Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis (triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]O)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[NH:40]1[CH:44]=[CH:43][CH:42]=[N:41]1>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: c1cn[nH]c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A solution of methanesulfonic anhydride (0.65 g, 3.72 mmol) in DCM (5 mL) was added slowly to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.08 g, 3.38 mmol) and triethylamine (1.42 mL, 1.02 g, 10.1 mmol) in DCM (10 mL) with stirring under nitrogen and external ice bath cooling. Stirring was continued at 0° C. for 2 h then pyrazole (0.3 g, 4.4 mmol) was added in one portion. Stirring at 20° C. was continued for 18 h, then mixture was partitioned between saturated aqueous NaHCO3 (40 mL) and DCM (3×20 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in 40-60 petroleum ether) gave the title compound (0.811 g) as an oil. MS: [M+H]+=371.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>O1CCOCC1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]([O:18][CH3:19])=[C:2]([N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:7]=1)([O:12][CH3:13])[CH3:9]
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(F)(F)F
Reactant: C1COCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene (03.004; 700 mg) was initially charged in dioxane (7 ml) and admixed successively with Pd(II) acetate (46 mg), cesium carbonate (2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (118 mg) and morpholine (0.27 ml). Thereafter, the reaction mixture was heated to 90° C. for 7 h and then left to stand overnight. Subsequently, it was filtered and the filtrate was concentrated by rotary evaporation. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient). 433 mg of the title compound were obtained.
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O.C(OC(=O)C[C@H](O)CI)C.C(OC(=O)C[C@H]1CO1)C.C(O)(=O)[C@H](CC(O)=O)O.[CH2:48]([NH2:51])[C:49]#[CH:50]>>[OH:18][C@@H:5]1[CH2:6][N:51]([CH2:48][C:49]#[CH:50])[C:3](=[O:19])[CH2:4]1
Reactant: COC(=O)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCN
Agent: CCOC(=O)C[C@H](O)CI
Agent: CCOC(=O)C[C@H]1CO1
Agent: O=C(O)C[C@H](O)C(=O)O
Product: C#CCN1C[C@@H](O)CC1=O

Procedure:
In accordance with Scheme I, (S)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]butanoic acid methyl ester 2, (S)-3-hydroxy-4-iodobutanoic acid ethyl ester 3 and (S)-oxiraneacetic acid ethyl ester 4 are prepared from (S)-malic acid 1 using previously described methods [S. Saito et. al. Chem. Lett. 1389, (1984) and M. Larcheveque et. al. Tetrahedron Lett. 1781, 28 (1987)]. The esters 2, 3 and 4 are individually reacted with propargylamine in an alcohol solvent at temperatures ranging from room temperature to the reflux temperature of the solvent, preferably in the presence of an alkali metal carbonate, to produce (S)-4-hyroxy-1-(2-propynyl)-2-pyrrolidinone 5. Compound 5 is then reacted with an aryl or a (C1 -C6) carboxylic acid anhydride such as acetic anhydride in the presence of pyridine and preferably dimethylaminopyridine in an ether or a chlorohydrocarbon solvent, such as dichloromethane, to give the intermediate of general formula 6, for example, (S)-4-(acetyloxy)-1-(2-propynyl)-2 -pyrrolidinone.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([O:8]C)=[O:7].N1CC2C(=CC=CC=2)C[C@H]1C(O)=O.CO>O.O1CCCC1>[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Agent: O=C(O)[C@@H]1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of sodium hydroxide (0.62 g, 15.5 mmol) in water (100 mL) was added to a solution of 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (5.62 g, 14.0 mmol) in tetrahydrofuran (100 mL). The solution was stirred overnight at room temperature. Tic indicated that the reaction was not complete. 1 M NaOH (20 mL) was added and the mixture was heated at reflux for 6 h. Methanol (100 mL) was added and the mixture was stirred overnight at room temperature. Again, tic indicated that the reaction was not complete so the reaction mixture was heated at reflux for 2 h, 1 M NaOH (100 mL) was added and the solution was heated at reflux for a further 4 h. The reaction mixture was allowed to stand overnight at room temperature, then the solvent was evaporated, and water (100 mL) and 1 M HCl (200 mL) were added. The mixture was stirred for 20 min and then the white solid was filtered off and dried overnight in a vacuum oven (25 mm Hg, 60° C.) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid (4.84 g, 89%) as a white solid, mp 213–215° C. (dec.).
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH2:7][S:8][CH:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:15][CH:9]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:6](=[O:5])[CH2:7][S:8]1
Reactant: COC(=O)CSC(C)CC(=O)OC
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)CSC1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a suspension of sodium methoxide (5.89 g, 109.2 mmol) in toluene (150 mL) was added methyl 3-(2-methoxy-2-oxoethylthio)butanoate (150 g, 72.8 mmol) dropwise. The resultant mixture was heated to reflux and stirred overnight. The resulting reaction mixture was cooled then poured into a mixture of 10.0 mL of acetic acid in 150.0 g of crushed ice. The solution was made basic (pH=8-9) by addition of saturated Na2CO3 and the resulting mixture extracted with ethyl acetate. The combined organic layers were then combined and washed with brine, dried over anhydrous Na2SO4, filtered, evaporated, and the residue purified by column chromatography (eluent: petroleum ether/ethyl acetate=20/1-5/1) to provide methyl 2-methyl-4-oxo-tetrahydrothiophene-3-carboxylate as a colorless oil (4.0 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:20])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of the 4′-chlorobiphenyl-4-sulfonic acid in 100 mL of thionyl chloride is heated at reflux for 6 h, and the resulting homogeneous solution is then cooled to RT. The mixture is concentrated under reduced pressure and the residue is triturated with diethyl ether and dried to afford 9.8 g (95%) of 4′-chlorobiphenyl-4-sulfonyl chloride as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:6]2[N:7]([C:17](=[O:34])[CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:21][CH2:20]3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:35])[CH:3]=1.C(#N)C>C(O)=O.CN(C)C=O.[Pd]>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]3[N:4]([CH3:35])[CH:3]=[CH:2][C:6]2=3)=[O:34])[CH2:20][CH2:21]1)[CH3:33]
Reactant: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2c(Cl)cn3C)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=CO
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2ccn3C)CC1

