Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(=O)C>O>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[NH:23][C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2n1
Yield: 80.4 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.78 g of 5-{4-(5-isopropoxy-3-methylimidazo [5,4-b]pyridin-2-ylmethoxy) benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 103) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.40 g of the title compound, melting at 210-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])([O-])=O.[H][H]>NC1C(C)=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: Cc1ccccc1N
Solvent: O
Product: CCOc1ccc(N)cc1N
Yield: 89.1 %

Procedure:
112 g (0.529 mol) of 2,4-dinitrophenetole were hydrogenated, in a 700 ml stirred autoclave, in 300 ml of o-toluidine with 15 g of water-moist palladium catalyst (0.5% by weight of palladium on charcoal), corresponding to 6 g of dry catalyst, at a temperature of about 80° C and a hydrogen pressure of between 5 and 10 bars. After 31/2 hours, the hydrogen absorption and the reaction had ended. After filtering off the catalyst, the solvent and the water of reaction formed were distilled off under normal pressure and the residue which remained was then fractionally distilled in vacuo. 71.7 g (89.3% of theory) of 2,4-diaminophenetole of solidification point 64.2° C were obtained in the boiling range of 150° - 180° C/5 mm Hg. 4.5 g of a higher-boiling residue remained.
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9])([O:3]CC)=O.[OH-].[K+].Cl>O>[O:13]([CH2:12][CH2:11][N:10]1[C:1](=[O:3])[NH:6][NH:7][C:8]1=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NNC(=O)NCCOc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH][nH]c(=O)n1CCOc1ccccc1
Temperature: 95 °C

Procedure:
The 1-(ethoxycarbonyl)semicarbazide VII (10.28 g, 0.0385 mol) was added to a solution of potassium hydroxide (4.96 g, 0.0769 mol) in water (105 mL) and the suspension was stirred and heated in an oil bath at 95° C. (oil bath temp.) for one hour. The yellow mixture was cooled to 25° C. and filtered. The filtrate was further cooled in an ice bath and neutralized by the slow addition of 6.72 ml (0.0807 mol) of conc. HCl. After 15 min. a white precipitate of VI was collected by filtration, washed with water and dried to constant weight. Yield: 6.56 g (77%); mp 187°-189° C. 1H NMR (DMSO-d6,): δ=10.15 (s, 2H, equivalent NH's).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:22][C:17]=3[S:16][C:15]2=[N:28]C(=O)C(F)(F)F)(=O)=O)=CC=1.[CH3:36][S-:37].[Na+]>C(O)C>[NH:28]=[C:15]1[N:14]([CH2:13][CH2:12][CH2:11][S:37][CH3:36])[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:22][C:17]=2[S:16]1
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)OCCCn2c(=NC(=O)C(F)(F)F)sc3cc(OC(F)(F)F)ccc32)cc1
Agent: [Na+]
Solvent: CCO
Product: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Yield: 81.5 %

Procedure:
3-(2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)propyl p-toluenesulphonate (3.88 g) and sodium methanethiolate (1.03 g) in absolute ethanol (20 cc) are heated at 60° C. for 6 hours. After cooling to a temperature close to 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The oily residue is taken up in distilled water (50 cc) and the organic phase is extracted with ethyl ether (50 cc). After drying over magnesium sulphate and concentrating to dryness under reduced pressure, 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (1.88 g) is obtained, which is converted to the hydrochloride melting at 181° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[N:9]=2)[CH2:3][CH2:2]1.Cl[CH2:29][C:30]#[N:31].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C.O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH2:13][N:12]2[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[N:9]=[C:8]2[NH:7][CH:4]2[CH2:3][CH2:2][N:1]([CH2:29][C:30]#[N:31])[CH2:6][CH2:5]2)=[CH:15][CH:16]=1
Reactant: c1ccc2c(Cn3c(NC4CCNCC4)nc4ccccc43)ccnc2c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccnc3ccccc23)CC1
Yield: 18.4 %

