Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.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]>[F:13][C:14]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:21][C:22]=1[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)n2cnnc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3nncn23)c1
Yield: 48 %

Procedure:
The title compound of Example 235, step 2 (40 mg, 0.175 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide (77 mg, 0.175 mmol), K3PO4 (93 mg, 0.438 mmol) and Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (2 mL) and H2O (1 mL) was N2 purged and microwaved at 70° C. for 2 h. Preparative HPLCgave the title compound (38.75 mg, yield: 49.3%) as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ 8.60 (s, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.45 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.10-7.05 (m, 1H), 6.99-6.88 (m, 3H), 6.74 (d, J=8.8 Hz, 1H), 3.67 (s, 3H), 3.18 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). LCMS: 462.0 (M+H)+
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([O:58][CH3:59])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([O:58][CH3:59])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 83 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (46 mg, 83%). 1H NMR (400 MHz, DMSO-d6): δ 7.64 (dd, J=2 and 8 Hz, 1H), 7.50-7.32 (m, 9H), 7.14-7.11 (m, 2H), 3.98 (s, 3H), 2.40-2.32 (m, 2H), 2.11-2.03 (m, 2H), 2.03-1.94 (m, 1H), 1.69-1.60 (m, 1H). LCMS (Method F): RT=8.94 min, [M+H]+=398.
Reaction SMILES: [CH:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1ncccc1N
Yield: 57.3 %

Procedure:
A solution of 2-vinyl-3-nitropyridine (0.75 g, 5.0 mMol) from step 1 above dissolved in 50 mL of ethanol and 100 mg of 10% palladium on carbon was shaken under 55 psi of hydrogen using a parr hydrogenation apparatus until hydrogen uptake ceased. The mixture was filtered through a bed of celite and the filtrate concentrated in vacuo. The residue was purified by flash silica gel chromatography using 1% then 2% methanol in methylene chloride as an eluent to afford the title compound as a white crystalline solid (0.35 g).
Reaction SMILES: [Ca].C([N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH3:16])[CH2:10]1)C1C=CC=CC=1.[ClH:25]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:25].[ClH:25].[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C@H:15]([NH:14][C@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [Ca]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@H]2CCNC2)c1
Reaction time: 72 h

Procedure:
To a solution of 8.0 g of (R)-1-benzyl-3-pyrrolidinol and 16.5 ml of diisopropylethylamine dissolved in 400 ml of methylene chloride was added dropwise a solution of 13.4 g of anhydrous trifluoromethanesulfonic acid in 50 ml of a methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., then, a solution of 9.88 g of (R)-1-(3-methoxyphenyl)ethylamine in 100 ml of methylene chloride was added dropwise to the mixture at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→50:1) and NH silica gel column chromatography (hexane:ethyl acetate=25:1→10:1) to obtain 3.98 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine. MS•APCI (m/z): 311 [M+H]+ (2) To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)-ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: C(=O)(O)[O-].[Na+].[S-2].[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)([O-:11])=[O:10]>O.CO>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: COc1cc(N)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
Sodium bicarbonate (5.62 g, 66.87 mmol) was added to a solution of sodium sulfide (5.5 g, 70.58 mmol) in deionized water (60 mL). When the sodium bicarbonate was completely dissolved, methanol (50 mL) was added, and the solution was cooled to 0° C. A precipitate formed, which was removed by filtration through a Celite pad. The filtered solution was added quickly to a solution of 3,5-dinitroanisole (7.36 g, 37.15 mmol) in methanol (50 mL). The resulting suspension was heated to reflux for 30 min and then the solution was concentrated in vacuo to remove methanol. The aqueous residue was poured into 200 mL of ice-water, and the resulting orange precipitate was collected by filtration. After air-drying, 3-methoxy-5-nitro-phenylamine (5.82 g, 93%) was obtained as light brown solid: ES(+)-HRMS m/e calculated for C7H8N2O3 (M+H)+ 169.0608, found 169.0608.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[S:17][C:16]([Cl:18])=[N:15][C:14]=1[Cl:19])[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[S:17][C:16]([Cl:18])=[N:15][C:14]=1[Cl:19])[O:12][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)c1sc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC(OC1CCCCO1)c1sc(Cl)nc1Cl

Procedure:
A soln. of 3-((tert-butyldimethylsilyl)oxy)-1-(2,4-dichlorothiazol-5-yl)propan-1-ol (6.62 g, 19.3 mmol), 3,4-dihydro-2H-pyran (8.9 mL, 96.7 mmol) and PPTS (0.49 g, 1.93 mmol) in DCM (75 mL) was stirred under reflux for 2 h. Subsequently, the volatiles were removed in vacuo and the residue was purified by means of CC (1-10% EtOAc/Hept) to provide the product as colorless oil as an isomeric mixture.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:26])[C:21](=[O:25])[CH:22](Br)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:19][N:20]([CH3:26])[C:21](=[O:25])[CH:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CC(Br)C(=O)N(C)C
Reactant: Oc1ccc(Oc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(Oc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)N(C)C
Yield: 88 %

