Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][C:22]([O:25][CH3:26])([CH3:24])[CH2:21][N:20]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][NH:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:44]1[CH:43]=[C:42]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][C:22]([O:25][CH3:26])([CH3:24])[CH2:21][N:20]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:46]=[N:45]1
Reactant: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Yield: 63 %

Procedure:
A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (420 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (173 mg, 0.89 mmol), Pd(dppf)Cl2 (65 mg, 0.089 mmol), and a solution of Na2CO3 (2.0 M, 0.9 mL) in 1,4-dioxane (15 mL) under argon in a sealed vial was heated in a microwave oven at 120° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography petroleum ether:EtOAc (3:1˜1:1) as eluting solvents to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (283 mg, 63%). MS (ESI) m/z: 505 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:20]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1.C1C=CC2C(=NO[N+]=2[O-])C=1.[OH-].[Na+]>CO.C(#N)C.C(OCC)(=O)C>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:26]2[C:23]2[CH:24]=[CH:25][C:20](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: [Na+]
Agent: [O-][n+]1onc2ccccc21
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(/C=C/c3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (500 mg) obtained in Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled and benzofuroxan (259 mg) dissolved in acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at 50° C. The reaction mixture was ice-cooled. After 1N sodium hydroxide was added, ethyl acetate was added and the mixture was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the title compound (540 mg, yield 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH:27]=[CH:26][N:25]=1
Reactant: BrCc1ccnc(Br)c1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(Br)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (950 mg, 3 mmol), (prepared as described for the starting material in Example 24), 2-bromo-4-bromomethylpyridine (765 mg, 3 mmol) and potassium carbonate (2.38 g 17 mmol) in DMF (10 ml) was heated at 80° C. for 2 hours. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane and the solid product collected by filtration, washed with ethyl acetate/hexane and dried to give 7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (647 mg, 44%).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH2:18].O>C(Cl)(Cl)Cl>[CH3:17][NH:18][CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1ccc(OCC(=O)O)cc1
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(C)C(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
4-(2-bromopropionyl)phenoxyacetic acid (5 g, 17.5 mmol) in chloroform (50 ml) was stirred vigorously at 35-40° C. and a solution of 40% methylamine in water (4.05 ml, 52 mmol) was added dropwise over 30 mins. Stirring was continued at this temperature for a further 1.5 h after addition. The mixture was evaporated to dryness and the crude residue was purified by column chromatography (silica gel: 10% methanol in chloroform) to give the title product (2.7 g, 65%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Fc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH3:30][O:31][CH2:32][CH:33]=O>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:33][CH2:32][O:31][CH3:30])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COCC=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Product: COCCN1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and methoxyacetaldehyde instead of acetone. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H30ClN6O2 (M+H)+: m/z=445.2; Found: 445.2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][C:33]=1[Cl:41]>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)=[C:33]([Cl:41])[CH:34]=1)(=[O:37])[NH2:38]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: NC(=O)c1ccc(Br)c(Cl)c1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cc4Cl)ccc3o2)CC1
Yield: 37.7 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromo-3-chlorobenzamide (105 mg, 0.48 mmol) as a brown solid. M.P.: 178-182° C. MS (m/z): 442.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][N:14]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH2:19][C:16]1[CH:15]=[N:14][C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[N:18][CH:17]=1
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 112.9 %

Procedure:
Thionyl chloride (0.427 mL, 5.86 mmol) was added to a suspension of (2-((4-chlorophenyl)amino)pyrimidin-5-yl)methanol (0.23 g, 0.976 mmol) in DCM (10 mL) cooled to 0° C. The mixture was stirred for 18 h while warming to room temperature. The reaction mixture was concentrated and the residue triturated with ether to give 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a pale yellow solid (0.28 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (s, 1H), 8.60 (s, 2H), 7.85-7.64 (m, 2H), 7.41-7.20 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:44]([NH:51][C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.25 g, 4.52 mmol) in CH2Cl2 (50 mL) at 25° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g, 6.79 mmol; commercially available from Sigma Aldrich) followed by 1-hydroxybenzotriazole hydrate (1.04 g, 6.79 mmol; commercially available from Sigma Aldrich) and the reaction was stirred for 5 min at 25° C. Subsequently, benzyl amine (0.533 g, 4.98 mmol; commercially available from Sigma Aldrich) was added and the reaction was stirred for an additional 4 hrs as a fine white precipitate developed. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine. After drying and concentration, the product was purified by silica gel chromatography (20% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.65 g, 39%): MS(APCI+): m/z366.1 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[NH2:12])O1.Br[C:22]1[CH:23]=[N:24][N:25](C(OC(C)(C)C)=O)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:24]1[CH:23]=[C:22]([C:9]2[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=2)[NH2:12])[CH:26]=[N:25]1
Reactant: CC1(C)OB(c2cc(N)cc(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)n1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2cn[nH]c2)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 1.7 %