Procedure:
A mixture of N-(4-piperidinyl)-1-(4-quinolinylmethyl)-1H-benzimidazol-2-amine (comp. 23) (0.0129 mol), chloroacetonitrile (0.0155 mol), potassium iodide (0.00129 mol) and potassium carbonate (0.0258 mol) in 4-methyl-2-pentanone (80 ml) was stirred and refluxed for 5 hours. H2O was added. The solvent was evaporated. H2O and CH2Cl2 were added. The precipitate was filtered off. The filtrate was separated into its layers. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue (3.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.3; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.94 g 4-[[1-(4-quinolinylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile; mp. 190° C. (interm. 41).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[CH:18]=3)(O)[CH2:12][S:11]2)=[CH:5][C:4]=1C.[C:31](O)(=O)C>>[BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:28])(=[O:29])[N:25]([CH3:26])[CH3:27])[CH:18]=3)=[CH:12][S:11]2)=[C:7]([CH3:31])[CH:8]=1
Reactant: CC(=O)O
Reactant: Cc1cc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)ccc1Cl
Agent: Br
Product: Cc1cc(Cl)ccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(4-chloro-3-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide in boiling glacial acetic acid, with subsequent precipitation with diethyl ether. Colorless crystals from glacial acetic acid; melting point 231° C. (with decomposition).
Reaction SMILES: [I-].C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]([CH2:23][O:24][CH3:25])[C:21]([CH3:22])=[N+:16]3[CH:15]=2)[CH2:11][C@H:10]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34]CC=C)=[O:33])[CH2:9]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C(O)C>[OH:42][C@@H:40]([C@H:39]1[C:38](=[O:43])[N:30]2[C:31]([C:32]([O-:34])=[O:33])=[C:27]([S:26][C@H:10]3[CH2:11][C@@H:12]([CH2:13][C:14]4[S:18][C:17]5=[CH:19][N:20]([CH2:23][O:24][CH3:25])[C:21]([CH3:22])=[N+:16]5[CH:15]=4)[NH:8][CH2:9]3)[C@H:28]([CH3:44])[C@H:29]12)[CH3:41]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(COC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCO
Solvent: C1CCOC1
Product: COCn1cc2sc(C[C@@H]3C[C@H](SC4=C(C(=O)[O-])N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3)c[n+]2c1C
Yield: 6.9 %

Procedure:
Anhydrous THF (0.5 ml) and 0.5 ml of dry ethanol are added to 47.9 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide. Triphenylphosphine (5.8 mg), 0.012 ml of morpholine, and 3.2 mg of tetrakis(triphenylphosphine)palladium(0) are successively added in an argon atmosphere at room temperature for 75 min. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 2.2 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([OH:23])[C:11]=2[CH:24]=1.O>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([O:23][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=2[CH:24]=1
Reactant: CCCCBr
Reactant: O=c1oc2ccc(Br)cc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(-c2ccccc2)c(=O)oc2ccc(Br)cc12
Reaction time: 48 h

Procedure:
Butyl bromide (0.05 ml) was added with stirring to a mixture of a solution of 6-bromo-4-hydroxy-3-phenyl-2H-1-benzopyran-2-one (80 mg) (Synthesis 1993, 99), in dry dimethylformamide (0.5 ml) and potassium carbonate (70 mg). The mixture was stirred for 48 hours and water (5 ml) was added. The mixture was extracted with diethyl ether and the extract washed with water, dried and evaporated under reduced pressure. The residue was washed with water and dried to give 6-bromo-4-butoxy-3-phenyl-2H-1-benzopyran-2-one, m.p. 87-9° C. (compound 29)
Reaction SMILES: [CH2:1]([C@@H:8]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:19])[C@@H:12]([NH:20][C@H:21]([C:30]([O:32]CC)=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([C@@H:8]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:19])[C@@H:12]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:11][S:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSC[C@@H]1Cc1ccccc1
Yield: 73.3 %

Procedure:
326 mg of α-{3(S)-benzyl-6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxoperhydro-1,4-thiazepin-4-yl}acetic acid were hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 5, to give 225 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#N)[C:5](OCC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.CC(C)=[O:27].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:10]=[CH:11][C:12]=1[CH:13]=[O:27]
Reactant: CCOC(=O)c1ccc(C#N)c(Br)c1
Reactant: CC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a stirring cold (−78° C.) solution of ethyl 3-bromo-4-cyanobenzoate (0.41 mol, 104 g) in THF (2.3 L was added dropwise a solution of diisobutylaluminum hydride (2.0 mol, 1.36 L; 1.5 M in toluene) over a period of 1.5 h. After addition was completed, the mixture was warmed to rt over a period of 3 h. The mixture was then cooled to 0–5° C. and 40 ml of acetone was added slowly. The mixture was then transferred via a cannula to a cold (0° C.) stirring aqueous solution of HCl (2.2 L 3 N) over a period of 1.5 h, maintaining the temperature of the aqueous solution below 30° C. After the transfer was completed, the mixture was stirred for another 0.25 h. The organic solution was separated and the aqueous was extracted twice with EtOAc (3 L). The combined organic extracts were washed with brine, dried with MgSO4 (anhyd.) and concentrated to give 74 g (83%) of the title compound as a light yellow solid.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>CO>[F:18][C:17]([F:19])([F:20])[CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:11]=1)[OH:21]
Reactant: O=C(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reaction time: 0.42 h

Procedure:
2.71 g of sodium borohydride were added in small fractions over 35 minutes at 0° C. to a solution of 56.1 g of the raw product of Step A in 235 ml of methanol and the mixture was stirred for 25 minutes while allowing the temperature to rise to room temperature. The mixture was added to aqueous 1N hydrochloric acid solution and water was added with stirring. The decanted aqueous phase was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 13.3 g of (R, S) 2,2,2-trifluoro-1-(m-phenoxy-phenyl)-ethanol.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][C:9]=2[CH2:11][CH3:12])[C:4]([CH3:16])=[N:3]1.[Li+].[OH-]>CCO>[CH2:11]([C:9]1[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[C:10]=1[NH:2][N:3]=[C:4]2[CH3:16])[CH3:12]
Reactant: CCc1cc(C(=O)O)cc2c(C)nn(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)O)cc2c(C)n[nH]c12
Temperature: 25 °C
Yield: 68.6 %

