Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(OC(C)C)(OC(C)C)OC(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([Zn])=[CH:26][CH:25]=1.OP(O)(O)=O>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:26][CH:25]=1
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc([Zn])cc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution containing 13.8 g (100 mmol) 2-chlorobenzonitrile, 1.93 g (7.50 mmol) nickel bis(acetylacetonate), and 2.31 mL (9.38 mmol) triisopropyl phosphite in 15 mL of THF was rapidly added to the 4-methylphenylzinc reagent mixture. The mixture was then heated to 40° C., maintained at this temperature for 135 min, then cooled to 0° C. 75 mL of 10% H3PO4 was added in portions while keeping the temperature below 25° C. With the mixture stirring vigorously at room temperature, a rapid flow of air was bubbled through the solution for 15 min to oxidize any remaining nickel(0) to nickel(II). The lower aqueous layer was separated and the remaining organic (THF) phase was extracted twice with isooctane, using 100 mL for the first extraction and 75 mL for the second (isooctane layer is on top, THF layer is on the bottom). The combined isooctane extracts were concentrated by distillation at atmospheric pressure until at least 190 mL of distillate had been collected. 110 mL of isooctane was added to the distillation pot residue and this solution was cooled to 25° C. The resultant solution (ca. 190 mL) was then washed with 25 mL of 30% aqueous methanol, and the lower phase was discarded. The stirred solution was then seeded with 5 mg of 2-(4′-methylphenyl)benzonitrile and cooled to −10° C. to effect crystallization. After crystallization had proceeded at −10° C. for 30 min, stirring was halted and the cold mother liquor was siphoned away from the settled solid. The remaining material was treated with 150 mL of isooctane and heated to 35-40° C. with stirring until all the solids had dissolved (ca. 30 min). The solution was then seeded with 5 mg of 2-(4′-methylphenyl)benzonitrile at room temperature and cooled again to −10° C. to effect crystallization. After 30 min at −10° C. the crystallized product was collected by filtration and the filter cake washed with 25 mL of cold (−10° C.) isooctane. The product was dried under reduced pressure (0.5 Torr; 25° C.) to afford 12.5 g (65%) of 2-(4-methylphenyl)benzonitrile (65% recovered yield based on 2-chlorobenzonitrile) as a fine white crystalline solid (m.p.=50° C.; identity confirmed by 1H- and 13C-NMR).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CS(C)=O>[O:17]([C:2]1[CH:9]=[C:8]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [O-]c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2)cc1Oc1ccccc1

Procedure:
2,4-Dichlorobenzonitrile (12.04 g, 0.07 mole) was treated with 17.8 g sodium phenolate (0.155 mole) in 100 ml DMSO at 100°-110°C during 48 hours under nitrogen and stirring. Then, the DMSO was evaporated and the residue was dissolved in ether. The ether solution was then washed with water. After evaporation of the ether, the product was recrystallized from MeOH. Yield 11.5 g; mp 85°-86°C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:2][C:3]2[CH:12]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:30][CH:29]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 4.0 mL suspension of methyl 2-amino-4-(phenoxymethyl)benzoate hydrochloride 0.40 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 8 mg, palladium acetate 3 mg and cesium carbonate 0.89 g was added 1-fluoro-4-iodobenzene 0.47 mL, and it was heated and refluxed under nitrogen atmosphere for 16 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-(phenoxymethyl)benzoate 0.22 g of pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[N:12]1)[CH3:10].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[N:13]=[N:12]1)[CH3:10]
Reactant: CC(c1c(F)cccc1F)n1cc(C(=O)O)nn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C(C)c2c(F)cccc2F)nn1

Procedure:
6.5 g (35 millimoles) of 1-(2,6-difluorophenyl)ethyl azide and 2.45 g (35 millimoles) of propinecarboxylic acid in 50 ml of toluene are heated for 24 hours to 60°-70° C. The cooled reaction mixture is extracted with 100 ml of 1N sodium hydroxide solution and the extract is acidified with hydrochloric acid to give 1-[1-(2,6-difluorophenyl)ethyl-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 135°-138° C. (dec.). 7.1 g (26.6 millimoles) of 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid, 150 ml of ethanol and 1 ml of sulfuric acid are heated for 10 hours to reflux. Working up gives ethyl 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylate with a melting point of 118°-121° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:35][CH:34]=1)[C@@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(O[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Product: CC(C)c1ccc(O[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@@H](O)c2ccc(O)cc2)cc1
Yield: 98.9 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using (R)-4-benzyl-3-[(2R,3S)-3-(4-benzyloxyphenyl)-3-hydroxy-2-(4-isopropylphenoxy)propionyl]oxazolidine-2-one (9.00 g), which is the product of Reference example 30(b) and palladium on carbon (5%, 1.80 g) and the reaction mixture was treated to afford the desired compound (7.48 g) as a mass of foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.2 %