Procedure:
In 100 ml of methyl ethyl ketone, 2.3 g of the intermediate of Preparation 1 of 2-(4-hydroxyphenoxy)quinoline, 1.8 g of N,N-dimethyl-α-bromopropionic acid amide and 1.4 g of potassium carbonate were added and the mixture was refluxed for 5 hours. After the reaction, the precipitated crystal was separated by a filtration and the solvent was distilled off and the product was dried under a reduced pressure. The resulting crude crystal was recrystallized from a solvent of methanol-water to obtain 3.6 g (yield 88%) of white crystal of the object compound.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([CH3:7])([NH2:6])[CH3:5].S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[K+].[K+].[CH:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[F:2][CH2:3][C:4]([CH3:7])([N:6]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:5]
Reactant: CCCCCC=O
Reactant: CC(C)(N)CF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCCCCC=NC(C)(C)CF
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a suspension of 1-fluoro-2-methylpropan-2-amine hydrochloride (ABCR) (2 g, 15.7 mmol), anhydrous magnesium sulfate (3.77 g, 31.4 mmol) and potassium carbonate (2.17 g, 15.68 mmol) in dichloromethane (100 mL) was added drop wise hexanal (1.93 mL, 15.7 mmol) at 0° C. The reaction mixture was stirred for 10 h at room temperature, then filtered and concentrated to obtain the title compound as a pale yellow liquid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][CH:32]=O.N1CCCCC1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][CH:32]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: COc1ccccc1CCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1CCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(2-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.40 g (quant., yellow oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH3:17])[CH:9]=2)=[N:6][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH3:17])[CH:9]=3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCOc1cccc(-c2ncc(Br)cn2)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Product: CCCOc1cccc(-c2ncc(-c3ccc(OCc4ccccc4)cc3)cn2)c1

Procedure:
5-Bromo-2-(3-propoxyphenyl)pyrimidine and 4-benzyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid) are reacted analogously to Example 1 to give 5-(4-benzyloxyphenyl)-2-(3-propoxyphenyl)pyrimidine. ##STR41##
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]3[CH2:25][C@H:24]3[CH2:26]O)[CH2:18][CH2:17]2)[CH2:3]1.[CH2:29]([N:31](CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+].[C-]#N.[K+]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[CH3:1][C:2]1([CH3:28])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]3[CH2:25][C@H:24]3[CH2:26][C:29]#[N:31])[CH2:18][CH2:17]2)[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CO)CC2)CC(C)(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CC#N)CC2)CC(C)(C)C1
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL) was stirred at an external temperature of 0° C. under a nitrogen atmosphere. Triethylamine (0.065 mL, 0.468 mmol) and methanesulfonyl chloride (0.018 mL, 0.233 mmol) were added in that order to the mixture, followed by stirring for 30 minutes under the same conditions. Saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then washed with ethyl acetate and water and extracted with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was dissolved again in dimethylsulfoxide (3 mL), and then tetrabutylammonium iodide (12 mg, 0.032 mmol) and potassium cyanide (34 mg, 0.522 mmol) were added thereto and the mixture was stirred for 2 hours at an external temperature of 70° C. Ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed twice with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 8 mg of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrile as a colorless oil, and 19 mg of trans-1-(2-chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetrantethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]([OH:22])[CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+]>C(O)C>[C:1]1([S:7][CH2:8][C@H:9]2[O:22][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CSc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(SC[C@@H]2CO2)cc1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Under nitrogen, to a solution of (2S)-3-phenylthio-1-tosyloxy-2-propanol (3.9 g) in ethanol (40 ml) was added 20% sodium methoxide in ethanol (4.7 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. After being filtrated off to remove precipitates, the filtrate was concentrated in vacuo. The residue was dissolved into a mixture of aqueous 0.1N sodium hydroxide and diethyl ether. After separation, the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give (2S)-1-phenylthio-2,3-epoxypropane (1.5 g).
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1]/[CH:2]=[CH:3]\[C:15]#[C:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11]
Reactant: C#CC(OCC)OCC
Reactant: Cl/C=C\Cl
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: c1ccccc1
Product: CCOC(C#C/C=C\Cl)OCC
Temperature: 25 °C
Reaction time: 4.2 h
Yield: 53 %

