Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](Cl)[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]1=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([SH:58])([CH3:57])([CH3:56])[CH3:55].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([S:58][C:54]([CH3:57])([CH3:56])[CH3:55])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]1=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S
Reactant: O=c1cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Sc1cc(=O)n(Cc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 54 %

Procedure:
A mixture of 3-benzyl-6-chloro-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), tert-butylmercaptan (0.1 ml) and potassium carbonate (0.14 g) in acetonitrile (10 ml) was heated under reflux for 8 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.2 g, 54%).
Reaction SMILES: [C:1]([C:5](=[O:37])[CH:6](Cl)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:35][C:34]1[CH:33]=[CH:32][C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[CH:11][C:10]=1[NH:9][C:7]([CH:6]([O:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:5](=[O:37])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8]
Reactant: COC(=O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Oc2ccc(C(=O)OC)cc2NS(C)(=O)=O)C(=O)C(C)(C)C)c1
Yield: 61 %

Procedure:
A suspension of 8.35 g (15 mmol) of 2, 3.68 g (15 mmol) of methyl 4-hydroxy-3-(methanesulfonamido)-benzoate 3 and 6.22 g (45 mmol) of potassium carbonate in 180 mL of acetone was heated at reflux overnight. Thin layer chromatographic analysis indicated reaction was complete. The solvent was removed under vacuum to near dryness, and the residue was treated with a mixture of ethyl acetate and water. The organic liquid phase was washed with dilute hydrochloric acid and then with brine, and then concentrated under vacuum to an oil. The crude product was purified by column chromatography on silica gel using an elution solvent of 30 volume percent ethyl acetate in ligroin. There was thus obtained 7 g (61% yield ) of coupler Y-1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1)[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C(=O)c1ccccc1)C1CCNCC1
Solvent: CCO
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)c4ccccc4)CC3)c12
Temperature: 150 °C

Procedure:
To 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (0.154 g) and N-methyl-N-4-piperidinylbenzamide D15 (0.2 g) was added Ethanol (5 mL) and the reaction was heated at 150° C. for 30 minutes in the microwave. The reaction was heated again at 150° C. for 20 minutes. During the cooling, a white precipitate formed. This precipitate was filtered off and washed with Ethanol before being dried in vacuo at 40° C. to afford product in 49 mg. The filtrate was removed in vacuo and the crude residue purified by MDAP using the formic acid method. Fractions corresponding to the desired product were combined and solvent removed to give the product E32 in 22 mg. LCMS [M+H]+350.12@0.66 min (2 min run)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[OH:20])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(O)Cc1cccc(F)c1
Product: COc1ccc(C(=O)Cc2cccc(F)c2)c(O)c1
Temperature: 65 °C
Reaction time: 9 h

Procedure:
(3-Fluorophenyl)acetic acid (3.7 g) and 3-methoxyphenol (3.0 g) were dissolved into BF3Et2O (60 ml, 20 eq) under argon. The mixture was stirred at 60-70° C. until disappearance of the starting materials (9 h) and poured into large volume of ice water. After extraction with ethyl acetate the combined organic layers were washed with water, dried and evaporated. The crude product was purified by column chromatography using CH2Cl2 as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 12.41 (br s, 1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.38 (m, 1H), 7.09-7.13 (m, 3H), 6.56 (dd, 1H, J 9.0, 2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl>C(O)C.C(OCC)(=O)C>[C:3]([NH:6][CH:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(Cc1cccnc1)NC(C)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
44.45 cm3 of aqueous 6N sodium hydroxide are added dropwise to a solution of 51.4 g of diethyl 2-(acetylamino)-2-(3-pyridylmethyl)malonate in 857 cm3 of ethanol. The mixture is stirred for 1 hour 30 minutes at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. 22.2 cm3 of 12N hydrochloric acid are added dropwise; a precipitate forms. The reaction medium is warmed to room temperature and, after stirring for 2 hours, its pH is 5-6. It is concentrated under reduced pressure (4 kPa) at a temperature in the region of 50° C., to give a sticky dark-beige solid which is dried for 16 hours in an oven under vacuum (0.1 kPa) at a temperature in the region of 50° C. This residue is taken up in 1000 cm3 of dioxane and then heated to a temperature in the region of 100° C. for 1 hour. The dioxane is evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., and the residue is dissolved in 250 cm3 of water. This solution is neutralized by addition of 4 cm3 of aqueous 10N sodium hydroxide, followed by addition of 750 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is extracted and the aqueous phase is washed with twice 300 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid residue obtained is taken up in 70 cm3 of ethyl acetate and 20 cm3 of heptane and then filtered on a sinter funnel. 27.76 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form of a beige-colored solid melting at 118° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J=14 and 9 Hz: 1H); 3.04 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H); 8.38 (d, J=8 Hz: 1H); 8.45 (mt: 2H)]. By re-extracting the aqueous phase with twice 500 cm3 of ethyl acetate and after drying and concentration of the combined organic phases under reduced pressure, 4 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are recovered in the form of a beige-yellow solid melting at 121° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.57 (m, 2H), 7.76 (s, 1H), 7.90-8.06 (m, 2H), 9.32 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]([CH3:9])[CH2:6][CH2:7][CH3:8]>C(O)(=O)C.[Pt]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(C)=CCCBr
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCCC(C)CCCBr
Yield: 70 %

