Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B(O)O)=[CH:37][C:32]=2[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:36]2[CH:35]=[CH:34][C:33]3[O:29][CH2:30][CH2:31][C:32]=3[CH:37]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.96 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.54 g) in 1,4-dioxane were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.09 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.75 g, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Cl>CN(C)C(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[N:2]([CH3:12])[CH3:1]
Reactant: CN(C)c1ncnc2nc[nH]c12
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 62.2 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.63 g of 6-dimethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.9 g of 9-(2-chloro-6-fluorobenzyl)-6-dimethylaminopurine as colorless needles (yield: 62%); m.p. 134°-135° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[O:17])=[CH:11][C:10]=2[C:34]([F:37])([F:36])[F:35])[CH2:4][CH2:3]1.C1COCC1.Br[C:44]1[N:48]2[C:49]3[C:54]([N:55]=[C:56]([NH:57][CH2:58][CH:59]([CH3:61])[CH3:60])[C:47]2=[N:46][CH:45]=1)=[CH:53][CH:52]=[CH:51][CH:50]=3.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(=O)([O-])[O-].[K+].[K+].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:58]([NH:57][C:56]1[C:47]2[N:48]([C:44]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[C:10]([C:34]([F:35])([F:36])[F:37])[CH:11]=4)=[O:17])=[CH:24][CH:23]=3)=[CH:45][N:46]=2)[C:49]2[C:54]([N:55]=1)=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:59]([CH3:61])[CH3:60]
Reactant: CC(C)CNc1nc2ccccc2n2c(Br)cnc12
Reactant: CN1CCN(Cc2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2C(F)(F)F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Product: CC(C)CNc1nc2ccccc2n2c(-c3ccc(NC(=O)Nc4ccc(CN5CCN(C)CC5)c(C(F)(F)F)c4)cc3)cnc12
Temperature: 140 °C
Yield: 16.7 %

Procedure:
1-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (244 mg, 0.47 mmol) was dissolved in potassium carbonate (1.41 mL, 1M in water) and THF (1 mL) and stirred overnight at rt in a sealed vial. (1-bromo-imidazo[1,2-a]quinoxalin-4-yl)-isobutyl-amine (75 mg, 0.235 mmol), Pd(OAc)2 (10.6 mg, 0.047 mmol) and P(oTol)3 (28.6 mg, 0.094 mmol) were added and the mixture was heated at 140° C. under microwave irradiation for 40 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 1-[4-(4-isobutylamino-imidazo[1,2-a]quinoxalin-1-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea (24.8 mg, 14%): 1H-NMR (300 MHz, d6-DMSO): δ=9.30 (1H, s), 9.24 (1H, s), 7.98 (1H, s), 7.68-7.50 (6H, m), 7.47 (3H, m), 7.27 (2H, m), 6.93 (1H, dd), 3.51 (2H, s), 3.37 (2H, dd), 2.38 (8H, br s), 2.19 (3H, s), 2.09 (1H, sept), 0.91 (6H, d) ppm; UPLC-MS: RT=1.03 min; m/z (ES+) 631.7 [MH+]; required MW=630.7.
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CC=1S([O-])=O.[Na+].[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](Cl)=[C:23]([N+:28]([O-])=O)[CH:22]=1)(=[O:20])=[O:19].P([O-])([O-])([O-])=O.P(O)([O-])([O-])=O.[Na+].[Na+].P(O)(O)([O-])=O.[Na+].[H][H]>O.[Ni].[Ni].[Al]>[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1)(=[O:19])=[O:20]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Product: Nc1cccc(S(=O)(=O)CCO)c1
Temperature: 80 °C
Yield: 90 %

Procedure:
34.2 g of moist paste of 2-chloro-5-nitrophenyl 2-hydroxyethyl sulphone from Example 1 [or an equimolar amount of 4-chloro-3-nitrophenyl 2-hydroxyethyl sulphone]are stirred into 250 ml of water and 50 ml of a phosphate buffer solution which has been prepared by dissolving 0.5 mole of disodium phosphate and 0.33 mole of monosodium phosphate in 1 l of water. When 1-2 g of a nonionic emulsifier and 1.5 g of Raney nickel, prepared from a 70:30 aluminium-nickel alloy, have been added, the mixture is heated to 80° C. Hydrogen is then injected to 20 bar. The subsequent feed of hydrogen is controlled at such a rate that the pressure is constant at 10-15 bar. When the consumption of hydrogen declines markedly, a sample is withdrawn and examined by chromatography (see Example 1) to check the completeness of the reduction. If, in a given case, 5-amino-2-chlorophenyl 2-hydroxyethyl sulphone [or 3 -amino-4-chlorophenyl 2-hydroxyethyl sulphone] is still detectable, approximately 0.5-1.0 g more catalyst is added and hydrogenation is carried out again at 80° C. and 20 bar. When the reduction and dehalogenation are complete, the pressure in the autoclave is released and the latter is flushed with nitrogen, and the catalyst is removed from the warm reaction solution by suction filtration. The solution is cooled and acidified with hydrochloric acid, and the content of 3-aminophenyl 2-hydroxyethyl sulphone in the solution is determined by diazotization with 10% strength sodium nitrite solution. The yield is approximately 90% of theory. The solution of 3-aminophenyl 2-hydroxyethyl sulphone thus obtained can be processed further directly in this form; it can, for example, be diazotized and the diazonium salt solution can be coupled, as described in Japanese Patent Application No. 05,667/70, with 7-acetylamino-1-naphthol-3-sulphonic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:18]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 120 °C

