Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Pb](SC#N)[S:2][C:3]#[N:4].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[C:13]([S:2][C:3]#[N:4])[CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Oc1ccccc1Br
Reactant: N#CS[Pb]SC#N
Solvent: ClCCl
Product: N#CSc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of lead thiocyanate (6.49 g, 20.05 mmol) in CH2Cl2 (125 mL) under nitrogen at 0° C. PhICl2 (4.41 g, 16.05 mmol) was added in one portion. After 20 min at 0° C. a solution of 2-bromophenol (2.31 g, 1.55 mL, 13.37 mmol) in CH2Cl2 (10 mL) was added. After stirring the mixture for 45 min at 0° C. the salts were filtered and the solvent evaporated. The crude mixture was purified by silica gel flash chromatography (hexane-EtOAc 5:1→2:1) to yield 1 (2-bromo4-thiocyanatophenol) (1031 mg, 33%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 97 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using isopropylamine (1 M in DMF) instead of methylamine, to the title compound (110 mg, 97%) which was obtained as an off white solid. MS: m/e=352.5 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=4[CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=4[CH:15]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C#N)cc4)on3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(CN)cc4)on3)ccc21

Procedure:
0.95 g (2.7 millimoles) of 5-(4-cyanophenyl)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-isoxazole (Example 19) were added a little at a time, at room temperature, to a suspension of 0.28 g (7.4 millimoles) of lithium aluminum hydride in 30 ml of dry ether. The mixture was then refluxed for 3 hours and cooled, after which hydrolysis was carried out carefully with water, the phases were separated, the aqueous phase was extracted again with ether and the combined organic extracts were dried over sodium sulfate and evaporated down. 0.9 g of the title compound of melting point 138°-143° C. remained as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Yield: 87.5 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-4-[(2-phenyl)allyl]4-hydroxypiperidine (1.67 g, 5.26 mmol) in ethyl acetate (25 ml) was hydrogenated over 1% palladium on activated carbon (0.8 g) at room temperature and 1 atm pressure of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated to yield the title compound (1.47 g, 87%) as a pale yellow glass. δH (250 MHz, CDCl3) 1.27 (3 H, d, J=7), 1.36-1.60 (13 H, m), 1.73 (1 H, dd, J=15 and 4), 2.01 (1 H, dd, J=15 and 10), 2.98-3.06 (3 H, m), 3.60-3.88 (2 H, m) and 7.16-7.36 (5 H, m); m/z (ES) 320 (M+ +1).
Reaction SMILES: C([C:4]1O[C:6](C(O)=O)=[CH:7][C:8](=[O:10])[CH:9]=1)(O)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>CO>[CH:14]1([N:17]2[CH:4]=[CH:9][C:8](=[O:10])[CH:7]=[CH:6]2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc(=O)cc(C(=O)O)o1
Solvent: CO
Product: O=c1ccn(C2CC2)cc1

Procedure:
The starting material may be obtained as follows. A solution of 2,6-dicarboxy-4-pyrone (10.0 g.) and cyclopropylamine (3.8 ml.) in MeOH (300 ml.) was stirred at room temperature overnight. The precipitated salt was filtered off, dried under vacuum and heated to 200° for 30 minutes. The resulting black gum was extracted with methylene chloride (3×150 ml.). The extracts were concentrated and purified by chromatography on Kieselgel 60 (100 g.) using methylene chloride/MeOH 100:0 to 80:20 v/v to give 1-cyclopropyl-4-pyridone (1.26 g.) as an oil having n.m.r. in CDCl3 : 1.03(m, 4H); 3.38(m, 1H); 6.3(d, 2H); 7.4(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-cyclopropylpyridinium toluene-p-sulphonate.
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[CH:8]=[C:9]([C:22]([O:24]CC)=[O:23])[C:10](=[O:21])[C:11]3[CH:12]=[CH:13][C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:5]([C:6]=32)[O:4][CH2:3]1.C(O)(=O)C.Cl>O>[CH3:1][CH:2]1[N:7]2[CH:8]=[C:9]([C:22]([OH:24])=[O:23])[C:10](=[O:21])[C:11]3[CH:12]=[CH:13][C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:5]([C:6]=32)[O:4][CH2:3]1
Reactant: CCOC(=O)c1cn2c3c(c(-c4ccccc4)ccc3c1=O)OCC2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1COc2c(-c3ccccc3)ccc3c(=O)c(C(=O)O)cn1c23
Reaction time: 1 h

