Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O1CCCC1.O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (60 g, 472 mmol) in tetrahydrofuran/water (=1/1, 600 mL) was added sodium hydrogen carbonate (43.6 g, 519 mmol), and benzyl chloroformate (74.1 mL, 519 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 16 hr, 2N hydrochloric acid (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (82.5 g, 67%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (17.7 g, 14%).
Reaction SMILES: C([O:3][C:4]([C@H:6]([OH:34])[C@H:7]([NH:19][C:20]([CH2:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:5])C.C1COCC1.[OH-].[Na+]>CC(O)=O>[C:4]([C@H:6]([OH:34])[C@H:7]([NH:19][C:20]([CH2:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1C(F)(F)F)NC(=O)CCCc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CCCc1ccccc1C(=O)O)N[C@H](Cc1ccccc1C(F)(F)F)[C@@H](O)C(=O)O
Reaction time: 4 h
Yield: 100 %

Procedure:
2-{3-[(1R,2R)-2-Ethoxycarbonyl-2-hydroxy-1-(2-trifluoromethyl-benzyl)-ethylcarbamoyl]-propyl}-benzoic acid was combined with THF (5 mL) and 10 M aqueous NaOH (96 μL, 4.0 eq.). The reaction was stirred for 4 hours. Upon completion of the reaction was completed, AcOH (1.5 mL) was added and the product was purified by preparative HPLC to yield the title compound (10 mg, 100% purity). MS m/z [M+H]+ calc'd for C22H22F3NO6, 454.14. found 454.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[OH-].[K+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate (270 mg, 0.43 mmol) in ethanol (10 mL) was added KOH (200 mg, 3.56 mmol) and water (4 mL). The resulting solution was stirred at room temperature for 1 h and neutralized with 1 N HCl solution. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 35.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.5 mg (11%) of the formic acid salt of 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperazin-1-yl]propanoic acid as a off-white solid. LCMS (Method 28) [M+H]+=603.1, RT=0.81 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.4, 7.0 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.08 (t, 1H, J=73.6 Hz), 5.24 (s, 1H), 3.50-3.47 (m, 4H), 2.57 (t, 2H, J=7.2 Hz), 2.49-2.39 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Yield: 9.3 %

Procedure:
A solution of ethyl 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylate (1.5 g) in methanol (20 mL) and THF(10 mL) is treated with aqueous 10% KOH (7.5 mL) and refluxed for 2 hours. The solution is evaporated, brought to pH 1 with 1 M HCl, and the precipitate filtered. The solid is purified by flash chromatography on silica, eluting with dichloromethane/methanol (98:2). Fractions homogeneous in the required product are combined and evaporated. The residue is recrystallized from ethyl acetate to give 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylic acid as colourless crystals (0.13 g), m.p. 218-219° C. 1H NMR (CDCl3) 5.1 (2H,s), 5.2(2H,s), 6.68(1H,d), 6.72(1H,s), 7.3-7.5(11H,m), 7.7(1H,d).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:21]2[CH2:22][CH2:23][C:17]3[C:16]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)=[O:36])=[CH:33][CH:32]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2ccc(Cl)cc2)C3)cc1

Procedure:
The compound pa was prepared following the general procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt with 4-Chlorobenzoic acid chloride: LC-MS m/z=521 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].[CH3:15][N:16]1[C:20]([CH3:21])=[CH:19][C:18]([C:22](Cl)=[O:23])=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:22]([C:18]1[CH:19]=[C:20]([CH3:21])[N:16]([CH3:15])[N:17]=1)=[O:23])(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Reactant: Cc1cc(C(=O)Cl)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)c1cc(C)n(C)n1
Yield: 68.5 %

