Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([NH:9][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:11](OCC)=[O:12])=O.S([O-])([O-])(=O)=O.[Mg+2].C(OCC)C>C1COCC1>[CH3:7][NH:9][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH2:11][OH:12]
Reactant: CCOC(=O)C(CC)(NC=O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CO)(NC)c1ccccc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a suspension of 900 mg (23.71 mmol) of lithium aluminum hydride (LiAlH4) in 30 mL of anhydrous THF were added dropwise a solution of 3.09 g (13.15 mmol) of 7, previously prepared, in 18 mL of anhydrous THF. After 4 h under reflux, the reaction mixture was allowed to cool to room temperature and an additional amount of lithium aluminum hydride (900 mg) was introduced. Reflux was maintained for 4 h then an aqueous saturated solution of magnesium sulfate was slowly added at −10° C. under vigorous stirring until formation of a precipitate. The solid was filtered and washed several times with THF. The organic solvent was evaporated under reduced pressure until obtaining of an aqueous solution. The solution was added with 100 mL of diethyl ether and the organic layer was dried over sodium sulfate. Evaporation of the solvent afforded 1.84 g of 8 as a yellow oil. (78% yield).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([F:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[F:13])=[N:27]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2F)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2F)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 21 %

Procedure:
Triethylamine (0.20 g, 2.0 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2,6-difluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (chloroform), to give a white solid of N-ethyl-3-(2,6-difluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.11 g, yield: 21.0%). mp: 102-104° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.21 (t, J=7.3 Hz, 3H), 2.19 (s, 3H), 3.32 (dq, J=6.0 and 7.3 Hz, 2H), 5.00-5.25 (m, 1H), 6.25 (s, 1H), 7.36 (d, JHF=7.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:27][C:28]1[NH:29][N:30]=[CH:31][C:32]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3C4CCC(CC4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
tert-Butyl (3S)-3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (190 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (266 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (35 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (146 mg) as a pale-yellow solid.
Reaction SMILES: [C-]#[Si+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH3:3][O:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: CCCCCCCCOC
Agent: [C-]#[Si+]
Product: C=CCCCC=CCOC

Procedure:
Nitrogen gas was introduced downflow to a 1″×18″ 316 s.s. hot tube reactor system containing 67 ml of silicon carbide (SiC) at a total rate of 6.2 ml/min. The hot tube reactor was heated to 450° C. at which time 1-methoxyoctane (MO), obtained from hydrogenation of 1-methoxy-2,7-octadiene, was added downflow at 0.1 ml/min. Under these conditions 1-methoxyoctane was converted to a mixture of 1-octene and mixed internal octenes at 3.3% wt conversion with a selectivity to 1-octene of 10 m % and mixed internal octenes of 90 m %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[C:19]3=[CH:20][CH:21]=[CH:22][N:18]3[CH2:17][C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[C:19]3=[CH:20][CH:21]=[CH:22][N:18]3[CH2:17][C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:9][CH2:8]1
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(CN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 11-[1-(3,4-dichlorobenzoyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.8 g; 0.011 mole in 100 ml THF) was added a 1 molar solution of lithium aluminum hydride in THF (17 ml, 0.017 mole). This was then stirred at room temperature for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[N:10]([CH:14]([CH2:16]O)[CH3:15])[C:9]2=[O:18])=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[N:10]([CH:14]([CH3:15])[CH2:16][Cl:21])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CO)N1C(=O)N(c2ccc(Cl)cc2)CC1C
Solvent: ClC(Cl)Cl
Product: CC(CCl)N1C(=O)N(c2ccc(Cl)cc2)CC1C
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 16 g. of 1-(p-chlorophenyl)-3-(1-(hydroxymethyl)ethyl)-4-methyl-2-imidazolidinone in 400 ml. of anhydrous chloroform, 14.5 g. of SOCl2 is added dropwise with stirring while the temperature is maintained at 0° C. The mixture is then refluxed for 45 minutes, concentrated under vacuum and taken up with benzene, then evaporated to dryness again, yielding 15.1 grams (94%) of the title compound, m.p. 70°-72° C. (from diisopropyl ether). The corresponding m-chlorophenyl-substituted compound is prepared in the same way. Yield 97%, b.p. 200° C./0.5 mm Hg.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28]([C:30]4[S:31][C:32]([Cl:35])=[CH:33][CH:34]=4)=[O:29])[O:23][C:22]3=[O:36])=[CH:17][C:16]=2[Cl:37])[C:10]1=[O:38])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Cl-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:35][C:32]1[S:31][C:30]([C:28]([NH:27][CH2:26][C@@H:24]2[O:23][C:22](=[O:36])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][OH:6])[C:10]4=[O:38])=[C:16]([Cl:37])[CH:17]=3)[CH2:25]2)=[O:29])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](OCCN1CCCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCN(CCO)C3=O)c(Cl)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 355 mg (0.47 mmol) of the product from example 70A in 9 ml of THF is admixed with 290 mg (1.10 mmol) of a 1 molar solution of tetrabutylammonium fluoride in THF. The mixture is stirred at RT for 2 h. Then it is admixed with 80 ml of water, 50 ml of ethyl acetate and 6 ml of sodium chloride solution, and the phases are separated. The organic phase is extracted twice with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the mixture is freed of the solvent and the residue is prepurified by chromatography on silica gel (20:1 dichloromethane/methanol). Subsequent purification by means of preparative HPLC with an acetonitrile/water mixture affords 39 mg (16% of theory) of the desired product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]([CH2:16][C:17]([OH:19])=O)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:17](=[O:19])[CH2:16][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[S:3]1(=[O:5])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: CNS(=O)(=O)c1cc2ccccc2cc1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CN1C(=O)Cc2cc3ccccc3cc2S1(=O)=O
Yield: 61.1 %