Procedure:
A mixture of 11.5 g of ethyl 2,3-dihydro-3-methyl-7-oxo-10-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate and 75 ml of glacial acetic acid was heated to reflux temperature and 75 ml of 6N hydrochloric acid was subsequently added. Refluxing was continued for one hour after which time 150 ml of water was added. The solution was cooled and filtered to provide light brown solid 2,3-dihydro-3-methyl-7-oxo-10-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, m.p. 295°-296° C. Recrystallization from aqueous N,N-dimethylformamide gave light yellow crystals. Analysis: Calculated for C19H15NO4 : %C, 71.0; %H, 4.7; %N, 4.4; Found: %C, 70.4; %H, 4.6; %N, 4.3. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(F)c(F)cc2n1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CCNCC1
Reaction time: 8 h

Procedure:
A solution of 5,6-difluoro-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D88) (0.7 mmol, 240 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated under argon with 10% palladium on charcoal (50 mg, ˜0.25 eq wt) and the mixture was stirred overnight under 25-30 PSI, then 8 h under 50 PSI of hydrogen at room temperature. The mixture was concentrated under reduced pressure to give a yellow/orange oil which crystallized with a touch of methanol (from evaporation of the methanol). The residue was dissolved again in 10 mL ethanol and 2 mL of acetic acid, then 50 mg of palladium on charcoal was added again under argon and the mixture was stirred under 50 PSI of hydrogen for 9 days, until completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound as the acetate salt. M+H 254.2, M−H 252.2
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>ClCCl>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 19.83 gm (143.56 mMol) 4-nitroaniline in 150 mL dichloromethane and 12.9 mL (159.5 mMol) pyridine at 0° C. were slowly added 24.5 gm (154.8 mMol) 4-fluorobenzoyl chloride. The reaction mixture was then stirred for 15 minutes at 0° C., at which time the reaction mixture became homogeneous, and then for an hour at room temperature. To this mixture were then added 100 mL water and the solid which formed was collected by filtration. The filter cake was washed with hexane (80 mL) followed by water (100 mL) and it was then dried under vacuum at 60° C. to give 34.1 gm (91%) N-(4-fluorobenzoyl)-4-nitroaniline.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Yield: 78.3 %

Procedure:
Activated manganese dioxide (47 mg, 0.54 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c][1,5]naphthyridine (40 mg, 0.11 mmol) in toluene (4.0 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (32 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCC(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCC(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Yield: 99.6 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-[1-(2-chloro-6-methyl-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (15.37 g) in ethanol (350 ml) was hydrogenated over 10% palladium on carbon for 18 hours. The reaction mixture was filtered through celite and solvent evaporated to give, as a solid 1-(tert-butoxycarbonyl)-4-[1-(6-methylpyrimidin-4-yl)-4-piperidylcarbonyl] piperazine (14.07 g).
Reaction SMILES: O[N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]2[C:21](=[S:24])[NH:22][N:23]=[C:4]2[C:3]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[N:16]1([C:8]2[CH:7]=[C:6]3[C:11]([NH:2][C:3](=[O:25])[C:4]4[N:5]3[C:21](=[S:24])[NH:22][N:23]=4)=[CH:10][C:9]=2[C:12]([F:14])([F:15])[F:13])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=c1c2n[nH]c(=S)n2c2cc(-n3ccnc3)c(C(F)(F)F)cc2n1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1[nH]c2cc(C(F)(F)F)c(-n3ccnc3)cc2n2c(=S)[nH]nc12
Yield: 38.1 %