Procedure:
To a solution of methyl 7-ethyl-3-methyl-1H-indazole-5-carboxylic acid (240 mg, 1.10 mmol) in EtOH (13 mL) was added 1 M LiOH (2.2 mL). The mixture was heated overnight at reflux and cooled to room temperature. The solvents were removed under reduced pressure and the resultant material was suspended in 1 N HCl. The solids were isolated by vacuum filtration, washed with water, dried at 45° C. under vacuum to afford the title compound (154 mg, 69%) containing ˜10% of des-methyl material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[O:6]([CH2:5][CH2:4][CH2:3][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCCCOc1ccccc1
Temperature: 100 °C
Yield: 183.3 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The solution was heated at 100° C. for 1.5 hours. The reaction solution was carefully poured onto 500 ml of ice water. The precipitated oily substance was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted by chloroform:methanol (96:4 v/v). The obtained crude crystals were recrystallized from ethanol to give 1.2 g of dimethyl 4-[2-[4-(3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cc(-c2cnccn2)cs1
Product: O=C/C=C/c1cc(-c2cnccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinyl-2-thiophenecarboxaldehyde (prepared as described in Reference Example 92) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[NH3:31]>>[NH2:31][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: N
Product: CCCn1c(N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 41 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.2 g, 0.45 mmol) (prepared as given in Example 1), ammonia solution (20 ml) was heated at 125-130° C. in a sealed tube for 5 days. Reaction mixture was cooled to 0° C. and solid was filtered, washed with methanol, dried and purified by column chromatography using silica gel (100-200 mesh) and 6 to 8% methanol in DCM as an eluent to obtain 2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.079 g, 41%) as a white solid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][S:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:12]2[CH:27]=[CH:28][C:29]([C:31]([O:33]C)=[O:32])=[CH:30][C:11]=2[N:10]=1>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][S:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:12]2[CH:27]=[CH:28][C:29]([C:31]([OH:33])=[O:32])=[CH:30][C:11]=2[N:10]=1
Reactant: COC(=O)c1ccc2c(c1)nc(SCc1cccc(Br)c1)n2CCCN(C)CCc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCn1c(SCc2cccc(Br)c2)nc2cc(C(=O)O)ccc21)CCc1ccccn1
Temperature: 25 °C

Procedure:
Lithium hydroxide (0.315 g, 3 eq) is added to a solution of methyl 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate (1.03 g, 1 eq) in a mixture of tetrahydrofuran (10 ml) and water (5 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Ethyl acetate and water are added to the residue. The mixture is acidified by adding acetic acid to pH 5. After decanting and extracting, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: dichloromethane/methanol 95/5 to 80/20) produces the expected compound in the form of a foam (0.85 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.C[C:50]1[S:54][C:53]([C:55]2C=CC=CC=2)=N[C:51]=1[CH2:61][C:62]([OH:64])=O>CC(N(C)C)=O>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:62](=[O:64])[CH2:61][C:51]5[CH:55]=[CH:53][S:54][CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: Cc1sc(-c2ccccc2)nc1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) (see Example 24, Step A) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and (5-methyl-2-phenyl-1,3-thiazol-4-yl)acetic acid (80 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: 0-100% 90:9:1 DCM:MeOH:NH4OH(aq)) to afford the title compound (50.1 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 6H), 2.43 (s, 3H), 3.31 (s, 2H), 3.81 (s, 2H), 6.45 (d, 1H, J=5.31 Hz), 6.84 (d, 1H, J=6.96 Hz), 7.08-7.11 (m, 1H), 7.14-7.18 (m, 1H), 7.23-7.25 (m, 1H), 7.38-7.46 (m, 5H), 7.59-7.62 (m, 1H), 7.68 (s, 1H), 7.75-7.81 (m, 3H), 7.89 (s, 1H), 8.21 (d, 1H, J=5.49 Hz), 8.48-8.51 (m, 1H), 8.79 (d, 1H, J=6.96 Hz) 9.50 (s, 1H), 10.35 (s, 1H). ES-LC/MS m/z=651 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:23])=[N:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2C=N[CH:15]=[CH:14][N:13]=2)=[C:7]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:6]=1.CS(C1C=C(C=CC=1O[C:38]1C=CN=C[N:39]=1)C(O)=O)(=O)=O>>[NH2:23][C:2]([NH2:1])=[N:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[N:13]=[CH:14][CH:15]=[CH:38][N:39]=2)=[C:7]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccncn1
Reactant: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1cnccn1
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1ncccn1

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(2-pyrazinyloxy)benzamide, m.p. 253-254°; with 3-methylsulfonyl-4-(4-pyrimidinyloxy)benzoic acid,