Procedure:
This was prepared from compound (1) in 70% yield by hydrogenation over platinum oxide in glacial acetic acid: b.p. 67°-70° C. at 8.5 mm; NMR (CDCl3) 0.86 (t, CH3CH2), 0.87 (d, CH3CH), 3.40 (m, 2H, CH2CH2Br)). The IR and NMR spectra of the compound were in complete agreement with the assigned structure and reported values.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CN(C=O)C.Cl[C:27]1[N:31]([CH3:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=1>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)=[CH:14][CH:13]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nn(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a mixture of 4-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (120 mg), sodium hydride (60% in oil, 21.0 mg) and DMF (5.0 ml) was added 2-chloro-1-methyl-1H-benzimidazole (84 mg), and the mixture was stirred under microwave irradiation at 180° C. for 1 hr. The reaction mixture was diluted with methanol, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.Cl>O.[Zn]>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:3]=1[CH2:4][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)CCC(=O)O)c(Cl)c1Cl
Agent: Cl
Agent: [Zn]
Solvent: O
Product: COc1ccc(CCCC(=O)O)c(Cl)c1Cl
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 3-(2,3-dichloro-4-methoxybenzoyl)-propionic acid (125 g.), 0.45 mole), amalgamated zinc (500 g.) and 12 N HCl (600 ml.) is stirred at 20°-25° C. for two hours and then refluxed for 16 hours. An additional 100 ml. of 12 N HCl is added and refluxing is continued for five hours. The mixture then is cooled and diluted with water (2 l.). The product is extracted with chloroform. The extract is washed with water and dried over sodium sulfate and evaporated. The residue is crystallized from ethanol-water (1:1) to obtain 4-(2,3-dichloro-4-methoxyphenyl)butyric acid (103.7 g.), melting point 120°-123° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:19])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:20]([C:23]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:21]=[CH2:22]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:19])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:32]=[CH:33][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:35][C:23]=1[CH2:20][CH:21]=[CH2:22])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH3:18])=[O:16]
Reactant: C=CCc1cc(C(=O)OC)ccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Product: C=CCc1cc(C(=O)OC)ccc1OCCCCCOc1ccc2c(=O)cc(C(=O)OC)oc2c1CCC
Yield: 95.7 %

