Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide as a yellow solid (50 mg, 38%).
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=[O:6])[CH2:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][CH2:7][C:2](=[O:5])[CH2:3][C:4]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: Nc1ccccc1
Reactant: O=C1CC(Cl)(CCl)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
7.8 Parts of 4-chloro-4-chloromethyloxetan-2-one are dissolved in 150 parts of methylenechloride containing 4.2 parts of anhydrous sodium bicarbonate and the solution is cooled to 0° C. 4.7 Parts of aniline are then added over 30 minutes and the reaction mixture is finally stirred for 48 hours at room temperature. The solids are then filtered off and the filtrate evaporated. The residue is crystallised twice from chloroform to give γ-chloroacetoacetanilide, m.p. 142°-143° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[I-].[Na+]>[OH:7][CH2:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:15][CH2:14][C:13]1[CH:17]=[CH:18][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CO)cc1
Yield: 57.3 %

Procedure:
A mixture of (S)-2-pyrrolidinemethanol (3.0 g), 4-methoxyphenethyl bromide (7.0 g), sodium carbonate (3.5 g) and sodium iodide (100 mg) in acetonitrile (40 ml) was heated under reflux for 16 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water and extracted with 2M hydrochloric acid. The acidic extract was washed with ethyl acetate, basified with solid sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil, (4.0 g, 57%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Temperature: 75 °C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 3.00 g, 12.34 mmol), and 4-bromo-2-chloro-fluorobenzene (2.58 g, 12.34 mmol) in THF (42 mL)) were added Palladium catalyst Pd(PPh3)4 (0.428 g, 0.37 mmol) and the freshly prepared sodium hydroxide solution (1.50 g, 37.02 mmol in 17 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.11 g (70%) of the product 4-(3-chloro-4-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[F:13][C:14]([F:30])([F:29])[C:15]1[CH:16]=[C:17]([S:25](Cl)(=[O:27])=[O:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][S:25]([C:17]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:15]([C:14]([F:13])([F:29])[F:30])[CH:16]=2)(=[O:27])=[O:26])=[N:9][C:10]=1[CH3:11])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOCc1ccc(N)nc1C
Product: CCOCc1ccc(NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.07 g) and 3,5-di(trifluoromethyl)-benzenesulfonyl chloride (0.145 g) as an off-white solid (0.032 g). MS (ESI−): 441.1 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20](Cl)=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([CH3:25])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC1(C(=O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: C1COCCO1
Product: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.512 mmoles), trimethylboroxine (0.24 g, 1.91 mmoles), potassium carbonate (0.22 g, 1.59 mmoles), and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.051 mmoles) in dioxane (10 ml) was refluxed for three hours, then cooled to room temperature. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% ethyl acetate in hexane) to yield 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid (0.166 g, 87%). M+Na: 394
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:21]([NH:23][NH2:24])=[O:22])=[CH:14][N:15]([CH3:20])[C:16](=[O:19])[C:17]=2[F:18])=[C:7]([F:25])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:22][C:21]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:25])=[C:17]([F:18])[C:16](=[O:19])[N:15]([CH3:20])[CH:14]=2)=[N:23][N:24]=1
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nnc(N)o2)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 17 h
Yield: 89.2 %

Procedure:
Cyanogen bromide (36 mg, 0.31 mmol) was added to a suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (63 mg, 0.169 mmol) in dioxane (2 mL) followed by an aqueous NaHCO3 (2 mL of a 0.09 M solution) solution. After 17 hours, additional cyanogen bromide (14 mg) was added. After 19 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Crystallization (MeOH:THF) followed by trituration (Et2O:MeOH 5:1) gave clean desired product as a white solid (60 mg, 89%). MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.06 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.10 (td, 1H), 3.64 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Product: O=C(c1ccccc1)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
3Nitro-4-chloro-benzophenone is reacted with pyrrolidine as described in Examples 7 or 8 obtain 3-nitro-4-pyrrolidino-benzophenone with a yield of 95 %. The crystalline product melts at 89.5° - 90.5° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[N:5]2[N:4]=1.Cl[CH2:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[O:24]=[S:23]1(=[O:25])[CH2:22][CH2:21][CH2:20][N:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:5]2[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CSc1ncc2ccc(-c3ccccc3N)n2n1
Product: CSc1ncc2ccc(-c3ccccc3N3CCCS3(=O)=O)n2n1
Yield: 8 %

