Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>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].C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:26]([NH:33][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(NCc2ccccc2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Under argon, 1.73 g (17.95 mmol) of sodium tert-butoxide were weighed out into a dry flask, and 40 ml of abs. toluene were added. 5.2 g (14.96 mmol) of tert-butyl 3-(3-bromo-4-chlorophenyl)-2,2-dimethylpropanoate, 1.96 ml (17.95 mmol) of benzylamine, 685 mg (0.75 mmol) of tris(dibenzylideneacetone)dipalladium and 373 mg (0.60 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added in succession. The reaction mixture was stirred at 110° C. for 2.0 h, then cooled to RT and stirred at this temperature overnight. Saturated aqueous ammonium chloride solution and ethyl acetate were then added, and the reaction mixture was filtered off with suction through kieselguhr. After phase separation, the organic phase was washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative HPLC (mobile phase acetonitrile/water). This gave 2.78 g of the title compound (50% of theory).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[O:27]=[C:28]1[NH:33][C:32](=[O:34])[C:31](B(O)O)=[CH:30][NH:29]1.C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:31]2[C:32](=[O:34])[NH:33][C:28](=[O:27])[NH:29][CH:30]=2)[CH:3]=1)=[O:15]
Reactant: O=c1[nH]cc(B(O)O)c(=O)[nH]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3c[nH]c(=O)[nH]c3=O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 150 °C
Yield: 43.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)boronic acid (50 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.74 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and reaction mixture was heated in a microwave at 150° C. for 30 min. After cooling, 2 mL of water was added to the black mixture and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1) and sonicated. The solids that precipitated were filtered, washed with EtOH and DCM, and dried to afford the title compound (41 mg, 42%) as a light grey solid. LCMS E-S (M+H)=449.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1 H), 11.52 (br. s., 1 H), 11.47 (s, 1 H), 8.75 (t, J=5.05 Hz, 1 H), 8.36 (s, 1 H), 8.31 (s, 1 H), 8.23 (s, 1 H), 5.90 (s, 1 H), 5.27 (quin, J=6.69 Hz, 1 H), 4.37 (d, J=5.05 Hz, 2 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.52 (s, 3 H), 1.50 (s, 3 H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:15])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26](Cl)[CH:25]=2)[CH2:19]1.NCC1CCN(CC2C=CC=CC=2)C1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:18]([CH2:17][NH:16][C:13](=[O:15])[CH2:12][N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH2:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(O)Cn1ccc(-c2ccccc2)n1
Agent: NCC1CCN(Cc2ccccc2)C1
Product: O=C(Cn1ccc(-c2ccccc2)n1)NCC1CCN(Cc2ccccc2)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-phenylpyrazol-1-yl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-aminomethyl-1-benzylpyrrolidine gave N-[1-(benzyl)-pyrrolidin-3-(RS)-ylmethyl]-2-(3-phenylpyrazol-1-yl)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:11][O:10]1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13]
Reactant: c1nc[nH]n1
Reactant: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, 0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) and potassium carbonate (5.96 g, 0.043 mol) were added, followed by stirring at 60° C. for 2 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether--ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.5 g, yield: 25%) was obtained as colorless crystals.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])=[N+:2]=[N-:3].[Cl:13][C:14]1[C:21]([F:22])=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1.[H-].[Na+].O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([O:6][C:16]1[CH:15]=[C:14]([Cl:13])[C:21]([F:22])=[CH:20][C:17]=1[C:18]#[N:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Yield: 69.8 %

Procedure:
The product from step (a) (1.75 g) and 4-chloro-2,5-difluorobenzonitrile (1.86 g) in dry DMF (40 ml) were treated with 60% sodium hydride in mineral oil (470 mg) with stirring under nitrogen. The reaction mixture was stirred for 2.5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water (5×) then brine and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, 10% ether/isohexane as eluent) to give the sub-title compound (2.37 g) as a pale yellow oil.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:6]2[CH2:7][CH2:8][C:9]3[S:1][CH:2]=[CH:3][C:4]=3[C:5]2=[O:10])[CH:13]=1
Reactant: O=C1NCCc2sccc21
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccsc2CCN1c1cccnc1
Yield: 49.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-7d: 80 mg, 0.5221 mmol) was reacted with 3-bromo-pyridine (99 mg, 0.6266 mmol), 1,4-dioxane (15 mL), copper iodide (9.9 mg, 0.05221 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (22.2 mg, 0.15667 mmol) and potassium phosphate (277.1 mg, 1.3054 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 60 mg of the product (50% yield).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:10]([O:11][CH3:12])[CH3:9])=[O:19])=[C:16]([CH3:23])[CH:15]=1
