Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:14](O)[CH2:15][OH:16].ClCCl>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:8]2[O:16][CH2:15][CH2:14][O:9]2)[CH:10]=1
Reactant: OCCO
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Yield: 90.2 %

Procedure:
In a flask equipped with a Dean-Stark water separator, 5-chloro-2-nitrobenzaldehyde (12.0 g, 64.7 mmol), ethylene glycol (8.0 g, 129.3 mmol) and p-toluenesulfonic acid (0.2 g) were dissolved in toluene (150 mL). The mixture was stirred at reflux for 8 hours. Dichloromethane was added and the organic phase was washed with saturated sodium bicarbonate and brine, then dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (13.4 g, yield 90.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.CS(O)(=O)=O.[CH2:14](O)[CH2:15]C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH2:14][CH3:15]
Reactant: COC1=CC(=O)NC1
Reactant: CCCO
Agent: CS(=O)(=O)O
Product: CCCOC1=CC(=O)NC1

Procedure:
A mixture of 4-methoxy-3-pyrrolin-2-one (3 g), 1-propanol (3.5 ml) and methanesulfonic acid (0.2 g) was refluxed for 2 hours in the presence of 3A molecular sieves. Solvent was removed from the mixture, and the residue chromatographed on silica gel, eluting with 2% methanol in methylene chloride, to give 4-n-propoxy-3-pyrrolin-2-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](O)(CNCCO)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]21[O:19][CH2:2][CH2:1][NH:8][CH2:9]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: OCCNCC1(O)CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: c1ccc(CN2CCCC23CNCCO3)cc1
Temperature: 180 °C

Procedure:
85.0 g (340 mmol) of 1-benzyl-3-hydroxy-3-(2-hydroxyethylaminomethyl)-pyrrolidine are dissolved in a mixture of 280 ml of concentrated sulfuric acid and 140 ml of water and heated at 180° C. overnight. The mixture is made alkaline with 45% strength sodium hydroxide solution, precipitated salts are dissolved in water, and the solution is extracted five times with 200 ml of chloroform each time. The organic phases are dried over potassium carbonate, the desiccant is removed, and the solution is concentrated. The residue is distilled under high vacuum. 60.0 g (76% of theory) of the product are obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH:7]([S:13](Cl)(=[O:15])=[O:14])([S:9](Cl)(=[O:11])=[O:10])[CH3:8].C(N(CC)CC)C.[Cl-].[Cl-].[Ca+2]>C(COC)OC>[CH:7]1([S:13](=[O:15])(=[O:14])[O:6][CH2:1][CH2:2][CH2:3][CH2:4][O:5][S:9]1(=[O:11])=[O:10])[CH3:8]
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Reactant: OCCCCO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1S(=O)(=O)OCCCCOS1(=O)=O
Yield: 9.2 %

Procedure:
1,4-Butanediol, obtained from Aldrich Chemical Co. (3.6 g, 0.04 mole) was dissolved in 75 ml of glyme in a 1 liter round bottom flask. A solution of 1,1-ethanedisulfonyl chloride (9.1 g, 0.04 mole) dissolved in 25 ml of glyme wa added to the flask through a dropping funnel. The reaction mixture was kept below -20° C. with a dowanol-dry ice bath. Triethylamine (8.08 g, 0.08 mole) dissolved in 100 ml of glyme was added to the mixture through a 125 ml dropping funnel over a period of 1 hour. Care was taken to maintain anhydrous conditions by covering the dropping funnels with drying tubes containing CaCl2. The reaction mixture was brought to 25° C. in a cold water bath. The glyme was removed by roto-evaporation, at a temperature below 37° C. The oily yellow residue that remained after removal of the glyme was washed once with 100 ml of 5% sodium bicarbonate and once with 50 ml of cold distilled water, the resulting emulsion being centrifuged immediately to separate the product, and aqueous material decanted. The remaining precipitate was dried under vacuum. The white, powdery solid which remained weighed 0.90 g, representing a 9.2% yield. Product identification was confirmed by characteristic IR and proton NMR spectral features. The product decomposed between 115 and 138° C. The product was soluble to less than about 0.01 gram in 1 ml of either methylene chloride or acetonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 46.1 %

Procedure:
Following general procedure II, (R)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (175 mg, 0.34 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (149 mg, 0.51 mmol) to afford the desired product (100 mg, 46%) as a solid: ESI MS m/z 637 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH2:2][O:1][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])[CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1cnc2ccccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 90 %

Procedure:
3-(hydroxymethyl)quinoline (400 mg, 2.52 mmol), triphenyl phosphine (692 mg, 2.64 mmol, 1.05 equiv) and N-hydroxyphthalimide (430 mg, 2.64 mmol, 1.05 equiv) were dissolved in 10 mL of dry THF. Diethylazodicarboxylate (0.44 mL, 2.80 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture placed in a freezer for 2 hours, and then filtered to give the desired product (0.69 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([N:21]2[CH2:20][C:19]3[C:23](=[CH:24][C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][CH2:14]4)=[CH:17][CH:18]=3)[C:22]2=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: BrC1CCCC1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1C1CCCC1
Yield: 75.5 %

