Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][S:11](=[O:13])(=[O:12])[N:10]([CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Oc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)Oc1cccc(Cl)c1
Yield: 22.3 %

Procedure:
A solution of 25.7 g (0.2 mole) of 3-chlorophenol and 34.9 g (0.24 mole) of dimethylsulfamoyl chloride (Aldrich) in 150 ml of toluene was stirred and heated at reflux for 16 h, cooled and treated with 300 ml of 15% sodium hydroxide solution. The layers were separated and the organic layer was washed with two 200 ml portions of 15% sodium hydroxide solution, 300 ml of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the brown viscous oil was purified by chromatography (4.5×90 in glass column, 530 g of silica gel, ethyl acetate-hexanes, 1:6). Fractions containing the desired product were combined and the solvents were evaporated under reduced pressure to yield 10.5 g (47%) of the title compound as a light yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[C:11]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=2[C:4]#[N:5])=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Product: N#Cc1c(Cl)cncc1-c1ccc(C(=O)c2ccccc2)cc1
Yield: 80 %

Procedure:
Following conditions described in Step 1 of Example 50, 3,5-dichloroisonicotinonitrile was reacted with 4-benzoylphenylboronic acid to give 3-(4-benzoylphenyl)-5-chloroisonicotinonitrile (˜80% pure). MS (ES+) m/z: 351 (M+H); LC retention time: 3.980 min (analytical HPLC Method A). Step 2:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.ClC1C=C(C(OO)=[O:43])C=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18]([CH:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[O:43])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(S(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 9 %

Procedure:
To a stirred and cooled (0° C.) mixture of 7.2 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine and 95 parts of dichloromethane was added dropwise a solution of 2.6 parts of 3-chlorobenzenecarboperoxoic acid in dichloromethane. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was washed with a sodium carbonate solution and with water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.7 parts (9%) of 4-[[1-[(4-fluorophenyl)methyl]1H-benzimidazol-2-yl]sulfinyl]-1-[(4-methylphenyl)sulfonyl]piperidine; mp. 166.2° C. (30).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)CCCCCCCCCCCCCCC.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 6' (6 g., 11.0 mmol) was dissolved in dry pyridine (120 ml.), and the solution was cooled at -10°. Palmitoyl chloride (4.7 ml., 16.8 mmol) was added dropwise while the reaction mixture was stirred at -10°. After an additional 30 min. the mixture was allowed to warm up to room temperature and then stirred for 2 h. The product was isolated by conventional chloroform extraction. After purification on a column of silica gel, the yield of 7 was 7.6 g (88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)nc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (500 mg, 2.25 mmol) in ethanol (20 mL) was added 10% Pd/C (80 mg, 0.75 mmol) and the resulting mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through celite, washed with ethanol and concentrated to give 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
Reaction SMILES: CC1C=C(C)C=C(C)C=1C=[N:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[CH2:20]([Li])CCC.CI>O1CCCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([NH2:5])[CH3:20])=[CH:12][N:11]=1
Reactant: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
To a stirred solution of N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (10.9 g) in dried tetrahydrofuran (150 ml) cooled to -70° C. under N2 atmosphere was added butyl-lithium (10 w/v % in hexane, 26 ml), causing an immediate intense color to occur. After 30 minutes stirring at the temperature, methyl iodide (5.7 g) was added dropwise, and then the mixture was stirred for three hours without cooling. The solvent was removed under reduced pressure. To the residue, ethanol (50 ml) and 2N-hydrochloric acid (50 ml) were added and heated under reflux for one hour. The cooled solution was poured into water (100 ml) and extracted with methylene chloride (50 ml×2). The aqueous fraction was neutralized with 2N-sodium hydroxide and extracted with methylene chloride (50 ml×2). The extract was dried over sodium sulfate and evaporated to obtain 1-(2-chloro-5-pyridyl)ethylamine (4 g). nD20 1.5440
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].NC1C=CC=CC=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: COc1cccc(CNc2ccccc2N2CCCCC2)c1
Yield: 87 %

Procedure:
To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 795 μL of 3-methoxybenzyl bromide (1 equivalent) and 1.57 g of potassium carbonate (2 equivalents). The whole is heated to 100° C. for 2-3 hrs, until disappearance of the starting aniline. The medium is poured onto ice and then extracted with ethyl acetate. The organic phase washed with water is dried on magnesium sulfate, filtered and evaporated under reduced pressure. By silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) 1.46 g of the desired product may be isolated.
Reaction SMILES: B.[Na].[F:3][C:4]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:5]=1[C:6](O)=[O:7].B(F)(F)F.CCOCC>O1CCCC1>[F:14][C:9]1[C:10]([F:13])=[CH:11][CH:12]=[C:4]([F:3])[C:5]=1[CH2:6][OH:7]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: B
Agent: FB(F)F
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1c(F)ccc(F)c1F
Temperature: 0 °C
Yield: 102 %

