Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 hours, the solution was poured into ice water and left stirring for 30 minutes. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-Iodo-1-trityl-1H-imidazole (92%) as a white solid. MH+(437).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:25]1[CH:26]=[C:22]([I:21])[N:23]=[CH:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trityl chloride (3.8 g, 13.6 mmol) was added to a cooled (0° C.) solution of 4-iodoimidazole (2.25 g, 11.6 mmol) and triethylamine (2 ml, 14.3 mmol) in methylene chloride (25 ml). After stirring for 30 min the reaction mixture was warmed to room temperature and stirred ther for 2 h. The reaction mixture was washed well with water and saturated NaHCO3 then dried (Na2SO4). Concentration gave the product as a white solid. 1H NMR (CDCl3) d 6.92 (s, 1 H), 7.08-7.20 (m, 6 H), 7.28-7.40 (m, 10 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22][OH:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[O:23]=[CH:22][CH2:21][NH:20][C:19](=[O:24])[O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
A solution (30 ml) of oxalyl chloride (1.72 ml, 20.0 mmol) in dichloromethane was added dropwise to a solution (10 ml) of dimethyl sulfoxide (2.84 ml, 40.0 mmol) in dichloromethane at −78° C., and the mixture was stirred at the same temperature for 5 min. A solution (45 ml) of benzyl(2-hydroxyethyl)carbamate (1.95 g, 10.0 mmol) in dichloromethane was added to the reaction mixture and the mixture was further stirred for 15 min. Triethylamine (6.93 ml, 50.0 mmol) was added, and the mixture was stirred for 5 min. The temperature was raised to room temperature and the reaction mixture was stirred for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (7:3-3:2, v/v) to give the title compound (930 mg, 48%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5]C)=O.[CH3:20][C:21]([Mg]Cl)([CH3:24])[CH2:22][CH3:23]>C1COCC1>[CH3:20][C:21]([CH3:24])([CH2:22][CH3:23])[C:3](=[O:5])[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:1]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)C1CCCNN1Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Reaction time: 5 h
Yield: 69 %

Procedure:
A solution of methyl 2-oxo-2-[2-benzylperhydropyridazinyl]acetate (9.0 g, 29.4 mmol) in 30 ml dry THF was cooled to −78° C. and treated with 35 ml of 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at for 5 hours, the mixture was poured into saturated. ammonium chloride (150 ml) and extracted into ethyl acetate. The organic layer was washed with water, dried and concentrated. The crude material was purified by silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 7.0 g product (69% yield) as clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.76 (t, 3H, J=7.0); 1.06 (s, 6H); 1.69 (m, 6H); 2.80 (m, 1H); 3.15 (m, 1H), 4.03 (m, 1H); 4.13 (m, 1H), 5.18 (m, 2H), 7.36 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:53]1[CH2:57][C:56](=[O:58])[NH:55][CH2:54]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:53]4[CH2:57][C:56](=[O:58])[NH:55][CH2:54]4)=[O:23])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: O=C1CNCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (452 mg, 1.00 mmol, 1.00 equiv), dichloromethane (50 mL), EDCI (384 mg, 2.00 mmol, 2.00 equiv), HOBt (270 mg, 2.00 mmol, 2.00 equiv), TEA (303 mg, 2.99 mmol, 3.00 equiv), imidazolidin-4-one hydrochloride (135 mg, 1.10 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 200 mg (38%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[BrH:11]>>[BrH:10].[NH2:1][C:2]1[C:7]([CH2:8][Br:11])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Product: Nc1ncc(Br)cc1CBr
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (34.6 g, 170.0 mmol) in hydrobromic acid (48% in H2O, 93 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, the precipitated product filtered and washed with H2O (100 mL) and dried. The title product was obtained as a light yellow solid (36.1 g, 56%, py 96.5%).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1.[CH:21](=O)[C:22]1[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[O:26])[CH:23]=1.C(OC(=O)C)(=O)C>CCCCCC>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH:20]=[CH:21][C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH:25]=[O:26])=[N:17]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
To 15 liters of xylene preheated to 100° were added sequentially 7-chloroquinaldine (3 kg, 16.9 moles; see C. M. Leir, J. Org. Chem., 42, 911-913 (1977)), isophthalaldehyde (3.4 kg, 25.3 moles), and acetic anhydride (4.69 liters, 5.07 kg, 49.7 moles). The mixture was heated at reflux for about 8 to 9 hours and then cooled to room temperature. Hexane (16 liters) was added and the resultant precipitate was collected by filtration. Recrystallization from ethyl acetate yielded pure title compound (67%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9]>N1CCCCC1>[CH3:12][O:11][C:7](=[O:10])[CH2:8][CH2:9][S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CS
Solvent: C1CCNCC1
Product: COC(=O)CCSCC(=O)OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of methyl thioglycolate (91.0 mL, 1.0 mol) and piperidine (2 mL, 4.05 mmol) was added methyl acrylate (99.2 mL, 1.1 mol) dropwise. The reaction mixture was stirred at 50° C. for 2 h. The excess methyl acrylate and piperidine were then removed by distillation to afford methyl-3-(2-methoxy-2-oxoethylthio)-propanoate as a colourless oil (185 g, 96%). Without further purification, the crude product was used directly to the next step.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[NH3:24]>>[C:1](=[NH:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 65 %