Procedure:
Neat cis-1,2-dichloroethylene (4.5 ml, 60 mmol) followed by butylamine (8.0 ml, 81 mmol) was added to a solution of copper iodide (0.90 g, 4.73 mmol) and palladium tetrakis(triphenylphosphine) (1 g, 0.86 mmol) in 40 mL of dry benzene stirring at 25° C. under argon. Immediately thereafter, a solution of 3,3-diethoxypropyne (5 g, 39 mmol) in 10 mL of benzene was added via cannula. The reaction vessel was wrapped in foil to shield it from light, and the reaction mixture was stirred for 4.2 h at 25° C. The dark brown reaction mixture was filtered by suction through a coarse frit and diluted to approximately 10 ml with diethylether. The solution was washed with 75 mL of water and 120 mL saturated brine, and the organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was flash chromatographed on SiO2 using 5%, then 10%, and then 15% diethylether/pentane as eluent to provide the desired product as a clear liquid (3.9 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]3[CH2:14][NH:15][C:16](=[O:19])[C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)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]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]3[CH2:14][N:15]([C:25]4[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[C:16](=[O:19])[C:17]=3[CH:18]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccnc1Br
Reactant: COc1ccc(Cc2cc3c(c4ccccc24)CNC3=O)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc3c(c4ccccc24)CN(c2ncccc2C(F)(F)F)C3=O)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(6-methoxypyridin-3-yl)methyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.050 g, 0.16 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-bromo-3-(trifluoromethyl)pyridine (0.037 g, 0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.014 g, 0.025 mmol), cesium carbonate (0.075 g, 0.23 mmol), and tris[dibenzylideneacetone]dipalladium (0) (7.5 mg, 0.0082 mmol). The mixture was irradiated in a microwave reactor at 140° C. for 1.5 hr, cooled to ambient temperature, and diluted with ethyl acetate. The organic solution was washed with water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 450.1423 for [M+H]+ [calc'd for C25H19F3N3O2, [M+H]+=450.1424]: 1H NMR (400 MHz, CDCl3) δ 8.79-8.77 (m, 1H), 8.20-8.12 (m, 3H), 7.95-7.91 (m, 1H), 7.76 (s, 1H), 7.69-7.62 (m, 2H), 7.52-7.44 (m, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.34 (s, 2H), 4.46 (s, 2H), 3.94 (s, 3H) ppm.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1>C(O)(=O)C>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)ccc1-n1cccc1

Procedure:
100 g (0.75 mole) of 2,5-dimethoxytetrahydrofuran are added dropwise to a stirred solution of 86.3 g (0.5 mole) of 4-chloro-2-nitroaniline in 500 ml. of glacial acetic acid. The solution is refluxed under a nitrogen atmosphere for 30 minutes, filtered, and poured into 2500 ml. of water. The aqueous solution is extracted with chloroform. The chloroform solution is dried with anhydrous sodium sulfate and concentrated to a brown oil. The brown oil is dissolved in an ether-petroleum ether-mixture and placed in a refrigerator overnight. An orange solid precipitates and is recrystallized from an ether petroleum ether mixture to give 1-(4-chloro-2-nitrophenyl) pyrrole, m.p. 55°-56° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)c2cc(Br)c3c(c2)CCO3)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)c2cc(Br)c3occc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 7-bromo-5-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran (353 mg, 1 mmol; Intermediate 78), NBS (178 mg, 1 mmol) and dibenzoylperoxide (24 mg, 0.1 mmol) in carbon tetrachloride (20 mL) was heated to 80° C. for 2 h. TEA (2 mL) was added and the mixture was heated for another 2 h. Flash chromatography using EtOAc/hexane 10:90→25:75 as eluent gave the title product as a white crystalline material. Yield: 130 mg (37%). 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 6.93 (d, 1H), 7.30 (d, 2H), 7.78 (d, 1H), 7.84 (d, 2H), 8.02 (d, 1H), 8.19 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Br:14][C:15]1[CH:16]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetyl-2-nitroaniline (3.41 g, 18.94 mmol), 1,3-dibromobenzene (4.6 ml, 38.06 mmol), potassium carbonate (2.62 g, 19 mmol) and a catalytic amount of copper bronze is heated with stirring to 180° C. under a stream of nitrogen for 2 days. After cooling the solid reaction cake is extracted with a mixture of dichloromethane and methanol (9:1). The extract is concentrated under reduced pressure. The residue is extracted with ethyl acetate. This extract is concentrated under reduced pressure and the residue is eluted through silica gel with a mixture of petroleum ether and ethyl acetate (4:1) to afford the pure product. Yield 0.67 g (10.6%). Mp. 142-144° C.