Procedure:
Analogous to Example 1506b, 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine (0.777 g, 3.03 mmol) was reacted with 3-Chloropropane-1-sulfonyl chloride to afford 7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfanyl)pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (83 mg, 8%). 1H-NMR (DMSO-d6): 8.79 (s, 1H), 7.84 (dd, 1H, J=5.04 Hz), 7.72 (dd, 1H, J=5.04 Hz), 7.46 (m, 2H), 7.29 (d, 1H, J=4.72 Hz), 6.91 (d, 1H, J=4.72 Hz), 3.38 (t, 2H, J=6.81), 3.19 (t, 2H, J=7.49), 2.48 (s, 3H), 2.27 (quin, 2H, J=7.49).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[Na+].[I-:16]>O1CCOCC1.[Cu]I>[I:16][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)NC(C)Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)Cc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 70 h

Procedure:
To 6.00 g (23.4 mmol) N-(1-(4-bromophenyl)propan-2-yl)acetamide (II.1) in 65 mL dioxan are added 0.45 g (2.34 mmol) CuI, 0.50 mL (4.70 mmol) N,N″-dimethyl-ethylendiamine and 7.02 g (46.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 70 h. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4, filtered and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried at 50° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>CN(C=O)C.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]2[O:9][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: c1cocn1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Yield: 25539.1 %

Procedure:
A solution of 1-fluoro-4-iodobenzene (1 g, 0.0144 mmol) in DMF (15 mL) was purged with argon, and oxazole (6.4 g/3.3 mL, 0.02898 mmol), copper iodide (5.5 g, 0.02898 mmol) and palladium (II) acetate (0.15 g, 0.000724 mmol) was added. The reaction mixture was purged with argon for 5 min and refluxed under argon for 12 h. The solution was cooled to room temperature and diluted with ice cold water (100 mL). The reaction mixture was extracted with ethyl acetate (200 mL) and filtered through Celite® reagent. The organic solvent was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column using a 25 g column (7% ethyl acetate in hexane) to give 2-(4-fluorophenyl)oxazole (0.6 g, 26%) as yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 8.03-7.99 (m, 2H), 7.34 (t, 3H); LC-MS m/z calculated for [M+H]+ 164.05. found 164.1.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]1[C:37]([NH2:42])=[N:38][CH:39]=[CH:40][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[O:6]=[C:4]([NH:42][C:37]1[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3]
Reactant: Nc1ncccc1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccn1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (1.214 g, 6.42 mmol) and N-methylmorpholine (0.741 mL, 6.74 mmol) in DCM (16.04 mL) was added isobutyl chloroformate (0.839 mL, 6.42 mmol). The resulting cloudy light yellow mixture was stirred at −10° C. After 15 min at −10° C., to the mixture was then added a solution of N3-(pyridin-2-yl)pyridine-2,3-diamine (0.5974 g, 3.21 mmol) in DCM (16 mL) at −10° C. with stirring. The resulting mixture was allowed to warm to rt with stirring. After 15.5 h at rt, to the mixture was added satd. NH4Cl (50 mL). The organic layer was separated. The aqueous mixture was extracted with DCM (50 mL×1). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAC in hexane for 14 min, then 50 to 100% gradient of EtOAc in hexane over 14 min, and then 100% isocratic of EtOAC for 30 min as eluent to give (S)-tert-butyl 1-oxo-1-(3-(pyridin-2-ylamino)pyridin-2-ylamino)propan-2-ylcarbamate as a light pink foamy solid: LC-MS (ESI) m/z 358.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:9]1([CH3:30])[CH2:14][CH2:13][C:12]2[C:15]([CH3:29])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:11]=2[O:10]1)C(OC)=O.[OH-].[K+].C(O)CO.O.CCOCC>O>[CH3:30][C:9]1([CH2:4][C:3]([OH:31])=[O:2])[CH2:14][CH2:13][C:12]2[C:15]([CH3:29])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:11]=2[O:10]1
Reactant: COC(=O)C(C(=O)OC)C1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: OCCO
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2