Procedure:
To a solution of sodium boron hydride (51.6 g) in tetrahydrofuran (500 ml) is added dropwise a solution of 2,5,6-trifluorobenzoic acid (120 g) in tetrahydrofuran (200 ml) with stirring at below 10° C., and thereto is further added dropwise a solution of BF3.(C2H5)2O (232 ml) in tetrahydrofuran (500 ml) under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water (1.5 liter) and is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 g), as pale yellow oil, b.p. 112° C. (30 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][O:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:29][O:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (0.15 g, 0.38 mmol, prepared in Example 48) and (S)-(+)-2-(methoxymethyl)pyrrolidine (2 mL) was heated at 80° C. for 3 days. The mixture was cooled to rt and separated by preparative HPLC directly. The desired fractions were combined, neutralized by 10% sodium carbonate, and extracted with EtOAc (3×). The extracts were combined, dried over magnesium sulfate, and evaporated to furnish pure product, 0.04 g (22%). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 7.89 (m, 3H), 7.78 (m, 2H), 7.42 (m, 3H), 7.00 (m, 2H), 6.44 (s, 1H), 6.34 (s, 2H), 6.10 (m, 1H), 5.85 (d, 1H), 4.06 (m, 2H), 3.40 (m, 1H), 3.21 (s, 3H), 3.08 (m, 4H), 1.82 (m, 4H); MS ES 469 (M+H)+ calc 469.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl.C1COCC1>[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[C:14]([CH3:23])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[C:18]=1[Cl:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(C)c(OC)c1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(NC(=O)OC(C)(C)C)c1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
A solution of sulfurylchloride (6.7 ml, 79.8 mmol, 1.05 equiv) in DCM (140 mL) is added dropwise (75 min) to a cold (−15° C.) solution of (3,5-dimethoxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (20.4 g, 76.3 mmol) in THF (330 ml), under an argon atmosphere. The reaction mixture is allowed to stir for 3 h at −15° C. and then poured onto a mixture of ice/H2O (400 mL), a saturated aqueous solution of NaHCO3 (400 ml), and EtOAc (400 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×200 mL). The combined organic phase is washed with H2O (3×200 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in diethyl ether followed by silica gel column chromatography (Hex/acetone, 95:5) to afford the title compound. ESI-MS: 302.2 [MH]+, TLC: Rf=0.13 (Hex/acetone, 9:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2>[Pd].C1C2C(CCCC2)CCC1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2
Reactant: OCCn1c2c(c3c(N4CCCC4)nc(N4CCCC4)nc31)CCCC2
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCC2CCCCC2C1
Product: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of 9-(2-hydroxyethyl)-2,4-di-1-pyrrolidinyl-5,6,7,8-tetrahydro-9H-pyrimido[4,5-b]indole (VII, EXAMPLE2, 5.14 g) and palladium on carbon (10%, 1.4 g) in decalin (250 mL) is heated at reflux for 3 hr. The mixture is cooled to 20°-25°, diluted with methylene chloride (250 mL) and filtered through diatomaceous earth. Removal of the solvent from the filtrate, followed by chromatography (silica gel, 1% methanol/chloroform) of the resulting residue gives the title compound, mp=110°-111; MS (m/z) 351, 323, 307, 296 and 279; NMR (CDCl3) 7.89, 7.23, 7.13, 6.97, 4.38, 4.05, 3.92, 3.62 and 2.0-1.9 δ.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH:14]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.Cl.[NH2:25][C:26]1[CH:58]=[CH:57][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:38]=[C:37]([CH2:39][O:40][C:41]4[CH:54]=[CH:53][C:44]([CH2:45][CH:46]5[S:50][C:49](=[O:51])[NH:48][C:47]5=[O:52])=[CH:43][CH:42]=4)[N:36]([CH3:55])[C:35]=3[CH:56]=2)=[CH:28][CH:27]=1>CN(C)C=O>[O:51]=[C:49]1[NH:48][C:47](=[O:52])[CH:46]([CH2:45][C:44]2[CH:43]=[CH:42][C:41]([O:40][CH2:39][C:37]3[N:36]([CH3:55])[C:35]4[CH:56]=[C:31]([O:30][C:29]5[CH:57]=[CH:58][C:26]([NH:25][C:20]([CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]6)=[O:22])=[CH:27][CH:28]=5)[CH:32]=[CH:33][C:34]=4[N:38]=3)=[CH:54][CH:53]=2)[S:50]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(O)C1CCCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCCC4)cc3)cc21
Reaction time: 1.5 h