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.3 ml, 10.04 mmol) is added to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (0.45 g, 4.6 mmol) in toluene (15 ml). After 30 minutes at RT the solution is cooled to 0° C. and a solution of 4-bromo-2-methylbenzoyl chloride (0.977 g, 4.81 mmol) in toluene (5 ml) is slowly added. The reaction is stirred at RT for 2 h at 0° C. and then diluted with ethyl acetate. The mixture is washed with 0.1M aq. HCl solution followed by brine. The organic extract is separated, dried over (MgSO4) and concentrated in vacuo to afford a colourless oil. Purification by chromatography on silica, eluting with ethyl acetate:iso-hexane (1:1) yields the title product as a colourless oil. MS m/z 258.0 [M+H]+1H NMR (400 MHz, CDCl3) δ 2.32 (3H, s), 3.0 (3H, br s), 3.50 (3H, br s), 7.15 (1H, d), 7.35 (1H, d), 7.37 (1H, s).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[S:28][C:27]=2[C:26]([C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[C:46]([C:47]=3[CH:48]=2)=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:25][CH:24]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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].CCCCCC>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([N:40]3[C:39]4[CH:38]=[CH:37][C:36]([C:26]5[C:27]6[S:28][C:29]7[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=7[C:31]=6[CH:23]=[CH:24][CH:25]=5)=[CH:48][C:47]=4[C:46]4[C:41]3=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-n2c(-c3ccc(-n4c5ccccc5c5cc(-c6cccc7c6sc6ccccc67)ccc54)cc3)nc3ccccc32)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
In a 100-mL three-neck flask were put 0.36 g (1.0 mmol) of N-phenyl-2-(4-bromophenyl)benzimidazole and 0.36 g (1.0 mmol) of 3-(dibenzothiophen-4-yl)-9H-carbazole, and the air in the flask was replaced with nitrogen. To this mixture were added 10 mL of toluene, 0.10 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution), 0.15 g (4.3 mmol) of sodium tert-butoxide. This mixture was degassed while being stirred under reduced pressure. After this mixture was heated to 80° C., 5.0 mg (0.025 mmol) of bis(dibenzylideneacetone)palladium(0) was added thereto, and then the mixture was stirred at 80° C. for 3 hours. After the stirring, 14 mg (0.025 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture, and then it was further stirred at 110° C. for 7.5 hours. After the stirring, about 30 mL of toluene was added to the mixture, and then it was stirred at 80° C. This mixture was subjected to hot filtration with ethyl acetate through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina. The obtained filtrate was concentrated to give a white solid. The obtained solid was dissolved in toluene. The mixture was purified by silica gel column chromatography (a developing solvent in which the hexane/ethyl acetate ratio was 4:1), and further recrystallized from toluene/hexane, so that 0.41 g of a white solid was obtained in 65% yield. The synthesis scheme of Step 2 is illustrated in (b-1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1C(OC)=O.[OH-].[Na+].C(O)(=O)C.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)C.O>[CH3:7][C:6]1[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:3][S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNc1cscc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (commercially available from Avocado, catalog number 10115, 5.00 g, 29.2 mmol) in 95% ethanol (25 mL) was added 1.0 N NaOH (35 mL). The mixture was heated to reflux and stirred for 2.5 hrs. The resulting solution was cooled to room temperature before the addition of glacial acetic acid (2.05 mL, 35.8 mmol). After stirring for 5 minutes at room temperature, diethyl ethoxymethylenemalonate (DEEM, 6.5 mL, 32.2 mmol) was added. The mixture was stirred vigorously until it nearly solidified (ca. 5 min), and then it was left standing at room temp for 3 hours. 95% ethanol (60 mL) was added, and the mixture was warmed on a steam bath until solution was achieved. Water (50 mL) was added with continued heating on the steam bath, resulting in a slightly cloudy solution. The flask was removed from the steam bath and allowed to cool to room temp and then placed in a 0° C. refrigerator, at which point crystallization of the product as fine white filaments was rapid. After standing at 0° C. for. 2 hours, the mixture was filtered. The collected solid was washed with 50% ethanol/water and dried, affording a white solid (5.79 g). The filtrate was diluted with water to a total volume of 500 mL, left overnight at 0° C., and filtered to afford a second crop (0.96 g) that was of equal purity to the first crop by HPLC analysis.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Example 18, Step B, 400 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (20 mL) was added drop wise a solution of 1-chloro-4-isothiocyanato-2-trifluoromethylbenzene (380 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (470 mg, 2.4 mmol, 1.5 eq.) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was washed with H2O (25 mL), NaHCO3 (aq., 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc/hexanes) to yield (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=452.1 (M+H)+; MW Calc'd for C19H13ClF3N5OS: 451.86.