Procedure:
Add tert-butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 1.87 mmol) and Pd/C (10%, 50 mg) in ethanol (10 mL), flush with H2, stir under hydrogen atmosphere for 48 hrs at room temperature, filter and concentrate the filtrate to yield a white solid (220 mg, 73.9%). MS: (M+23): 367.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]O.C(N(S(F)(F)[F:17])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][F:17]
Reactant: OCc1cc(Cl)ccc1Br
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(Cl)ccc1Br
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a suspension of 2-bromo-5-chlorobenzyl alcohol (2.0 g, 9.0 mmol, Fluorochem) in anhydrous DCM (30 mL) was added (diethylamino)sulfur trifluoride (1.30 mL, 10 mmol), at about −75° C. After complete addition the mixture was allowed to warm slowly to rt, over about 1 h. Then saturated aqueous sodium bicarbonate (8 mL) was added and the mixture was partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted twice with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/hexanes 1:1) to give 1-bromo-4-chloro-2-(fluoromethyl)benzene (1.31 g, 5.9 mmol, 65%) as a pale yellow oil: 1H-NMR (CDCl3, Bruker 400 MHz) δ 5.42 (2 H, d, J=47.0 Hz) 7.19 (1 H, dd, J=8.8, 2.5 Hz) 7.41 (1 H, d, J=2.5 Hz) 7.48 (1 H, d, J=8.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].N1C(C)=CC=CC=1C.CS([Cl:44])(=O)=O.S([O-])(=O)(=O)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][Cl:44])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CO)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CCl)c2)c1

Procedure:
To a solution of 3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethanol, LiCl (1-4 equiv.), and 2,6-lutidine (1-2 equiv.) in DMF is added with stirring, cooling, and exclusion of moisture methanesulfonyl chloride (1-1.5 equiv.). The reaction mixture is stirred at ambient or elevated temperature until the alcohol and the intermediate mesylate have disappeared. The solvent is then distilled into a cooled receiver in an oil pump vacuum. The residue is diluted with EtOAc and aqueous NaHCO3 solution. The phases are separated. The organic phase is washed with brine, dried over MgSO4, and evaporated, and the residue is used directly in the subsequent step. A purer product is obtained by filtration over silica gel with EtOAc or a mixture of EtOAc with a nonpolar solvent. The product is not stable in storage and should be carried forward promptly.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(NC(C)C)(C)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.[Cu]I>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
A mixture of ethyl 5-bromo-thiophene-2-carboxylate (500 mg, 2.13 mmol), trimethylsilylacetylene (0.445 mL, 3.2 mmol), Pd(PPh3)4 (15 mg) and CuI (10 mg) in diisopropylamine (10 mL) was heated at 80° C. for 2 h. After being cooled to room temperature, the mixture was filtered through CELITE, and the filtrate was poured into water. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated in vacuo to give ethyl 5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate (529 mg). MS 253 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C@@H:45]4[CH2:49][O:48]C(C)(C)[O:46]4)[CH2:39][CH2:38]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.FC(F)(F)C(O)=O>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C@@H:45]([OH:46])[CH2:49][OH:48])[CH2:39][CH2:38]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC[C@@H]2COC(C)(C)O2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC[C@@H](O)CO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.3 %