Procedure:
In the same manner as in Example 51, the title compound (44 mg) was prepared from the compound (50 mg) obtained in Example 50 and cyclopentyl bromide (27 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:26]=[CH:25][C:7]2[N:8]([CH3:24])[C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[CH2:11][C:12](O)([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=2[CH:5]=1)[CH3:2].Cl>C(O)C>[CH2:1]([S:3][C:4]1[CH:26]=[CH:25][C:7]2[N:8]([CH3:24])[C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[CH2:11][C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CC1(O)Cc2ccccc2N(C)c2ccc(SCC)cc21
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=C1Cc2ccccc2N(C)c2ccc(SCC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 35 g of 2-ethylthio-5-methyl-11-hydroxy-11-ethoxycarbonylmethyl-10,11-dihydro [5H] dibenzo (b,f) azepine, 500 ml of ethanol and 50 ml of 2N hydrochloric acid was stirred for 3 hours at room temperature. The mixture was poured into 2 kg of ice and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel with a 98-2 mixture of benzene-ethyl acetate as eluant which was evaporated to obtain 27.3 g of 2-ethylthio-5-methyl-11-ethoxycarbonylmethylene-10,11-dihydro [5H] dibenzo (b,f) azepine in the form of a yellow oil soluble in alcohol, chlorinated solvents and ethyl acetate and insoluble in water.
Reaction SMILES: [Na].O=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:5]=O.Cl.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25]([NH2:27])=[NH:26]>C(O)(C)C.C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25]1[N:27]=[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:26]=1
Reactant: O=CCC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
Under inert atmosphere, 5 g of sodium salt of the β-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and salt content of 25% (residue by calcination), and 8 mL hydrochloric acid in isopropanol in 50 mL toluene is suspended. 3.7 g (2-methyl-5-nitrophenyl)guanidine is added, and the mixture is stirred at room temperature for an hour. The mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled to 10° C., and the precipitate is filtrated; this is crushed in warm water, yielding, upon filtration and drying, 2.5 g of product with HPLC purity of 96% (A %), identified through GC-MS.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[CH:34]=[CH:33][S:32][C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]3)=[C:28]3[CH:34]=[CH:33][S:32][C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (88.5 mg, 0.662 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (from step 2 in Example 2, 56.9 mg, 0.236 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (73.3 mg, 0.210 mmol) in DCM (2.0 mL), followed by pyridine (162.6 mg, 2.056 mmol) was then added and the mixture was stirred at room temperature for a further 2 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark oil (118.2 mg, 98%). LCMS calc. for C27H28F2N5O3S2 (M+H)+: m/z=572.2. found 572.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CCCC2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of 3-chloro-4-methylphenol (1.00 g) in N,N-dimethylformamide (8 ml) was added potassium carbonate powder (1.44 g) and the mixture was heated to 80° C. Thereto was added cyclopentylmethyl methanesulfonate (1.57 g) and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature. Water was added and the mixture was extracted 3 times with hexane. The organic layers were combined and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane) to give 2-chloro-4-((cyclopentyl)methyloxy)toluene (1.46 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][N:8]=[C:9]([C:11](OC)=[O:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-].Cl.[OH-].[Na+]>O1CCCC1>[O:1]1[C:6]2=[CH:7][N:8]=[C:9]([CH2:11][OH:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(cn1)OCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)OCCC2
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a vessel was added with stirring methyl 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate (7.4 g, 1 eq) and tetrahydrofuran (THF) (32 mL). The mixture was heated to 55° C. whereupon 2M LiBH4 in THF solution (20 mL, 1.05 eq.) was added over 1 h. The stirring continued at 55° C. until reduction was complete at which point the mixture was cooled to 45° C. and 6N HCl (37 mL) was carefully added to the mixture. The stirring was continued for 1 h then the mixture was cooled to 25° C. The pH was adjusted to ˜9.5 to 10 with 50 wt % aqueous NaOH solution. The organics were extracted with 2-methyltetrahydrofuran (2×37 mL). The combined organic layers were concentrated under reduced pressure and crystallized to provide (3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methanol as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (s, 1H), 6.91-6.99 (m, 1H), 4.65 (s, 2H), 4.18-4.29 (m, 2H), 3.42 (s, 1H), 2.79 (t, J=6.50 Hz, 2H), 1.96-2.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm 151.09, 150.39, 137.87, 131.40, 121.14, 66.51, 64.10, 24.22, 21.55; HRMS (M+H) m/z, calcd for C9H12NO2, 166.0868; found, 166.0861.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 86.5 %

Procedure:
Example 56 was prepared in an analogous manner to Example 43 from Intermediate 10 (0.040 g) and propargylamine (0.006 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.028 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:41][CH:40]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, light yellow solid (103 mg, 80%), MS (ISP) m/z=516.3 [(M+H)+], mp 249° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-morpholin-4-yl-benzoic acid.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:11](=[O:14])[NH:12][N:13]=[C:6]2[CH:5]=1)[CH2:2][CH3:3]>C(O)(=O)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:13]2[NH:12][C:11](=[O:14])[N:7]=[C:6]2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2n[nH]c(=O)n2c(C)n1
Solvent: CC(=O)O
Product: CCCc1cc2nc(=O)[nH]n2c(C)n1
Yield: 77.4 %