Procedure:
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), Cul (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120° C. (oil bath temperature) for 15 h. The mixture was cooled down to 45-50° C. and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:18]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
4-t-Butylbromobenzene (2.5 mmol), phenol (3.5 or 5.0 mmol), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2 PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (3.5 mmol), molecular sieves (625 mg) and toluene (1.5 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C. under argon until the aryl halide was consumed as determined by GC analysis. Upon cooling at room temperature, dichloromethane was added and the solvent was removed by filtration. The remaining molecular sieves were stirred with another portion of dichloromethane for 1 h at room temperature, and the solvent was removed by filtration. The combined organic phases were washed with 5% aqueous NaOH. The aqueous layer was then extracted three times with dichloromethane and the combined organic layers were washed with brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (2% EtOAc/hexane) gave the analytically pure product as a clear oil (457 mg, 81% yield). 1H NMR (300 MHz, CDCl3) δ 7.22-7.34 (m, 4 H), 6.90-7.05 (m, 5 H), 1.30 (s, 9 H); 13 C NMR (75 MHz, CDCl3) δ 157.6, 154.7, 146.0, 129.6, 126.5, 122.9, 118.6, 118.5, 34.3, 31.5; IR (neat): 3068, 3962, 8867, 1590, 1508, 1489, 1240 cm−1.
Reaction SMILES: C(O)(=O)CCC(O)=O.[NH2:9][C:10]1[C:27]([Cl:28])=[CH:26][C:13]([C:14]([NH:16][CH:17]2[CH2:21][N:20](CC)[N:19]([CH2:24][CH3:25])[CH2:18]2)=[O:15])=[C:12]([O:29][CH3:30])[CH:11]=1.CO.Cl[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:27]([Cl:28])=[CH:26][C:13]([C:14]([NH:16][CH:17]2[CH2:18][N:19]([CH2:24][CH3:25])[N:20]=[CH:21]2)=[O:15])=[C:12]([O:29][CH3:30])[CH:11]=1
Reactant: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)C=N1
Temperature: -20 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 8.90 g (0.020 mole) of 4-amino-5-chloro-N-(1,2-diethyl-4-pyrazolidinyl)-2-methoxybenzamide succinate in 400 ml of reagent grade methanol, cooled to -20° C. and under nitrogen atmosphere was added dropwise 80 ml of 5% aqueous sodium hypochlorite over a 20 min period while maintaining the reaction mixture at -20° C. The reaction mixture was stirred for an additional one hour period at 0° C. then diluted with one liter of chloroform. The diluted mixture was washed with 500 ml of water. The aqueous layer was extracted with 200 ml of chloroform. The combined chloroform layers were dried over sodium sulfate and concentrated in vacuo. The crude product was partially purified by column chromatography on a silica column (eluted with ethyl acetate:hexane:methanol, 4.5:4.5:1). Further purification was effected by high pressure liquid chromatography, using the same solvent system as eluant. On evaporation, the residue was triturated with cold diethyl ether to give 1.90 g (32.0%) of title product, m.p. 132.5°-134.0° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:6]([Cl:22])[CH:5]=1>[OH-].[Na+].C1COCC1>[Cl:22][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(OCCN2CCN(C)CC2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(Cl)c1OCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-Chloro-5-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoic acid methyl ester (3.7 g, 10.7 mmol) in 2 N NaOH (20 ml) and THF (40 ml) is heated at reflux for 1 hour. The reaction mixture is washed with Et2O. The aqueous phase is concentrated in vacuo, and water (50 ml) is added. The pH is adjusted to 3-4 using 2 N HCl. To this solution is added DOWEX 50WX4 (previously washed with MeOH, 2 N HCl and water), and the resulting mixture is stirred at room temperature for 1 hour. The resin is filtered, washed with water, and the product is released from the resin by washing with MeOH/NH4OH. The solution is concentrated in vacuo, diluted with DCM and MeOH, dried (Na2SO4) and the solvent removed in vacuo to yield the title compound as a light cream solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][C@@H:32]([N:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[CH3:40])[CH2:31]2)[N:24]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:29][C:28]2[C:23]([CH3:22])=[N:24][C:25]([N:30]3[CH2:34][CH2:33][C@@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C@@H:36]4[CH3:40])[CH2:31]3)=[CH:26][CH:27]=2)[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Product: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (66 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 111 mg of a crude solid, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
Tert-butyl 4-(4-trifluoromethylbenzyloxy)-piperidine-1-carboxylate (2.56 g, 7.12 mmol) prepared in Reference Example 122 was dissolved in methylene chloride (20 ml), to which trifluoroacetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with sodium hydroxide aqueous solution and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylbenzyloxy)piperidine (1.85 g, yield 99%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:15].[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:15])=[CH:20][CH:19]=1)#[N:17]
Reactant: CC(C)NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h
Yield: 18.5 %