Procedure:
4.715 g (9.7 millimol) of 3-chloro-4-[[4-[4-(diethylamino)-butyl]-1-piperidinyl]acetyl ]-1-methyl-1,4,9,10-tetrahydropyr rolo[3,2-b][1,5]benzodiazepin- 10-one were dissolved in a mixture of 5 ml of 85% formic acid and 25 ml of dimethylformamide and after the addition of 0.5 g of 10% palladium/activated charcoal the mixture was refluxed for 3 hours. 7.0 ml of formic acid were added, the mixture was refluxed for a further 6 hours and then, after the addition of a further 4.0 ml of formic acid and 0.8 g of 10% palladium/activated charcoal, the mixture was finally refluxed for a further 8 hours. The mixture was filtered while hot, the filtrate was evaporated down in vacuo and the residue was purified by column chromatography (silica gel; dichloromethane/ethyl acetate/methanol/conc. ammonia 3.5:1.5:0.46:0.06 v/v). 1.45 g (33% of theory) of colourless crystals were obtained, m.p. 196°-198° C. (acetonitrile), which were found according to thin layer chromatography and IR, UV and 1H-NMR spectra, to be identical to a preparation obtained according to Example 39.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:42][S:43]([OH:46])(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([O-:46])(=[O:45])=[O:44].[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S+:14]([C:39]2[CH:40]=[CH:41][C:36]([O:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:37][CH:38]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: O=S(c1ccc(Oc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)[O-]
Product: c1ccc(Oc2ccc([S+](c3ccc(Oc4ccccc4)cc3)c3ccc(Oc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Yield: 81.3 %