Procedure:
To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (500 mg, 1.742 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (473 mg, 1.916 mmol), PdCl2(dppf) (127 mg, 0.174 mmol) and Cs2CO3 (1135 mg, 3.48 mmol). The mixture was stirred at 100° C. for 16 h under N2. The mixture was filtered and concentrated, which was purified by silica column chromatography (PE/EA=1:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.2) were combined and concentrated. Then the residue was purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a yellow solid of 3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (8 mg, 0.030 mmol, 1.7% yield): 1H NMR (400 MHz, CD3OD) δ 7.93 (s., 2H), 7.08 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H). ES-LCMS m/z 228.1 (M+H).
Reaction SMILES: COC1C=CC=C(OC)C=1.C(Cl)(=O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)C#C.C1C2C(=CC=CC=2)C=CC=1O.[C:53]1([C:59]2([C:73]3[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][C:74]=3[O:81][CH3:82])[O:64]C3C=CC4C(C=3C=C2)=CC=CC=4)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(=S)=S.C1(C)C=CC=CC=1>[CH3:82][O:81][C:74]1[CH:75]=[C:76]([O:79][CH3:80])[CH:77]=[CH:78][C:73]=1[C:59]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:64]
Reactant: COc1ccc(C2(c3ccccc3)C=Cc3c(ccc4ccccc34)O2)c(OC)c1
Agent: C#CCO
Agent: COc1cccc(OC)c1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccccc2)c(OC)c1

Procedure:
2,4-dimethoxybenzophenone was prepared by the Friedel-Crafts reaction of 1,3-dimethoxybenzene with benzoyl chloride in carbon disulfide using aluminum chloride as the catalyst 11.4 grams (0.05 mole) of the resulting benzophenone was converted to the propargyl alcohol using the conditions described in Example 1, Step 2. The crude propargyl alcohol was taken up in 150 milliliters of toluene. 3 grams (0.02 mole) of 2-naphthol and 30 grams of anhydrous acidic alumina were added to the toluene solution. The resulting slurry was refluxed for 3 hours, cooled and filtered. The alumina was separated from the reaction mixture and washed with toluene until no more photochromic was extracted therefrom. The solvent solutions were combined and the toluene solvent removed on a rotary evaporator. The residue was chromatographed on silica using a 4:1 mixture of hexane and ethyl acetate as elutant. The photochromic fractions were combined and re-chromatographed using a 3:7 mixture of hexane and chloroform as elutant. The photochromic product readily crystallized from hexane. 2.6 grams of crystallized product having a melting range of 132-134° C. were obtained. NMR analysis of the product confirmed it to be 3-phenyl-3-(2,4-dimethoxyphenyl)-3H-naphtho[2,1-b]pyran.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[C:23]([O:20][CH2:19][N:15]1[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]2[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4](=[O:22])[CH2:5]2)[CH2:17][C:16]1=[O:18])(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)C(C)(C)C)C(=O)C2)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.94 g, 3.0 m mol) and pyridine (25 ml), pivaloyl chloride (0.78 g, 6.5 m mol) dissolved in pyridine (5 ml) was added gradually at 0° C., and then the mixture was stirred for 18 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the residue was extracted with ethyl acetate (200 ml). The extract solution was washed with a saturated sodium bicarbonate aqueous solution and successively with water and was dried over magnesium sulfate. The residue obtained by removing the solvent from the extract under reduced pressure was purified by silica gel column chromatography (ethyl acetate, Rf value=0.8) to give the titled compound (0.75 g; yield 52%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:5][N:4]=1)[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31]Cl.[Na+].[I-].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31][N:11]1[CH2:10][CH2:9][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12]1
Reactant: ClCCc1cccs1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(CCc2cccs2)CC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (880 mg, 2.68 mmol), 2-(2-thienyl)ethyl chloride (385 mg, 2.63 mmol), NaI (470 mg, 3.1 mmol) and Na2CO3 (2.0 g) in acetonitrile (50 ml) was refluxed for 72 hours. It was cooled down to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was treated with CH2Cl2 (100 ml). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed to give the product (940 mg, 2.14 mmol) as an amber oil: IR (neat) 1660 cm-1 ; NMR (60 MHz, CDCl3) δ0.88 (t, 3H, CH3CH2CO), 1.39 (t, 3H, oxadiazolyl CH3), 1.60 to 3.20 (m, 16H), 6.70 to 7.40 (m, 3H, thienyl H's) 7.44 (s, 5 H, phenyl H's). ##STR33##
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].N1C=CC=CC=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].O>C(OCC)(=O)C>[C:12]([O:1][CH2:2][C:3](=[O:5])[CH3:4])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: CC(=O)CO
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of hydroxyacetone (190 g, 2.56 mol) and pyridine (210 ml, 2.6 mol) in ethyl acetate (1 L), propionyl chloride (197 g, 2.1 mol) was added dropwise at 5° C. The reaction liquid was stirred at room temperature for one hour, and then poured into water (700 ml). After phase separation, the organic layer was washed twice with a 1−N aqueous hydrochloric acid (700 ml), twice with water (700 ml), and once with saturated brine (500 ml), and dried over magnesium sulfate. After the magnesium sulfate was filtered out, the solvent was distilled off under reduced pressure, to obtain propionyloxyacetone (177 g, 1.36 mol). The thus-obtained propionyloxyacetone was used in the next process, without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29]C2CCCC2C=CC(C(O)=O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29][CH:16]2[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[CH3:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(CCCC=O)c(C)c1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c(C)c1

