Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl>[Br:19][CH2:20][C:21]([C:8]1[CH:9]=[CH:10][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)CBr)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (4.80 g, 32.0 mmol, 1.0 eq.) and 1-phenyloctane (6.84 g, 32.0 mmol) were dissolved in dry dichloromethane (10 mL) and cooled to −10° C. A solution of bromoacetyl bromide (3.14 mL, 32.0 mmol, 1.0 eq.) in dichloromethane (12 mL) was added dropwise and the mixture was allowed to return to r.t. while stirring overnight. The mixture was slowly poured into ice water (100 mL) and the aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The product was obtained as brown, highly viscous oil and was used in the next reaction without purification. Yield: 8.90 g (62%), purity: 69% (GC).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[Cl:24][CH2:25][C:26](=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:24][CH2:25][C:26]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 2-amino-3',4,4',5-tetramethoxybenzophenone (6.6 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) was added concentrated sulfuric acid (0.3 ml) and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue was poured in water, made basic with 2N--NaOH, and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to give ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (53%). Recrystallization from acetone-ether provided colorless prisms, m.p. 147°-148° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-6-carboxylic acid (39.5 g, 245 mmol) in methanol (200 mL) and dichloromethane (750 mL) was added 2 M (trimethylsilyl)diazomethane in hexanes (160 mL, 320 mmol) dropwise over 1 hour. The reaction was stirred at room temperature overnight. The following day the reaction was concentrated to a thick brown crude oil that was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (2×200 mL), saturated aqueous sodium chloride (2×200 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate concentrated under reduced pressure to form a suspension. The suspension was filtered to provide 43 g of the desired compound as an off-white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>O>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: OCc1ccccc1O
Reactant: CCS
Solvent: O
Product: CCSCc1ccccc1O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 99.2 g (0.8 mol) of 2-hydroxymethyl-phenol and 124 g (2 mol) of ethylmercaptan was heated for 5 hours to 170° C. in a VA autoclave, whilst stirring. After cooling to room temperature, the unconverted ethylmercaptan and the water of reaction were distilled off under normal pressure, and subsequently the 2-ethylthiomethyl-phenol was distilled off under 1.5 mm Hg. 128 g of 2-ethylthiomethyl-phenol (ca. 95% of theory) were obtained.
Reaction SMILES: [OH:1]S(O)(=O)=O.ON=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:20])[CH3:19])=[O:10]>O>[CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:9](=[O:10])[C:8]2=[O:1])([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1cccc2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of concentrated H2SO4 (210 ml) and H2O (50 ml), was added over 20 min (26.7 g, 0.13 mol) of 2-(hydroxyimino)-N-(2-isopropylphenyl)acetamide. The mixture was stirred at 75° C. for 2 hr, cooled and poured onto cracked ice. After standing for 15 min, it was extracted with EtOAc, washed with water, dried over MgSO4, and concentrated. Air drying afforded (23.8 g, 97%) of crude product). 1H NMR (300 MHz, CDCl3) δ 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t, 1H), 2.87(m, 1H), 1.30 (d, 6H); ESI (+) MS m/e=190 (MH+), ESI (−) MS m/e=188 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=O)[CH2:6][CH2:5]2.ClCCCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=13
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Cl)ccc32)CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To N-[2-(5-chloro-1-indolinyl)phenyl]-4-methyl-1-piperazinecarboxamide (13.5 g, 36.5 mmoles) was added a solution of polyphosphoric acid ethyl ester and 1,2-dichloroethane (250 ml) The solution was heated at 75° C. for 4 hours with exclusion of moisture. The solution was cooled and poured into a mixture of ice-sodium hydroxide solution (2 l) and dichloromethane (1.2 l). The mixture was stirred for 15 minutes. The layers were separated. The organic layer was washed with 2 l of 2N sodium hydroxide, then with brine (500 ml), and dried over anhydrous magnesium sulfate. Removal of the solvent at reduced pressure gave an oil. The oil was purified by flash chromatography on a silica gel column (1 kg, 230-400 mesh), packed and eluted initially with dichloromethane, then with dichloromethane containing an increasing methanol content in 1% increments to a final content of 5% (total 8 l). Concentration of the 5% methanol/dichloromethane eluent gave 3.8 g (28%) of product. Recrystallization from 2-propanol (50 ml) gave the analytical sample, mp 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1(C)C=CC(S(O[CH2:21][C@@H:22]2[O:24][CH2:23]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:21][C@@H:22]2[O:24][CH2:23]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (68.75 g), (R)-glycidyl 4-toluenesulphonate (65 g) and potassium carbonate (47.3 g) in dry dimethylformamide (1.5 L) was stirred and heated at 60° C. under nitrogen for 24 hours, then cooled and allowed to stand at ambient temperature for 24 hours. The mixture was poured into water (2 L) then extracted with ether (4×400 ml). The combined extracts were washed with brine (4×500 ml), dried over magnesium sulphate, and the solvent removed in vacuo to give an oil which was purified by flash chromatography over silica eluting with a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give an oil, which on trituration with ether (150 ml) gave (R)-5-bromo-2-(2,3-epoxypropoxy)benzaldehyde as a colourless solid (43.3 g).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccco1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Br)o1

Procedure:
To a one-neck-flask charged with 2-acetylfuran (5.51 g, 50 mmol) in DMF (40 ml) at 0° C., was added N-Bromosuccinimide (9.79 g, 55.0 mmol) portionwise with stirring. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water (400 mL), extracted with ether (150 mL×3). The combined organic layers was dried, concentrated and purified on a silica gel column (Hexanes:EtOAc=4:1) to afford a white solid GC-4-89 (3 g, 31.7%). 1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=3.6 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 2.46 (s, 3H)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:21][CH:20]=[CH2:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 13 h
Yield: 49.9 %

Procedure:
To a mixture of phthalimide (3.92 g, 26.6 mmol) and potassium carbonate (9.20 g, 66.6 mmol) in acetonitrile (44 ml), was added 4-bromo-1-butene (2.26 ml, 22.2 mmol) at room temperature. The resulting reaction mixture was stirred at 90° C. for 13 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (2.23 g). The compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a solution of methyl 3-chloro-4-methylbenzoate (920 mg, 5.0 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (1.067 g, 6.0 mmol) and 2,2′-Azobis(2-methylpropionitrile) (81 mg, 0.50 mmol). The mixture was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1) to give the desired product (200 mg, 19%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[CH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH:28]([CH2:29][CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:45]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4OC4CCc4ccccc4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.343 g, 0.718 mmol) and m-chloroperbenzoic acid (0.181 g, 0.79 mmol) were stirred in CH2Cl2 overnight. An additional portion of m-chloroperbenzoic acid was added and the reaction stirred overnight again. Standard aqueous workup and silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([O-])=O>O.C1COCC1.[Fe]>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([NH2:3])=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
Ammonium chloride (228 mg, 4.2 mmol) in water (4 mL) was added to a solution of 1-(4-nitro-phenyl)-piperidine (220 mg, 1.0 mmol) in THF (6 mL) and the resulting mixture was stirred at 75° C. for 30 minutes. Iron powder (238 mg, 4.2 mmol) was then added portion wise and the mixture stirred for 5 hours at 75° C. The reaction mixture was filtered over celite, the filtrate was basified with sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 180 mg (96%) of 4-Piperidin-1-yl-phenylamine. LCMS: 177.13 (M+1)+, 80.6%, 1H NMR: (DMSO-d6): δ 6.67 (m, 2H), 6.47 (m, 2H), 4.51 (s, 2H), 2.57 (t, 4H), 1.6 (q, 4H), 1.49 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]#[C:17][CH2:18][OH:19])[C:6]=2[CH:20]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl.CCOCC>N1C=CC=CC=1>[S:22]([O:19][CH2:18][C:17]#[C:16][C:7]1[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)(=[O:24])(=[O:23])[CH3:21]
Reactant: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A solution of 6 g of 3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propyn-1-ol in 50 ml. of pyridine is treated dropwise at -10° C. to 0° C. with 1.7 ml of methanesulfonyl chloride in 10 ml of pyridine and stirred at this temperature for 2 hours. After pouring onto ice, acidification with hydrochloric acid and extraction with ether, there is obtained 3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propyn-1-ol mesylate which melts at 100°-102° C. after recrystallization from ether.
Reaction SMILES: C(N(CC)CC)C.[S].[C:9]([O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)(=[O:11])[CH3:10].Cl>C(OCC)(=O)C.CS(C)=O>[C:9]([O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH:18]=[O:19])[C@H:14]1[CH2:20][CH2:21][S:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)c1csc(SCC[C@@H]2[C@@H](CO)CC[C@@H]2OC(C)=O)n1
Agent: Cl
Agent: [S]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triethylamine (3.7 mL) and sulfur trioxidepyridine complex (1.7 g) were added to a dimethyl sulfoxide (4.0 mL)/ethyl acetate (8.0 mL) solution of ethyl 2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate (500 mg) (see compound 7 described in the pamphlet of International Publication No. WO 2006/129788) at 10° C., followed by stirring at room temperature for 30 min. To the reaction solution, 1 N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (497 mg) having the following physical properties:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether was treated with 9.7 g of potassium t-butylate at -10° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at about 0° C. for 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The reaction mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the yellowish, crystalline residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=O)=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)([Br:36])[Br:35]>C(Cl)Cl>[Br:35][C:34]([Br:36])=[CH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (2.56 g, 0.011 mmol) in methanol (20 mL) was added a 25% sodium methoxide in methanol solution (2.5 mL). The mixture was stirred at room temperature for 1.5 hours. The reaction was then concentrated, re-dissolved in EtOAc and washed with water. The aqueous wash was back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (2.65 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.O=C1N(C2CCNCC2)[C:25]2C=CC=C[C:24]=2N1.BrCC(OCC)=O.C(N(C(C)C)CC)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from β-aminotetralins (VII) or phenethylamines (XI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6-7). For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimnidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with β-aminotetralins (VII) or phenethylamines (XI), in the presence of an amine base, under peptide coupling conditions described above, to afford benzimidazolinones (XVII) and (XVIII) of formula A in which Y =carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6-7).