Procedure:
A mixture of 5.8 g of bis-(4-phenoxyphenyl)sulfoxide and 2.55 g of diphenyl ether in 18 ml of methylene chloride was added dropwise over a period of 3 hours to 7.21 g of methane sulfonic acid at 100° C. The methylene chloride was distilled off as the addition proceeded. The mixture was then heated at 100° C. for 28 hours and worked up substantially according to the procedure previously described to give 7.74 g of tris-(4-phenoxyphenyl)sulfonium methane sulfonate (81.3 percent yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 20. (+3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol) and triethylamine (13.1 μL, 0.0938 mmol) in tetrahydrofuran (3 ml), was added iodoethane (5.6 μL, 0.070 mmol). Analysis show 60% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 9), 226 (74), 211 (28), 141 (47), 71 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:18])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120.mL) for 14 h at reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/z: 213 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>ClCCCl>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Cl)c(O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a solution of 2-hydroxy-p-anisic acid (0.2 g, 1.2 mmol) in DCE (8 mL) was added thionyl chloride (0.13 mL, 1.8 mmol) and a drop of DMF. After stirring at room temperature for 4.5 h the reaction mixture was concentrated and azeotroped several times with benzene to give the acid chloride 123 as a white solid (222 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)C>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry diethyl ether (150 mL) is added triethylamine (12.8 mL, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 mL, 69 mmol). The reaction mixture is allowed to warm to RT and then stirring is continued for 3 h. The resulting mixture is washed with water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution, brine then dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:22]#[C:23][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1ccncc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a suspension of 4-bromopyridine hydrochloride (3.9 g, 20 mmol), tetrakis(triphenylphosphine)palladium (2.32 g, 2.0 mmol), triethylamine (16.8 mL, 120 mmol) in dry DMF (150 mL) is added phenylacetylene (4.2 mL, 40 mmol) at room temperature. After stirring for 3 hours at 80° C., the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (100 mL), washed with H2O, brine (50 mL), dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 10/90) to afford the title compound as a solid (3.25 g, 91%). Mp 51-53° C. MS (+) ES: 180 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([C:18](O)=[O:19])=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N:38]1[CH:42]=[CH:41]N=C1)(N1C=CN=C1)=O.[C:43]1(NCCCCCCCC)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[C:43]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:41][CH2:42][NH:38][C:18]([C:5]2[CH:4]=[C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2]([NH2:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[CH:6]=2)=[O:19])[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCCCCCCCNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.4 %

Procedure:
To a solution of 2′-amino-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-5′-carboxylic acid (0.113 g, 0.27 mmol 1 eq) in DMF (2.7 mL) was added 1,1′-carbonyldiimidazole (0.120 g, 0.74 mmol 2.7 eq) and phenyl octylamine (0.070 mL, 0.35 mmol, 1.3 eq) and the reaction was stirred overnight at rt. Additional 1,1′-carbonyldiimidazole (0.124 g, 0.76 mmol 2.8 eq) and phenyl octylamine (0.070 mL, 0.35 mmol, 1.3 eq) was added and stirring was continued overnight. The solids were then filtered off and washed with EtOAc. The filtrate was washed with saturated NaHCO3 solution, 0.1 N HCl and brine. It was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc: Hexane+1% Formic acid) to afford the title compound (0.150 g, 37%) as a light yellow oil. 1H NMR (DMSO-d6 δ 8.20 (t, 1H); 7.81–7.70 (m, 8H); 7.61 (s, 2H); 7.25–7.12 (m, 5H); 4.87 (s, 2H); 3.19 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3540, 3350, 2950, 2850, 1620, 1545, 1480, 1420, 1325, 1180, 1120, 1110, 1080 cm−1; mass spectrum [(+)APCI], m/z 613 (M+H)+; Anal. Calcd. for C35H34F6N2O: C, 68.62; H, 5.59; N, 4.57. Found: C, 67.66; H, 5.96; N, 4.33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][Br:11]
Reactant: Br
Reactant: CC(=O)c1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.0 g of 2'-methylacetophenone in 60 ml of acetic acid was added successively 9.7 ml of 47% hydrobromic acid and 8.6 g of pyridinium hydrobromide perbromide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and a saturated sodium carbonate solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 5.4 g of the title compound as a colorless oily material.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[BrH:10].[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>C(O)(=O)C>[BrH:7].[Br:10][CH2:12][C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)c1ccncc1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C

Procedure:
A twelve-liter three neck flask fitted with an efficient mechanical stirrer, 250 mL dropping funnel, and internal thermometer was charged with glacial acetic acid (5000 mL), pyridinium bromide perbromide (90%, 830 g, 2.60 mol) and 30% hydrobromic acid in acetic acid (525 mL). After stirring at room temperature for ninety minutes, 4-acetylpyridine (250 g, 2.07 mol) was added dropwise over forty-five minutes. Upon completion of the addition the reaction mixture was cooled with an ice bath to 15° C. and the product, which had precipitated, was collected by filtration, washed with ether and air-dried. The crude α-bromo-4-acetylpyridine hydrobromide (566.3 g, 97%) was sufficiently pure for subsequent reactions, mp. 177.5°-182.0° C.