid thus collected was dried under reduced pressure to yield 52.4 g of 4,5-dihydro-3-methyl-1-(3-nitrophenyl)-1,2,4-triazol-5(1H)-one.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH:2]3[CH2:6][CH2:5][N:4]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=4)[C:3]3=[O:16])[CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC1(F)CNCCC1c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(F)(F)C3)C2=O)cc1F
Temperature: 120 °C

Procedure:
To a mixture of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (0.51 g, 1.8 mmol, Intermediate 6) and 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.3 g, 1 mmol, from step C) was added triethylamine (0.69 mL, 4.9 mmol) and the resulting mixture was heated in a sealed tube at 120° C. for 1 h. The reaction mixture was allowed to cool and then diluted with water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue (0.45 grams, 64%, mixture of 4 diastereoisomers) was used directly in the next step without further purification, LCMS (method P) RT 1.19 min, m/z 509 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.I[CH2:32][CH2:33][OH:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:34][CH2:33][CH2:32][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:7][CH2:8]1)[CH3:1]
Reactant: OCCI
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CCO)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (125 mg) obtained in Example 221 is suspended in ethanol (5 ml), and thereto are added 2-iodo-ethanol (105 μl) and sodium carbonate (57 mg), and the mixture is stirred at 50° C. for 15 hours. To the mixture is further added 2-iodo-ethanol (53 μl), and the mixture is further stirred at 80° C. for 6 hours. Again, 2-iodo-ethanol (53 μl) is added thereto, and the mixture is stirred at 80° C. for 24 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water, a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2, then ethyl acetate) to give trans-3-[4-(N-(2-hydroxyethyl)-N-methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (53 mg). Subsequently, this product is dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure. The resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (55 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]=[CH2:15])[CH:3]=1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[OH-].[Na+]>O1CCCC1>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH:14]=[CH2:15])[CH2:9][CH2:10]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C=Cc1cc(C)ccc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1cc(C)ccc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
16.1 (19); Leu.* 39.0 (39); Phe. 17.1 (16);
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccc2ncccc2c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccc3ncccc3c2)n1
Yield: 75 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 6-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt cyclohexane, 1:1), the title compound was obtained (324 mg). Yield: 75%. 1H NMR (250 MHz, DMSO-d6) δ 7.56-7.59 (m, 1H, Harom 3), 7.70 (dd, 1H, Harom 7, Jm=2.6 Hz, Jo=9.1 Hz), 7.87 (d, 1H, Harom 5, J=2.4 Hz), 8.12 (d, 1H, Harom 8, J=9.0 Hz), 8.37 (d, 1H, Harom 4, J=8.1 Hz), 8.56 (s, 1H, HPz 5) 8.65 (s, 1H, HPz 3), 8.93 (dd, 1H, Harom 2, J=1.0 Hz, J=4.9 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([CH3:16])([O:11][Si](C)(C)C)[CH3:10])=[CH:4][CH:3]=1.Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]([CH3:10])([OH:11])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(C)(O[Si](C)(C)C)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)C(=O)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of 3.4 g of 1-(4-chlorophenyl)-2-methyl-2-trimethylsilyloxy-propan-1-one in 10 mL of methanol 4 mL of 2N HCl was added and the mixture was stirred for 3 hr. The reaction was diluted with CH2Cl2 and washed with water, brine, dried and concentrated to give the title compound which was used in the next step without purification. 1H NMR: (500 MHz, CDCl3): δ 1.65 (s, 6H), 7.47 (d, 2H), 8.03 (d, 2H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:20]([C:26]([F:27])([F:29])[F:28])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (1.0 g, 1.99 mmol) prepared in Step 4 of Preparation 17, 1-BOC-piperazine (557.0 mg, 2.99 mmol), Pd2(dba)3 (91.0 mg, cat.), BINAP (124.0 mg, cat.) and sodium t-butoxide (287.0 mg, 2.99 mmol) were added to toluene (20.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 480.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:37](I)[CH3:38]>C(OCC)(=O)C>[CH2:37]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:38]
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C)c(C)cc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxylate (0.35 g), potassium carbonate (0.13 g) and N,N-dimethylformamide (8 mL) was added dropwise ethyl iodide (0.074 mL) under ice-cooling. The mixture was stirred at from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8), and the obtained colorless crystals were recrystallized from ethyl acetate-hexane to give the title compound (253 mg, yield 67%) as colorless prism crystals. melting point 134-135° C.