Procedure:
This compound is prepared by the method described in Example 2, Step B, except that an equivalent quantity of ethyl 3-methyl-4-(4-oxobutyl)benzoate is substituted for the ethyl 4-(4-oxobutyl)benzoate of Example 2, Step B. The title compound is obtained as a viscous, yellow oil.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1C(=O)C2=CC=CC=[C:14]2[C:13]1=[S:22])C.C1(=O)NC(=O)C2=CC=CC=C12>C1C=CC=CC=1>[C:3]1([CH2:2][CH2:1][S:9][S:22][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCCc1ccccc1
Reactant: CCN1C(=O)c2ccccc2C1=S
Agent: O=C1NC(=O)c2ccccc21
Solvent: c1ccccc1
Product: CCSSCCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 111.3 %

Procedure:
8 g (0.058 mol) of phenethylmercaptan are added with intensive stirring to a suspension of 12 g (0.058 mol) of N-ethylthiophthalimide in 70 ml of benzene. After a few minutes, a homogeneous solution forms and the phthalimide slowly begins to precipitate out therefrom. After stirring for 48 hours at room temperature, the mixture is filtered through a paper filter, the filtrate is concentrated in a vacuum and the crude 2-phenylethyl-ethyl-disulphide (12.8 g) obtained is distilled through a Vigreux column. There are thus obtained 10.5 g of pure product (91% of theory) which has a purity of 99% (gas-chromatographic estimation). Boiling point 87-88 mm Hg/0.04 mm Hg; nD20 =1.5742.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (59 mg, 0.24 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 60° C. for 5 hours. The reaction was concentrated and the residue was column chromatographed to give the title compound.
Reaction SMILES: [N:1]#[C:2]Br.Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:2]#[N:1])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Reactant: N#CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Cyanogen bromide (3.0M in CH2Cl2, 0.1 mL, 0.3 mmol) was added dropwise to a mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 100 mg, 0.3 mmol) and triethylamine (0.083 mL, 0.6 mmol) in CH2Cl2 (5 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 60 mg (54%) of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarbonitrile as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.4 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 3.87 (d, 2H, J=6.2 Hz), 3.58-3.47 (m, 2H), 3.08 (s, 3H), 1.96-1.86 (m, 2H), 1.53 (bs, 5H); LRMS (ESI), m/z 393 (M+Na).