Procedure:
Using the procedure of Example 2, 4.14 g (15.8 mmole) of methyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 5.63 g (16.5 mmole) of the compound from Example 10 gave 7.9 g (96%) of the title compound, mp 87°-88°. Calc: C, 68.95; H, 6.61; Found; C, 68.49; H, 6.54.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=O)C(O)CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 13.5 parts of dl-methyl 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoate, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts by volume of a 2% osmium tetroxide in dioxane solution is stirred at room temperature under nitrogen for about 4 hours. The reaction mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, then concentrated to dryness under reduced pressure. The resulting residue is purified by dry column chromatography on silica gel containing 8% of water, using 50% ethyl acetate in benzene, thus affording dl-methyl 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoate, characterized by an ultraviolet absorption maximum at about 228 millimicrons with a molecular extinction coefficient of about 10,200.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:28]
Reactant: CCOC(=O)c1c(C(=O)c2ccccc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)c2ccccc2N)nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate (629 mg, 1.53 mmole) was dissolved in ethanol (6.0 ml), and 10% palladium on carbon (58 mg) was added. After the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours, 10% palladium on carbon (60 mg) was added, and the mixture was further stirred for 2 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Precipitate was collected by filtration to give ethyl 4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (548 mg, 94.2%) as a yellow crystalline powder.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:17]=[C:16]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:25][C:19]1[C:18]2[N:17]=[C:16]([CH2:26][O:27][CH2:28][CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[CH:22]=[C:21]([CH3:24])[N:20]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
4-Morpholinecarbonyl chloride (202 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435, 1.57 mmol) in a mixture of triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was stirred at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine. The resulting glassy solid was triturated with acetonitrile to provide 0.417 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}morpholine-4-carboxamide as an off white powder, m.p. 156.5-159.5° C. Analysis: C19H30N6O3.0.20 HCl: %C, 57.37; %H, 7.65; %Cl, 1.78; %N, 21.13; Found: %C, 57.19; %H, 7.56; %Cl, 1.84; %N, 21.14. 1H NMR (300 MHz, CDCl3) δ6.51 (s, 1 H), 5.46 (bs, 2 H), 4.71 (s, 2 H), 4.45 (bs, 1 H), 4.17 (t, J=7.5 Hz, 2 H), 3.68 (t, J=4.9 Hz, 4 H), 3.57 (quartet, J=7.1 Hz, 2 H), 3.32 (m, 6 H), ), 2.49 (s, 3 H), 1.86 (quintet, J=7.5 Hz, 2 H), 1.58 (quintet, J=7.3 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H); MS(CI) m/e 391 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][C:15]=1[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[Cl:13])[CH2:20][NH:21][C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:23]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 194A (0.36 mL, 2.45 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1HNMR (300 MHz, DMSO-d6) 69.17 (s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.61 (m, 2H), 7.50 (t, 1H, J=8.0 Hz), 7.35 (dd, 1H, J=8.3 Hz, 2.2 Hz), 7.12 (t, 1H, 5.9 Hz), 4.37 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl).
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18]C2C=CC(CBr)=CC=2)=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18][C:9]2[CH:10]=[CH:2][C:3]([CH2:4][NH2:5])=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
To a stirred mixture of potassium phthalimide (3.60 g, 19.4 mM) and dry N,N-dimethylformamide (200 ml) was added dropwise a solution of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in dry N,N-dimethylformamide at room temperature, the mixture was stirred for 5 h at the same temperature. The mixture was poured into water, and the mixture was extracted with toluene. The extract was washed with 5N NaOH, water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was diluted with methanol (200 ml), and to the mixture was added dropwise hydrazine monohydrate (1.10 g, 21.1 mM). The mixture was stirred for 6 h under reflux, and this was cooled to the room temperature and concentrated in vacuo. The residue was diluted with chloroform and the mixture was filtered through celite. The filtrate was washed with 5N NaOH(x3) and brine(x2), dried with potassium carbonate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzylamine (3.02 g, 76%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(CC(=O)c2ccccc2)c1=O
Yield: 66 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and 2-bromoacetophenone by applying general procedure A. Yield 66%; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.34 (m, 4H), 3.86 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 5.58 (s, 2H), 7.15 (dd, J=3.6, 4.6 Hz, 1H), 7.24 (d, J=3.2 Hz, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.60 (m, 2H), 7.71 (m, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.09 (m, 2H), 8.16 (d, J=3.2 Hz, 1H) ppm; MS m/z=535 amu (M++1). Anal. (C27H25N3O5S2) C, H, N.