Procedure:
A solution of 250 mg (0.67 mmol) of 5-hydroxy-8-(1H-imidazol-1-yl)-1-thioxo-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 360 mg (1.37 mmol) of triphenylphosphine was stirred at 140° C. for 20 h. The solution was evaporated to dryness, and the solid residue was triturated with small portions of cold dichloromethane to give the crude product. Recrystallization from ethanol gave 90 mg (40%) of pure title compound. M.p.>300° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Brc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2cccc3ccccc23)cc1
Yield: 35.5 %

Procedure:
1-Bromonaphthalene (0.15 mole, 31.0 g),4-nitrothiophenol 0.11 mole, 17.0 g), potassium carbonate (0.15 moles, 20.7 g), copper bronze (0.3 moles, 18.9 g) and cuprous chloride (0.06 moles, 6.0 g) were refluxed in 500 ml pyridine for 3 days. The reaction was filtered while hot, and then concentrated. Ethyl acetate was added and the solution washed with water and 5N HCl, dried over sodium sulfate and concentrated. The product was purified twice by HPLC over silica gel eluted with 20% ethyl acetate/hexane followed by 5 ethyl acetate/hexane to yield 1-(4-nitrophenylthio)naphthalene 11.0 g, 26%. Mass Spec (FD) 282. Calculated for C16H11NO2S: C, 68.31 H, 3.94, N, 4.98. Found: C, 68.52; H, 4.00; N, 4.77.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:10]S(C(C)(C)C)=O)[CH3:9])=[CH:4][CH:3]=1.[ClH:17].O1CCOCC1.CCOCC>CO>[ClH:17].[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid[(R)-1-(6-bromo-pyridin-3-yl)-ethyl]-amide (650 mg, 2.13 mmol) in MeOH (5 mL) was added 4.0M HCl in dioxane (5.32 mL, 21.30 mmol). The clear reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture became cloudy during this time. Ether (20 mL) was added, and the mixture was stirred for 10 min and then filtered, washed with ether (20 mL) to afford (R)-1-(6-bromo-pyridin-3-yl)-ethylamine HCl salt (500 mg, 87%) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]S(O)(=O)=O>>[C:1]1([CH2:7][C:8]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1c2ccc(C#Cc3ccccc3)cc2nc2n1CCCCC2
Product: O=C(Cc1ccccc1)c1ccc2c(=O)n3c(nc2c1)CCCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (400 mg, 1.3 mmol), HgSO4 (0.1 g, 0.3 mmol, 0.2 equiv) and H2SO4 (6 mL) was stirred at room temperature for 2 h. After quenching with water and basifying with saturated sodium carbonate, the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated. The residue was purified by silica gel chromatography to give the desired product (30 mg). MS (ESI): 333 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.22-8.19 (d, J=8.16 Hz, 1H), 8.03-7.99 (d, J=7.14 Hz, 2H), 7.59-7.43 (m, 4H), 7.37-7.34 (d, J=8.19 Hz, 1H), 4.40 (s, 2H), 4.39-4.36 (t, J=5.34 Hz, 2H), 3.06-3.03 (t, J=3.60 Hz, 2H), 1.85-1.81 (m, 6H). mGluR5 PAM EC50: ++.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 7-fluoro-2-(2-methylphenylamino)-6-benzoxazolylacetate (1.31 g, 4.17 mmol) was dissolved in THF (30 ml), followed by the addition of 0.25N NaOH (30 ml). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (1.08 g, 86%) was obtained as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:12]([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:10][CH:12]([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: COc1cc(S)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)C(C)Sc1cc(Cl)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 3-chloro-5-methoxybenzenethiol (1.90 g), methyl 4-bromo-3-oxopentanoate (2.50 g) and K2CO3 (1.80 g) in DMF (dry) (36.3 mL) was stirred at room temperature overnight. The reaction was quenched with H2O and diluted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.09 g).
Reaction SMILES: [CH2:1]([CH2:4][NH:5][C:6]([CH3:10])([CH3:9])[C:7]#[N:8])[CH:2]=[CH2:3].O>C1C=CC=CC=1>[CH2:1]([CH2:4][NH:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH2:8])[CH:2]=[CH2:3]
Reactant: C=CCCNC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: C=CCCNC(C)(C)CN
Reaction time: 8 h