Procedure:
91.1 Grams of benzophenone and 0.1 g of benzoic acid were charged into a pressure reactor, and an ammonia gas under 8 atmospheres was continuously fed to the reactor through a gas dispersing plate at a feed rate of 2 l/min. at a reaction temperature of 200° C. Reaction was carried out for 2 hours. As a result, benzophenoneimine was obtained in yield of 65%.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[CH:5]=[C:6]([S:10][CH3:11])[C:7]=1[C:8]#[N:9].[H-].[Na+].Br[CH2:16][C:17]([NH2:19])=[O:18]>CN(C=O)C>[C:8]([C:7]1[C:6]([S:10][CH3:11])=[CH:5][C:4](=[O:12])[NH:3][C:2]=1[S:1][CH2:16][C:17]([NH2:19])=[O:18])#[N:9]
Reactant: CSc1cc(=O)[nH]c(S)c1C#N
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of the above 2-mercapto-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (12.5 g, 63.0 mmol) in DMF (300 mL), cooled to 0° C., was added sodium hydride (2.60 g, 65.0 mmol) as a 60% dispersion in mineral oil. The mixture was stirred at 0° C. for 30 min then 2-bromoacetamide (8.80 g, 63.8 mmol) was added as a solid in one portion. The mixture was allowed to slowly warm to room temperature and stirred for 15 h. The mixture poured into ice—H2O and stirred until all of the ice had melted, during which time a solid precipitated from solution. The mixture was acidified with 2N HCl then cooled to 0° C. and the solid collected by filtration. The material was washed with Et2O followed by hexanes to provide 11.2 g (69.9%) of 2-(3-cyano-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a tan solid.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:20][C:15]1[C:16]([NH2:19])=[N:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])=[CH:8][CH:9]=2)[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
5-(4-(Isopropylsulfonyl)phenyl)pyrazin-2-amine (10 g, 36.06 mmol) was dissolved in dry DMF (70 mL) and N-bromosuccinimide (6.418 g, 36.06 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water (200 mL) and stirred for 5 minutes. The solid was isolated by filtration and washed with water. The wet solid was dissolved in ethyl acetate and any insoluble material removed by filtration. The aqueous layer was separated and the organic phase washed with saturated aqueous Na2S2O3 (×1) and dried (MgSO4). The organic extracts were filtered through a plug of Florisil (200 mesh), eluting with ethyl acetate. The filtrate was concentrated to ca. 50 mL and resultant precipitate isolated by filtration and washed with Petroleum Ether. The solid was further dried under high vacuum to give the sub-title compound as a pale orange solid (8.0 g, 62% Yield)). 1HNMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 3.41-3.49 (m, 1H), 7.16 (br s, 2H), 7.89 (d, 2H), 8.17 (d, 2H) and 8.76 (s, 1H) ppm; MS (ES+) 356.1.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.C(Cl)(=O)C.O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([C:2](=[O:4])[CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.25 g (3.5 mmol) of acetyl chloride is then added and the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The solution is dried over magnesium sulfate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallizes from diisopropyl ether. 0.25 g of Compound 23 is obtained in the form of a white powder melting at 132° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.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.[Cu]I>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 81 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and CuI (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 57 mg, 65%).
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]>CO>[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 190 °C
Yield: 95.8 %