Procedure:
This naphthalene-2-acetic acid (2.6 g, 9.4 mmol) was 12 hrs refluxed in 100 mL xylene with the addition of 0.2 g p-toluene-sulfonic acid. The reaction mixture was cooled, filtered, washed with water and concentrated. Recrystallization from ethanol gave 1.5 g (61%) 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide (melting point: 126-127° C.).
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH:5]=[N:6]2.C[Li].Cl[C:18]1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH3:18][C:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][N:1]=2)[N:6]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: c1ccc2c(c1)cnc1cccnc12
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1nc2cccnc2c2ccccc12
Temperature: -78 °C
Yield: 77.7 %

Procedure:
1.0 g benzo[c][1,5]naphthyridine (5.5 mmol) was dissolved in 30 mL tetrahydrofuran (THF) and then cooled to −78° C. under nitrogen with stirring. 4.4 mL methyl lithium (MeLi) (6.6 mmol, 1.5M) was added and reacted for 1 hr. After quenching the reaction by a saturated ammonium chloride (NH4Cl) solution, extraction by ethyl acetate, drying, and concentration, 30 mL THF and 1.87 g 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (8.2 mmol) were added and reacted for 8 hr. After extraction by ethyl acetate, drying, concentration, and purification by silicon-gel column, 0.83 g light yellow solid was obtained, with a yield of 77%.
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([N:26]=[C:27]=[S:28])[C:22]([CH3:29])=[N:21]1>C1COCC1>[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([NH:26][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[S:28])[C:22]([CH3:29])=[N:21]1
Reactant: Cc1nn(C)c(C)c1N=C=S
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nn(C)c(C)c1NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.423 g, 10.6 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (1.6 g, 10.6 mmol). The mixture was stirred until a clear solution was obtained. A solution of (1,3,5-trimethyl-pyrazol-4-yl)-isothiocyanate (1.8 g, 10.6 mmol) of step A in 5 mL THF was slowly added and stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid foam was triturated with Et2O-hexane overnight to provide 2.0 g of the title compound as a tan solid, m.p. 165-166° C. (59% of theory).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([O:37][CH3:38])[C:31](N(OC)C)=[O:32])=[CH:26][CH:25]=2)=[N:21][N:20]=1)[CH3:18]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:31](=[O:32])[CH:30]([C:27]3[CH:28]=[CH:29][C:24]([C:22]4[O:23][C:19]([CH2:17][CH3:18])=[N:20][N:21]=4)=[CH:25][CH:26]=3)[O:37][CH3:38])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCc1nnc(-c2ccc(C(OC)C(=O)N(C)OC)cc2)o1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: CCc1nnc(-c2ccc(C(OC)C(=O)c3ccc(-c4cc(OC)c(Br)c(OC)c4)o3)cc2)o1
Yield: 12 %

Procedure:
The method used for the final coupling step of Example 12 was followed for the reaction of 2-(4-bromo-3,5-dimethoxyphenyl)furan with 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide. Purification by chromatography (20-100% EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanone as a yellow foam (0.037 g, 12% yield). MS: m/z 527.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[N:39]1([CH2:38][CH2:37][CH2:36][O:35][C:32]2[CH:33]=[CH:34][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[CH:24][CH:25]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: ClCCCOc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2ccc(OCCCN3CCOCC3)cc2)ccc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 22.1 %