Procedure:
Triethylamine (0.32 ml) and ethyl chloroformate (0.08 ml) were added dropwise to a solution of cyclohexanecarboxylic acid (0.09 ml) in anhydrous N,N-dimethylformamide (8 ml). After stirring the mixture for 90 minutes, 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) was added and this mixture was stirred at room temperature for 2 hours and then for 90 minutes in an oil bath at 50° C. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound (262 mg, pale orange powder, mp 182-184° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:38]1[CH2:50][CH:39]1[CH2:40][O:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[C:44]#[N:45]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH2:50][CH:39]([OH:38])[CH2:40][O:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44]#[N:45])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCN)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCNCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3.5 g (6.8 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-aminoethoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 1.55 g (8.9 mmol) of 2-(2,3-epoxypropoxy)-benzonitrile in 20 ml of isopropanol is heated under reflux for 2 hours. The oil obtained after concentration by evaporation (approximately 6 g) is purified by "flash" chromatography analogously to Example 1 and yields 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-ethoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester in the form of an amorphous solid.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:4]=1)#[N:9]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: N#Cc1ccn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccn(CC(C#N)(C#N)CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
0.27 g of 1-chloromethyl-3-cyano-1H-pyrole and 0.34 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 3ml of N,N-dimethylformamide. 0.29 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.37 g of [(3-cyano-1H-pyrole-1-yl) methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (48), hereinafter) shown by below formula.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].C(O)(=O)C.C(C1C=CC=CC=1)(=O)C>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reaction time: 0.08 h

Procedure:
The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 5 minutes, allowed to settle and 28 L of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 10° C. and stirring continued for 16 hours. A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous sodium chloride . The organinc solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
N-tert-butoxycarbonyl L-valine (11.67 g, 53.71 mmol) was dissolved in DMF (50 mL) and the solution cooled to 0° C. (icebath). L-valine methyl ester hydrochloride (9.01 g, 53.7 mmol) was suspended in DMF (25 mL) and N,N-diisopropylethylamine (6.94 g, 53.7 mmol) added. The resulting solution was added to the solution of N-tert-butoxycarbonyl L-valine together with DMF (5 mL). HOBt hydrate (8.23 g, 53.7 mmol) and then EDC hydrochloride (11.33 g, 59.10 mmol) were added in portions together with an additional 30 mL DMF. The reaction mixture was stirred at 0° C. for 2 h 30 min after which the icebath was removed and stirring continued for 22 h 30 min at room temperature. The solvent was evaporated and the residue taken up in EtOAc (250 mL). The solution/suspension was washed with 1 M aqueous H2SO4 (3×100 mL), 7.5% (w/w) K2CO3 solution (3×100 mL) and saturated brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a white solid (16.92 g, 95%); δH (200 MHz; d6-DMSO) 7.97 (1H, dd, J 8, NH(Val2)), 6.68 (1H, dd, J 9, NH(Val1)), 4.18 (1H, dd, J 8 and 6, CαH(Val2)), 3.86 (1H, dd, J 9 and 8, CαH(Val1)), 3.61 (3H, s, OCH3), 2.15-1.79 (2H, m, CH(CH3)), 1.37 (9H, s, (CH3)3), 0.91-0.80 (12H, m, CH3); δC (50 MHz, d6-DMSO): 171.7, 171.7, 155.3, 77.9, 59.4, 57.2, 51.5, 30.2, 29.8, 28.0, 19.0, 18.8, 18.1, 18.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][CH3:9])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[C:6]([Cl:19])=[N:8][CH3:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CNC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CN=C(Cl)c1cc(OC)c(OC)c([N+](=O)[O-])c1

Procedure:
To a stirred suspension of 3,4-dimethoxy-N-methyl-5-nitro-benzamide (0.40 g, 1.66 mmol) in toluene (10 mL) was added phosphorous pentachloride (0.38 g, 1.83 mmol) portionwise. Upon completion of addition, the reaction mixture was warmed to reflux till complete disappearance of starting material. Evaporation to dryness resulted in a crude solid that was washed with diethyl ether, affording 3,4-dimethoxy-N-methyl-5-nitro-benzimidoyl chloride, 0.37 g (85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=NC=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=C[N:28]=[C:27]([Cl:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][N:28]=[C:27]([Cl:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Clc1cc(Br)ccn1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2ccnc(Cl)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 4-Bromo-2-chloropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=360.1, 362.1 (M+H+).