Procedure:
Dry pyridinium hydrochloride (34.0 g, 0.294 mol) and 2-cyano-6-methoxy-benzothiazole (Aldrich Chemical Co., 3.0 g, 0.016 mol) were added into a 500 mL round bottom flask which was preheated in an oil bath at 100° C. The bath temperature was increased to 190° C. and the reaction mixture was refluxed at this temperature for 2 h. After the completion of reaction, it was cooled to room temperature to obtain a yellow solid which was dissolved in methanol. Silica was added to this solution and evaporated to dryness. This material was then chromatographed using 30% ethyl acetate/hexane to obtain 2.7 g of the product as a white solid (95%): mp 120° C.; 1H NMR (CD3OD) δ 5.68 (bs, 1H), 8.02-8.82 (m, 3H); --C NMR (CD3OD) δ 106.96, 114.26, 119.59, 126.53, 133.83, 138.93, 147.25, 160.23; MS m/e (rel intensity) 176 (100), 151 (3), 124 (5), 96 (15), 85 (4), 69 (7), 57 (5); Exact mass: calcd 176.0044, found 176.0047. ##STR25##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=NC(C)(C)C.[Li]CCCC.Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O:33]1CCCC1>>[C:27]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccccc1C=NC(C)(C)C
Reactant: ClCCCCCCCc1ccccc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (21.0 g, 0.12 mol) in tetrahydrofuran (75 mL), n-BuLi (1.54M, 78 mL, 0.12 mol) was added over 1 h such that the temperature was maintained between 20°-30° C. with cooling. The mixture was stirred for 30 min and 1-chloro-7-phenylheptane (21.05 g, 0.1 mol) in tetrahydrofuran (40 mL) was added quickly. The mixture was heated at 50° C. for 3 h and quenched by the slow addition of dilute hydrochloric acid. Hydrolysis was completed by heating the mixture at 50°-60° C. for 2.5 h. The mixture was cooled to ambient temperature and the organic phase separated. The aqueous phase was extracted with hexane, and the combined organic extracts were washed with water. The extracts were dried over magnesium sulphate and, after filtering and washing the filter cake with hexane, the organic solution was concentrated under vacuum to give 2-(8-phenyloctyl)benzaldehyde as an oil (34.56 g, 65.3% pure by HPLC assay, 77% corrected yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluorophenylacetic acid (11.2 g, 73 mmol.) in THF (125 ml) at 0° C. under nitrogen was added oxalyl chloride (7.1 ml, 82 mmol.) then DMF (4 drops) and the resulting effervescing mixture stirred at 0° C. for 30 minutes then at ambient temperature for a further 1 hour. The effervescence had ceased after this time and the solvent was evaporated. To the residue was added toluene (50 ml) and the solvent evaporated. The addition of toluene and evaporation was repeated to leave a residue of 4fluorophenylacetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:20])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
Into a suitable agitated reactor is charged 4-fluorophenylacetic acid (79.4 kg, 515 mol), N,N-dimethylformamide (0.5 kg, 6.8 mol), and toluene (318 kg). Oxalyl chloride (68.3 kg, 538 mol) is added at a rate as to maintain the temperature below 35° C. The solution is stirred for at least 7 hours at about 25° C., typically affording a 22.1 wt % solution of 4-fluorophenylacetyl chloride.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[N:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccncc2)c1
Yield: 84.6 %

Procedure:
Part A. A solution of 4-bromopyridine (1.0 g, 5.2 mmol) in acetonitrile-water (10 mL/5 mL) is treated with 3-carboethoxybenzeneboronic acid (0.93 g, 5.2 mmol), sodium carbonate (2.2 g, 21 mmol) and catalytic tetrakis(triphenylphosphine)palladium. The solution is heated to reflux for 12 h., then cooled and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by flash chromatography to afford ethyl 3-pyridin-4-yl-benzoate (1.0 g, 86%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of acryloyl chloride (3 mL; 3.342 g; 36.9 mmole) dissolved in dry dichloromethane (25 mL) was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (6.4902 g; 40.66 mmole) and N,N-diisopropylethylamine (15.6 mL; 11.575 g; 89.56 mmole) in dry dichloromethane (110 mL) was slowly added over a period of 1 hour to the cooled solution. Next, the ice bath was removed, and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (250 mL) was added to the reaction and the layers were separated. The organic solution was washed with diluted hydrochloric acid (0.2N; 3×300 mL), a saturated sodium bicarbonate solution (1×200 mL), water (3×250 mL), and finally brine (1×250 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (70:30) to elute the product. The purification gave 3.165 g (48.4%) of N-benzyloxyacrylamide (30) as a viscous colorless oil.
Reaction SMILES: [Zn:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[Zn+2:1].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: [Zn]
Product: O=[N+]([O-])[O-]
Product: [Zn+2]

Procedure:
stripping said zinc from said zinc-loaded cationic organic solvent by contacting with nitric acid to form an aqueous solution of zinc nitrate in a solvent stripping stage,