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 4-chloroiodobenzene (4.77 g:0.02 mole) in dry acetonitrile (30 ml) and triethylamine (2.02 g:0.02 mole) under nitrogen, was added copper iodide (0.2 g:1.05 mole), bis (triphenylphosphine)palladium dichloride (0.2 g=0.285 mmole) and trimethylsilylethyne (2.156 g:0.022 mole). The mixture was stirred for three hours during which time there was an exotherm at 20° C. and a darkening of the reacton mixture. The mixture was poured into saturated ammonium chloride solution (100 ml) and was extracted with ether (×3). The extracts were combined, washed with dilute hydrochloric acid and dried over magnesium sulfate and then filtered through charcoal. Removal of solvent in vacuo gave a brown oil which was titurated with hexane and filtered to remove by-products. The filtrate was evaporated to give yellow crystals (3.90 g).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=2)[N:5]=1)[CH3:3].ClC1C(C(Cl)C)=NC2C(N=1)=CC(F)=CC=2.CN(C)C=O.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>O>[Cl:14][C:13]1[C:4]([CH:2]([N:40]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:41])[CH3:3])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([F:15])=[CH:8][CH:7]=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)c1nc2ccc(F)cc2nc1Cl
Agent: CC(Cl)c1nc2ccc(F)cc2nc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1nc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of 2-(1-bromoethyl)-3-chloro-6-fluoroquinoxaline (57.17 g, 197.5 mmol) containing 3-chloro-2-(1-chloroethyl)-6-fluoroquinoxaline (48.39 g, 197.5 mmol) in N,N-dimethylformamide (700.0 ml, 197.5 mmol) was added potassium phthalimide (91.43 g, 493.6 mmol) at rt and the mixture was stirred at rt for 1 h. After 1 h, to the mixture was added water (2 L). The mixture was extracted with DCM (500 mL×3). The combined organic layers were washed with brine (1 L×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red liquid. The red liquid was filtered though a plug of silica (5.5 inch diameter×5 inch height), and eluented with 20% of EtOAc in hexane, then 30% of EtOAc in hexane, and then 100% of EtOAc as eluent to give two fractions. Second fraction, desired product 2-(1-(3-chloro-6-fluoroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (53.367 g, 75.97% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (dd, J=9.4, 5.9 Hz, 1H), 7.81-7.95 (m, 6H), 5.86 (q, J=6.8 Hz, 1H), 1.86 (d, J=7.0 Hz, 3H). Mass Spectrum (ESI) m/e=356.0 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH:12]=O.[CH2:14]1COCC1>>[CH:12]([C:4]1[NH:3][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH2:14]
Reactant: C1CCOC1
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: C=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
NaH (2.6 g, 66.2 mmol) at 0° C. was added to a mixture of 1H-indole-2-carbaldehyde (4.00 g, 27.6 mmol) and PPh3CH3Br (19.7 g, 55.2 mmol) in dry THF (100 mL). After being stirred at room temperature for 16 hours, the reaction was quenched with water. After partition, the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-vinyl-1H-indole (4.0 g, 83% yield) as a solid.
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.ClC1C=C(Cl)C(Cl)=CC=1[N+]([O-])=O.[Cl:28][C:29]1[C:49]([Cl:50])=[CH:48][C:32]([NH:33][C:34]2[S:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[C:35]=2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:31]([N+:51]([O-])=O)[CH:30]=1.Cl.[Sn+2]>C(O)C.CS(C)=O>[NH2:51][C:31]1[CH:30]=[C:29]([Cl:28])[C:49]([Cl:50])=[CH:48][C:32]=1[NH:33][C:34]1[S:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)c(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.0 g), 2,4,5-trichloronitrobenzene (6.8 g) and dimethyl sulfoxide (70 ml), crude crystals (10.3 g) of ethyl 2-(4,5-dichloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (100 ml), 18% hydrochloric acid (100 ml) and tin(II) chlorihe.dihydrate (22.8 g), ethyl 2-(2-amino4,5-dichloroanilino)benzo[b]thiophene-3-carboxylate (5.3 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH:10]=[CH2:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.[OH-:13].[Na+].OO>O1CCCC1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][CH2:11][OH:13])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: C=CCc1c(C)ccc(Cl)c1O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(O)c1CCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere, a solution of 6-chloro-3-methyl-2-(prop-2-en-1-yl)phenol (7b) (8.70 g, 47.6 mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to 0° C. Borane-tetrahydrofuran complex, 1.0M solution in tetrahydrofuran (100 mL, 0.10 mol) was dropwise added. The reaction mixture was stirred at room temperature for 2 hours then cooled again to 0° C. A 10N sodium hydroxide solution (32.7 mL) was added dropwise, followed by a 30% hydrogen peroxide solution. The resulting mixture was warm to room temperature and stirred for 90 minutes. The reaction mixture was quenched with a 10% hydrochloric acid solution (163 mL). Layers were separated and the aqueous layer was extract with ethyl acetate (2×70 mL). The combined organics layers were washed with brine (3×100 mL) then cooled with an ice bath. A saturated solution of sodium sulfite (150 mL) was carefully added and the mixture was stirred for few minutes. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 75/25), to provide 6-chloro-2-(3-hydroxypropyl)-3-methylphenol (7c) (6.74 g, 33.6 mmol, 70%).