Procedure:
A mixture of 0.43 g (1 mmole) of rac-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-ylpropanedioic acid dimethyl ester, 0.56 g (10 mmoles) of potassium hydroxide, and 25 ml of 9:1 ethylene glycol-water is stirred and refluxed for 8 hr. The mixture is cooled, diluted with water, and extracted with ether (the ether extract is discarded). The aqueous, alkaline solution is acidified with 3NHCl and the acid product isolated by ether extraction. The ether extracts are combined, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. Recrystallization of the residue from aqueous ethanol gives rac-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid which can be converted to Vitamin E by the procedures in Helv. Chim Acta 61, 837 (1978); Helv. Chim. Acta 59, 290 (1976) and Helv. Chim. Acta 64, 1158 (1981).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12]C#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CBr.[Mg].Cl.CC[O:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:22](=[O:21])[CH3:23])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: N#CCC1(c2ccc(Cl)cc2)CCC1
Agent: CBr
Agent: Cl
Agent: [Mg]
Product: CC(=O)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 2-[1-(4-chlorophenyl)cyclobutyl]acetonitrile (30 g) prepared as described in Example 1 in ether (100 ml) was added to the reaction product of methyl bromide gas and magnesium turnings (5.95 g) in ether (80 ml). The mixture was heated under reflux for four hours. Ice and then concentrated hydrochloric acid (105 ml) were added and the mixture heated under reflux until all solid material had dissolved. The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to yield a residue which was distilled twice to yield 1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one (b.p. 133°-136°/2.5 mm Hg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[NH:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: C1CNCCNC1
Product: CCOc1cc(N2CCCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 62 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and homopiperazine was used in place of N-methylpiperazine. In this manner, 97 mg (62%) of the captioned compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([CH3:19])[CH3:18])=[C:4]([Cl:9])[CH:3]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-2-chlorophenol (50 g) in N,N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2CO3 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85° C. for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6*100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D68) (56 g) as a yellow oil. δH (CDCl3, 400 MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]([CH2:36][OH:37])[CH2:14][CH:15]([C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)[C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:37][CH2:36][CH:13]([OH:12])[CH2:14][CH:15]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CC(O)CO)c1cc(F)c(F)c(F)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)CC(C(=O)NNC(=O)OC(C)(C)C)c2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
p-Toluenesulfonyl chloride (605 mg) was added to a solution of tert-butyl N′-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (1.09 g) in pyridine (11 mL) at room temperature. The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.03 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:18])[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[CH3:7]>O1CCCC1.CO.O>[CH3:4][CH:5]([CH3:18])[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)[CH3:7]
Reactant: COC(=O)c1ccc(C(C)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Lithium hydroxide hydrate (0.42 g, 10 mmol) was added to a solution methyl 4-(3-methylbutan-2-yl)benzoate (0.20 g, 1.0 mmol) in tetrahydrofuran (9 mL), methanol (3 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. Hydrochloric acid (3 mol/L) was added to make pH 1-2, and the product was extracted with dichloromethane (50 mL). The combined organic phase was washed with sodium chloride aqueous solution (20 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give pure product 4-(3-methylbutan-2-yl)benzoic acid (0.18 g, 94%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CCN(CC)CC.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:16]1>O1CCOCC1.O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17]2)=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: COC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.125 g (56.75 mmol) of glycine methylester hydrochloride in 60 ml of dioxane and 24 ml of H2O, 15 ml (107.8 mmol) of Et3N and then a solution of 10 g (40.53 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 10 ml of dioxane are added dropwise at 0–5° C. After stirring for 3 h at r.t., the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid; 1H-NMR (400 MHz, CDCl3): 0.3–0.40 (m, 2H), 0.65–0.72 (m, 2H), 1.20–1.35(m, 1H), 3.65 (m, 3H), 3.77 (d, 2H, J=5.04 Hz), 3.86 (d, 2H, J=7.08 Hz), 4.98 (brs, 1H), 6.96 (d, 2H, J=8.52 Hz), 7.77 (d, 2H, J=8.52 Hz).