Procedure:
A solution of 15.5 g of 7-n-propyl-5-methyl-1,2,4-triazolo[4,3-c]pyrimidin-3(2H)-one, prepared in Example 192, in 100 ml of acetic acid is heated to reflux for 20 h. The reaction mixture is then evaporated under vacuum, and the residue obtained crystallises in ethyl ether. The drained crystals are washed with ethyl ether and dried. 12 g of 7-n-propyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one are obtained in the form of crystals of melting point 173° C.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH3:10][N:8]([CH3:9])[C:6]([C:5]1[CH:11]=[C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:13]=[CH:14][C:4]=1[NH:1][C:2]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:3])=[O:7]
Reactant: C1COCCN1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
Into a 3 mL reaction vial were added 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (48 mg, 0.085 mmol), methylene chloride (1 mL) and morpholine (40 μL, 0.455 mmol, pre-treated with molecular sieves). The solution was stirred at room temperature for at least 12 h and monitored by HPLC. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 100 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuum. Purification by Mass-triggered HPLC (formic acid ACN/H2O gradient) followed by lyophilization provided 10.4 mg of the title compound as a white powder. 1H-NMR (500 MHz, d6-DMSO) δ 11.91 (br.s, 1H), 8.73 (br.s., 1H), 8.52 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.71 (m, 3H), 7.80 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.28 (app t, J=7.5 Hz, 1H), 7.11 (d, J=7 Hz, 1H), 7.03 (t, J=7 Hz, 1H), 3.80 (s, 3H), 3.60 (m, 4H), 3.51 (m, 4H), 2.96 (br s, 6H); MS: m/z 500.1 [M+H+].
Reaction SMILES: C([O:8][C:9]1[CH2:13][N:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:11](=[O:35])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH2:13][N:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:11](=[O:35])[CH:10]=1
Reactant: [H][H]
Reactant: O=C1C=C(OCc2ccccc2)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1C=C(O)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 15.2 %

Procedure:
A mixture of the 7-(4-benzyloxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (8 mg, 0.017 mmol) prepared in Example 1-8 and palladium hydroxide (2 mg) was dissolved in methanol. The obtained mixture was stirred in a hydrogen atmosphere for 1 hour. Thereafter, the reaction solution was filtered through celite, and the concentrated residue was then preparatively separated by preparative HPLC (column: Combi ODS (φ: 28.0 mm×50 mm), manufactured by Wako; developing solvent: 0.05% trifluoroacetic acid-containing water: 0.05% trifluoroacetic acid-containing acetonitrile=90:10 to 5:95), so as to obtain 7-(4-hydroxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (1 mg, 15%) in the form of a colorless oil substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH2:24].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:15])[NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[NH2:24])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COC(=O)C1(c2ccc(C(=O)Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(C(=O)NC3CCCCC3N)cc2)CC1
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Part A. 1-(4-Chlorocarbonyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.66 g, 2.77 mmol) was stirred in CH2Cl2 (10 mL) at rt under N2. 1,2-Cis-diamino-cyclohexane (0.66 mL, 2.0 eq) was added as one portion. The mixture was stirred for 10 min. Diluted HCl was added. The mixture was extracted with EtOAc (2×). The aqueous layer was basified with conc. NaOH, extracted with EtOAc (2×). The organic layers were washed with H2O and brine, dried over MgSO4, filtered, and concentrated to afford 1-[4-(2-amino-cyclohexylcarbamoyl)-phenyl]-cyclopropanecarboxylic acid methyl ester (0.35 g, yield: 39.8%). LC/MS (ESI+) 317.4 (M+H).
Reaction SMILES: [I:1]Cl.[N:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Ca+2]>CO>[I:1][C:10]1[CH:9]=[C:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[CH:13]=[CH:12][C:11]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(Nc2ccc(-n3cnnc3)cc2)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Ic1cc(-n2cnnc2)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
A solution of iodine monochloride (22.3 g, 137 mmol) in methanol (300 ml) was added over 0.75 h to a stirred suspension of 4-(1,2,4-triazol-4-yl)phenylaniline (20.0 g, 125 mmol) and calcium carbonate (25.0 g, 250 mmol) in methanol (800 ml) at -30° C. under nitrogen. The mixture was allowed to warm to room temperature and stirred for 16 h before filtering through a pad of celite. The filtrate was evaporated in vacuo and the residue dissolved in EtOAc and washed with 50% wlw sodium bisulphite solution. The solid material was filtered off and the organic layer dried (MgSO4), evaporated in vacuo and combined with the solid material to give the title product (23.9 g, 67%), δ (250 MHz, d6 -DMSO) 5.54 (2H, br s, NH2), 6.84 (1H, d, J=8.7 Hz, Ar--H), 7.38 (1H, dd, J=2.6 and 8.7 Hz, Ar--H), 7.87 (1H, d, J=2.5 Hz, Ar--H), 8.92 (2H, s, Ar--H).