Procedure:
10.8 g of 2-methoxycarbonylphenylsulfonamide, 8.6 g of 1,5-dimethylpyrazole-3-carbonyl chloride and 13.8 g of potassium carbonate in 200 ml of absolute acetone are refluxed for 8 h. The solvent is removed by distillation and then the residue is taken up in water and the pH is adjusted to 2. The precipitate is filtered off with suction and washed with H2O until neutral. The residue is stirred with ether, filtered off with suction and dried under reduced pressure. 11.6 g of N-(2-methoxycarbonylphenylsulfonyl)-1,5-dimethylpyrazole-3-carboxamide with a melting point of 176°-177° C. are obtained (active ingredient Example No. 40).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:24][CH2:23][CH:20]2[CH2:22][CH2:21]2)=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: NCC1CC1
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCN(CC(=O)NCC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethylglycine and 1-cyclopropylmethanamine: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.79 (dd, J=8.8, 2.8 Hz, 1H), 6.06 (bs, 1H), 3.97 (s, 2H), 3.56 (q, J=7.1 Hz, 2H), 3.13 (t, J=6.3 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 0.87 (m, 1H), 0.45 (m, 2H), 0.14 (m, 2H).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice-bath and n-butyllithium (100 ml of a 2.5M solution in hexane) added. The mixture was stirred at 0° C. for 15 minutes before adding 2,3-dihydrobenzo[b]furan (30 g) dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for a further 4 hours, poured onto an excess of solid carbon dioxide and left to stand for 3 days by which time the solvent had evaporated off. The residue was partitioned between ethyl acetate (1L) and 4N aqueous hydrochloric acid solution (240 ml), the layers separated and the aqueous layer extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was then triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-oic acid as a white solid (21 g)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.[ClH:31]>C(O)C>[ClH:31].[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NCc2ccccc2)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NCc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of ethyl 2-(benzylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.026 g, 0.10 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.015 g, 0.10 mmol) in 2M hydrochloric acid in ethanol (1.0 mL) was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.024 g, y. 56%).
Reaction SMILES: C1(S[C:8]2[S:9][C:10]([CH2:13][N:14]3[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]3)=[CH:11][N:12]=2)CCCCC1.[ClH:25].ClCl>ClC1C=CC=CC=1>[Cl:25][C:8]1[S:9][C:10]([CH2:13][N:14]2[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]2)=[CH:11][N:12]=1
Reactant: CN1COCN(Cc2cnc(SC3CCCCC3)s2)C1=N[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h

Procedure:
186 g of 3-(2-cyclohexylthio-thiazol-5-yl-methyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are introduced over a period of 5 minutes, with stirring, into a mixture of 300 g of hydrochloric acid (32%) and 150 g of chlorobenzene. 124 g of chlorine are introduced at 20° C. over a period of 4 hours. After 2 hours, excess chlorine is removed by the introduction of nitrogen, and the phases are then separated. The aqueous phase is adjusted to pH 5 with sodium hydroxide solution (30%) and then filtered, and the filtration residue is washed with water and dried in vacuo at 50° C. The title product is obtained in a purity of 97%.
Reaction SMILES: C(OC(=O)C)C.Cl.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:55])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[C:32]([NH:34][C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)=[O:33])=[CH:26][CH:25]=1)=O)(C)(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:55])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[C:32]([NH:34][C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Yield: 82 %

Procedure:
4.0 M hydrogen chloride ethyl acetate solution (10 mL) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(2,3-dihydrobenz o[1,4]dioxin-6-yl)-1-[3-(4-methylpiperazine-1-yl)propyl]ureidomethyl]benzamide (Reference Compound No. 13-1, 450 mg, 0.68 mmol) in a mixed solvent (ethyl acetate (10 mL) and methanol (10 mL)), and then the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution (150 mL) was added thereto, the whole was extracted with chloroform (150 mL), and then the organic layer was washed with brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH-modified silica gel, chloroform-methanol) to give 310 mg of the title compound as a colorless amorphous product. (Yield 82%)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O-:14])=O.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(O)(=O)C>[CH2:15]([N:22]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:1][C:23]1=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)[O-])c1
Reactant: S=C=NCc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COC(=O)c1ccc2[nH]c(=S)n(Cc3ccccc3)c(=O)c2c1