Procedure:
To a solution of rac-[(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-{4-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-piperazin-1-yl}-methanone (30 mg) in tetrahydrofuran (1 mL) was added 10 drops of trifluoroacetic acid. The mixture was stirred at room temperature for 2 d and concentrated. Purification of the crude residue by reversed phase HPLC (C18-silica gel, eluting with water and acetonitrile) gave the title compound as white solids (6.6 mg). HR-MS (ES, m/z) calculated for C36H47N6O4Cl2 [(M+H)+] 697.3031, observed 697.3027.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=[CH:16][N:15]=3)[C:6]=2[CH:12]=1
Reactant: Brc1ccc2c(c1)NCCCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCCCc4ccc(Br)cc43)c2cc1OC
Yield: 58 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 58% yield from 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 209°-217° C.; LC-MS: 414, 416 (MH+); anal. RP18-HPLC RT: 5.47 min.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13]C(=O)C)[CH:9]=[CH:8][C:7]=1[Br:17])(=O)C.C(OCC1C=CC=C(COC(=O)C)C=1Br)(=O)C.[OH-].[Na+].Cl>CO.C1(C)C=CC=CC=1>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[Br:17]
Reactant: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Agent: CC(=O)OCc1cccc(COC(C)=O)c1Br
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ccc(Br)c(CO)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
An about 93:7 mixture (36.7 g) of 2,4-bis(acetoxymethyl)-bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183 ml) and cooled to 10° C. To this solution was added dropwise 10% aqueous sodium hydroxide solution (133 g). The reaction mixture was stirred at room temperature for 1 hr, and the solvent (about 200 ml) was evanorated The residue was neutralized with dilute hydrochloric acid (about 200 ml). To the neutralized solution was added toluene (150 ml) and the mixture was stirred at 80-85° C. for 1 hr and cooled. The resulting crystals were collected by filtration and dried under reduced pressure to give an about 93:7 mixture (22.2 g, 83.7%) of 2,4-bis(hydroxymethyl)bromobenzene and 2,6-bis(hydroxymethyl)-bromobenzene as almost white crystals. 2,4-bis(Hydroxymethyl)-bromobenzene was isolated by preparative HPLC and used in the measurement.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:12]
Reactant: O=C(Cl)CCc1ccc(F)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(Cl)cc(F)cc21
Temperature: 0 °C
Yield: 55 %

Procedure:
To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH:18]([CH3:20])[S:17](=[O:22])(=[O:21])[CH:16]([CH3:23])[CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=[N:34]C=2C=1.N.O1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:34])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:15][CH:16]([CH3:23])[S:17](=[O:21])(=[O:22])[CH:18]([CH3:20])[CH2:19]1
Reactant: On1nnc2ccccc21
Reactant: CC1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CC(C)S1(=O)=O
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC1CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC(C)S1(=O)=O
Temperature: 100 °C
Yield: 80.4 %

Procedure:
5-bromo-3-(2,6-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylic acid (0.187 g, 0.467 mmol) was suspended in DMF (3 mL) with EDC (0.269 g, 1.40 mmol, 3 eq) and HOBt (0.072, 0.467 mmol) in a 10 mL microwave reaction vessel. 0.5M Ammonia in 1,4-dioxane (0.93 mL, 0.467 mmol) was added and heated on the microwave at 100° C. for 20 minutes. The reaction was diluted with water and extracted with Ethyl acetate. The combined organics were washed with 2× water, 2×1N NaOH, brine then dried with magnesium sulfate, to give 0.150 g (80%) of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:22][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCCCc1nc2ccccc2n1-c1ccccc1
Yield: 81 %

Procedure:
A solution of 2-(3-hydroxypropyl)-1-phenyl-1H-benzimidazole (1.15 g) and thionyl chloride (0.6 g) in chloroform (23 ml) was refluxed for 1.5 hours. After being cooled, the mixture was diluted with a saturated aqueous solution of sodium bicarbonate. The chloroform layer was washed with water and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 2-(3-chloropropyl)-1-phenyl-1H-benzimidazole (1.0 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:27]1[C:31]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:20]([N:27]1[C:31]([C:32]([OH:43])([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][CH:10]=2)[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: O=C(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
9,9 g of p-tert-butylaminocarbonylphenyl bromide is dissolved in 200 ml of dry tetrahydrofuran and cooled to -70° C. To the solution is added dropwise n-butyl lithium (5,3 g) in hexane and the mixture is stirred for one hour. 1-benzyl-5-[4-(4-fluorophenyl)-1-oxobutyl]-1H-imidazole (10,4 g) in 200 ml of tetrahydrofuran is added to the mixture at -70° C. and the mixture is allowed to warm to room temperature and stirring is continued over night. Saturated ammonium chloride is added to the mixture and the solution is extracted with ethyl acetate. Ethyl acetate fractions are combined and evaporated to dryness.