Procedure:
A suspension of potassium carbonate (138 mg) in a mixture of 1-{3-[4′-(3-chloropropoxy)biphenyl-4-yloxy]propyl}piperidine (100 mg), morpholine (65 mg) and N,N-dimethylformamide (1 mL) is stirred for four days at room temperature. The mixture is filtered, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane/methanol 82/2 as eluent. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 25 mg of 4-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)morpholine as a off white solid which is salted with 9.4 mg of oxalic acid yielding 15 mg of 4-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)-morpholine, dioxalate as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[Na].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([S:25][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(OCC=C(C)CBr)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC=C(C)CSCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
14.15 g (0.05 mol) of 4'-(4-bromo-3-methyl-2-butenyloxy)-acetophenone are added at 10°-15° during the course of 1 hour to 7.3 g (0.05 mol) of sodium salt of benzylmercaptan which is dissolved in 120 cc of dimethylformamide. The mixture is stirred at 20°-25° for 20 hours, is subsequently filtered and the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, is extracted with saturated salt solution and the ether solution is evaporated. The remaining yellowish oil is chromatographed on silica gel with hexane/ethyl acetate 2 : 1. After recrystallization from ether/hexane the 4'-(4-benzylthio-3-methyl-2-butenyloxy)-acetophenone is obtained as colourless crystals. M.P. 75°-76.5°.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.CC(C)([O-])C.[Na+].C(OCC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cncc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)[C@@H]3C2)c1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
The product from Example 15E (0.549 g, 2.30 mmol) in toluene (23 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, available from Alfa Aesar) (43 mg, 0.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, available from Strem Chemicals) (58 mg, 0.10 mmol), 3-bromo-5-methoxypyridine from Example 7A (0.43 g, 2.30 mmol) and sodium tert-butoxide (available from Aldrich Chemical Co.) (0.38 g, 3.90 mmol). After heating at 80° C. for 16 hours, the mixture was poured into diethyl ether (100 mL), washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% MeOH/CH2Cl2) to provide the title compound as a yellow oil (0.42 g, 57% yield). MS (DCI/NH3) m/z 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[S:16]1[C:20]([C:21]2[O:22][C:23]([CH3:28])=[C:24]([CH2:26]Cl)[N:25]=2)=[CH:19][C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2>>[S:16]1[C:20]([C:21]2[O:22][C:23]([CH3:28])=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)=[CH:19][C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCl
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1oc(-c2cc3ccccc3s2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give 2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole. The yield was 38%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 142-143° C.
Reaction SMILES: C1(O)C=CC=CC=1.C=O.C(NCC)C.N1CCCC1.C(NCCC)CC.[CH2:27]([N:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])[CH2:30][CH3:31])[CH3:28].C(N(CC1C=CC=CC=1O)CCC)CC>C(OC(C)C)(C)C>[OH:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][N:29]1[CH2:30][CH2:31][CH2:28][CH2:27]1
Reactant: CCN(CC)Cc1ccccc1O
Agent: C=O
Agent: CCCN(CCC)Cc1ccccc1O
Solvent: CCNCC
Solvent: CCCNCCC
Solvent: CC(C)OC(C)C
Product: Oc1ccccc1CN1CCCC1
Yield: 101.8 %

Procedure:
The procedure was as described in Example 1, but the phenol and paraformaldehyde in diisopropyl ether were reacted at 50° C. in separate runs with (a) 0.65 kg of diethylamine, (b) 0.632 kg pyrrolidine and (c) 0.90 kg of dipropylamine. Under the same reaction conditions and isolation conditions, 1.49 kg (about 93% of theory, relative to converted phenol) of o-diethylaminomethylphenol, 1.77 kg (about 96% of theory, relative to converted phenol) of o-dipropylaminomethylphenol and 1.50 kg (about 95% of theory, relative to converted phenol) of o-hydroxy-N-benzylpyrrolidine were obtained in (a), (b) and (c) respectively.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncccc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15% NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through Celite®, and the filter pad was washed thoroughly with THF followed by 5% CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83%) as a waxy light yellow solid: MS (ES) m/e 125 (M+H)+.
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.[CH3:12][O:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][OH:19].O.Cl>N1C=CC=CC=1>[CH3:12][O:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(C)CCCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(C)CCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.83 g (9.6 mmol) of p-toluenesulfonic acid chloride in 5 ml of pyridine was added dropwise to a solution of 1.06 g (8.0 mmol) of 5-methoxyhexanol in 5 ml of pyridine below 5° C. in an iced water bath. After stirring for 6 hours at room temperature, the reaction mixture was injected into 100 ml of cold water and, after being acidified with 6N-hydrochloric acid, was extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain 5-methoxyhexyl-p-toluenesulfonate.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[CH:10][C:9]=1[F:29])(C)(C)C.[ClH:31]>O.O1CCOCC1>[ClH:31].[ClH:31].[F:29][C:9]1[CH:10]=[C:11]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([OH:30])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Suspend [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid tert-butyl ester (1.36 g, 3.369 mmol) in water (8 mL) and 4N hydrochloric acid in dioxane (40 mL) and stir at ambient temperature for 3 hours. Concentration under vacuum quantitatively provides the title compound (1.42 g, 3.69 mmol). MS(ES), m/z 348 (M+1).