Procedure:
This process is illustrated in Scheme 2 below: Methyl 4-aminoisophthalate (2a) is treated with benzyl isothiocyanate, in a solvent such as pyridine or acetic acid, to give 3-benzyl-6-(methoxycarbonyl)-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one (2b). This compound is heated, in a refluxing alcohol, in the presence of hydrazine hydrate to give the corresponding hydrazine which is in turn cyclized by reaction with a carboxylic acid derivative R1COOH (such as an acid chloride or an orthoester). The 4-benzyl-7-(methoxycarbonyl)-4,5-dihydrotriazolo[4,3-a]quinazolin-5-one (2d) obtained is N4-debenzylated using aluminium chloride in benzene, and the intermediate secondary lactam is then substituted with a halide, in the presence of a base such as cesium carbonate, in a solvent such as dimethylformamide. The N-substituted analogue obtained (2f) is then hydrolysed, preferably in acidic medium, to give the corresponding acid (2g) which may be subsequently subjected to a coupling reaction of peptide type.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.F[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1ccc2ccccc2c1
Product: CN1CCC(Oc2ccc3ccccc3c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]([O:11][C:12](=[O:14])[CH3:13])[C:9](=[NH:15])[N:8]=[C:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)(=[O:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[C:1]([NH:4][C:5]1[N:10]([O:11][C:12](=[O:14])[CH3:13])[C:9](=[NH:15])[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(=N)n1OC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cc(N2CCCCC2)nc(=N)n1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture containing 0.5 g (0.0013 mole) of 6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine in 20 ml of acetonitrile and 0.5 ml of piperidine is stirred at room temperature for 3 hours, then evaporated under reduced pressure. After adding 30 ml of ether to the residue, the crystalline precipitate is filtered, washed with ether and then with water, finally dried to give the aimed product in a yield of 0.24 g (64%), m.p.: 217°-218° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[CH:27](OC(=O)C)=[O:28]>ClCCl>[CH:27]([NH:1][CH2:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CN)CC1
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CNC=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(3-(aminomethyl)-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.70 g, 1.86 mmol), acetic formic anhydride (270 mg, 3.72 mmol) and dichloromethane (20 mL). The resulting mixture was stirred at room temperature overnight. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 50% EtOAc in petroleum ether, to afford 490 mg (65%) of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38].CO>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Solvent: CO
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 80 °C
Yield: 27 %

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.352 mmol) and ammonia in MeOH 7M (7 ml, 49.0 mmol) was heated in a sealed tube at 80° C. for 48 h. The reaction mixture was evaporated onto silica gel and chromatographed, 0-50% 1:9 acetone:CHCl3 in EtOAc. The resulting solid was triturated in MeOH to give the title compound (54 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (br. s., 1H), 7.78 (d, J=5.3 Hz, 1H), 7.40-7.59 (m, 3H), 7.37 (td, J=7.4, 2.0 Hz, 1H), 7.14-7.31 (m, 2H), 6.52 (s, 2H), 5.58 (d, J=5.2 Hz, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.40 (t, J=4.6 Hz, 4H). MS (ESI): 549.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15]>ClCCl>[N:1]1([C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, pyrrolidine (363.9 μL, 4.4 mmol) and triethylamine (555.2 μL, 4.00 mmol) were dissolved in dichloromethane (5.0 mL), and the mixture was cooled to 0° C. While maintaining the reaction temperature at 0° C., 1-chloroethyl chloroformate (431.6 μL, 4.00 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The residue was then purified by silica gel column chromatography (dichloromethane, Rf=0.35) to obtain 424.2 mg (60% yield) of 1-chloro-ethyl pyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)=O.CO>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:13][CH3:14])[CH3:11])[N:5]=1)[CH3:2])[CH3:14]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CCc1ccccc1N
Solvent: O=CO
Solvent: CO
Product: CCc1ccccc1N=C(C)c1cccc(C(C)=Nc2ccccc2CC)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
One 9 of 2,6-diacetylpyridine and 3.0 ml of 2-ethylaniline were added to a round-bottom flask with 30 ml of methanol. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 24 hours at 50° C. The flask was then cooled to room temperature and placed in a freezer at −30° C. After 1 day, yellow crystals had formed. The crystals were isolated by filtration and identified by 1H NMR as the desired product (1.25 g, 55.2%). 1H NMR (CDCl3): δ8.38(d, 2, Hpyr), 7.86(t, 1, Hpyr), 7.20(m, 4, Haryl), 7.07(t, 2, Haryl), 6.65(d, 2, Haryl), 2.49(q, 4, Hbenzyl), 2.35(s, 6, N—C—CH3), 1.14(t, 6, CH2CH3).