Procedure:
According to general procedure B, 4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (174 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamide (35 mg, 19%) was provided after purification. HRMS: calcd for C15H16FN3O2S, 321.09472; found (EI, M+.), 321.0948. HPLC purity 100.0% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:31])[CH2:28][CH2:29][CH3:30]>O>[CH2:27]([O:31][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH2:28][CH2:29][CH3:30]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of butanol was stirred while heating at 100° C. for six hours. To the mixture, 0.14 g of potassium carbonate was added, and the reaction mixture was stirred while heating at 100° C. for further four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-butoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 72”).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]#[N:5].C(Cl)(Cl)(Cl)[Cl:19].ClN1C(=O)CCC1=O.O>CCOCC>[CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[Cl:19])[C:4]#[N:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 484 mg (2 mmol) of 3-methyl-2-(4-trifluoromethylphenylamino)butyronitrile (III; R is hydrogen) in 5 ml. of carbon tetrachloride is added 267 mg. (2 mmol) of N-chlorosuccinimide. The mixture is heated at 65°. After about 48 hours, the mixture is poured into water and ether. The organic fraction is separated, washed with water, and brine, dried over sodium sulfate, and solvent removed to give 3-methyl-2-(2-chloro-4-trifluoromethylphenylamino)butyronitrile (III; R is chloro).
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1.Cl[CH2:19][C:20]1[S:35][C:23]2[N:24]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:22]=2[CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[N:9]1([CH2:19][C:20]2[S:35][C:23]3[N:24]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:22]=3[CH:21]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(CCl)sc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Yield: 59.5 %

Procedure:
Potassium iodide (few crystals), potassium carbonate (140 mg) and benzimidazole (100 mg) were added to a solution of 6-chloromethyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (170 mg) in dimethylformamide (5 ml). After 2 h the reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution thrice and with brine, then dried over magnesium sulfate and evaporated. Column chromatography of the residue eluting with isohexane:ethyl acetate (1:1 to 0:1) containing 1% Et3N gave the title compound (130 mg).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.S(=O)(O)[O-].[NH4+]>CN(C)C=O.O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1I
Agent: O=S([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]c(Br)n1

Procedure:
2-Bromo-5-iodo-4-nitroimidazole (1.00 g, 3.15 mmol) was dissolved in dimethylformamide (8 ml) and water (3 ml). The obtained solution was stirred under cooling on ice, and then, a 50% to 55% ammonium bisulfite aqueous solution (3.6 ml, 23.5 mmol with a content of 52.5%) was added thereto. The obtained mixture was stirred at room temperature for 3 days. Thereafter, cold water (30 ml) was added to the reaction product, followed by extraction with ethyl acetate 3 times (167 ml in total). The organic layer was washed with 5% saline twice and then dried (MgSO4), followed by vacuum concentration and exsiccation.
Reaction SMILES: [CH2:1]([CH:5]1[CH:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7](=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([CH:5]1[CH:13]2[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][C:7](=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CC(=O)C=C2CCCC21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC1CC(=O)CC2CCCC12
Yield: 94 %

Procedure:
5-Butylbicyclo [4.3.0] non-1-en-3-one (120 g) is hydrogenated in ethyl acetate (125 ml) over 1.5 g of 5% palladium on carbon at a pressure of 4 atmospheres in a Parr apparatus. The solution is filtered through celite to remove the catalyst, concentrated, and the residue is vacuum distilled through a 12" Vigreaux column to yield 114 g (bp 98°-102° C. at 0.5 mm) of 5-butylbicyclo [4.3.0] nonan-3-one represented by the structure: ##STR10##