Procedure:
2-Allylmethylamino-2-methylpropionitrile (1.3 g.,) in benzene (20 ml., dry) was added dropwise to a stirred solution of sodium dihydro-bis [2-methoxy-ethoxy]aluminate (6.7 g.,) in benzene (30 ml., dry) under an atmosphere of nitrogen and stirred overnight. The excess reducing agent was decomposed by the dropwise addition of water. The phases were separated, the organic phase was washed with water, the aqueous phase was washed with benzene and the combined organic extract was dried (MgSO4) and the solvent was removed in vacuo to give a pale yellow liquid (1.8 g.). Distillation at 80°-90°/15 mm. gave 2-allylmethylamino-2-methylpropylamine as a colourless liquid (0.8 g., 60%).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[NH2:29][C:30]([NH:32][C:33]1[NH:34][C:35]2[C:40]([C:41]=1[C:42]([NH2:44])=[O:43])=[CH:39][CH:38]=[C:37]([CH2:45]O)[CH:36]=2)=[O:31].O>O1CCCC1>[NH2:29][C:30]([NH:32][C:33]1[NH:34][C:35]2[C:40]([C:41]=1[C:42]([NH2:44])=[O:43])=[CH:39][CH:38]=[C:37]([CH2:45][N:15]=[N+:16]=[N-:17])[CH:36]=2)=[O:31]
Reactant: NC(=O)Nc1[nH]c2cc(CO)ccc2c1C(N)=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
Diphenylphosphoryl azide (42 μL, 0.19 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29 μL, 0.19 mmol) were added to a solution of 2-aminocarbonylamino-6-hydroxymethylindole-3-carboxamide (Compound 16-1, 40 mg, 0.16 mmol) in anhydrous tetrahydrofuran (5 mL) under ice-cooling, the mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (5.0 mg) as a yellow solid (yield 11%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)/C=C/C(O)=O>C(OCC)(=O)C.C(O)C>[O:9]([CH2:8][CH2:7][N:6]1[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=[C:2]1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc2ccccc2n1CCOc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2nc3ccccc3n2CCOc2ccccc2)CC1

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(phenoxy)ethyl]benzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.14 g), there are obtained crude crystals, which are recrylstallized from ethyl acetate-ethanol to give 1-[2-(phenoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (2.99 g) as pale yellow plates, m.p. 152°-153.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11]Cl.Cl>ClC1C=CC=CC=1>[Cl:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: ClCl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C(O)c1ccc(CCl)cc1
Temperature: 0 °C

Procedure:
272 parts of 4-methyl-benzoic acid are dissolved in 750 parts of chlorobenzene at 100° C. and are chlorinated at this temperature by the introduction of elementary chlorine under UV light; the chlorination process is ended when 71 parts of hydrochloric acid have been formed. The reaction mixture is then cooled to about 0° C., with stirring, and the precipitate which has separated out is filtered off, freed from chlorobenzene by being washed several times with low-boiling petroleum ether and dried. 307 parts of 4-(chloromethyl)-benzoic acid with a melting point of 196° to 200° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: Cn1ccnc1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1ccnc1C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.82 g (10 mmol) of 1-methyl-imidazole and 2.7 g (10 mmol) of 4-iodobenzoic acid chloride are combined in 10 ml of acetonitrile while cooling with an ice bath, 1.4 ml (10 mmol) of triethylamine are added and the mixture is then stirred for 16 hours at ambient temperature. The crude product is taken up in 30 ml of ethyl acetate, washed with H2O, dried, concentrated in vacuo and purified by flash chromatography (silica gel; methylene chloride).