Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC(N)=O)C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:17]1([CH2:23][C:24]([N:26]=[C:27]=[O:28])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:29][C:30]1[CH:50]=[CH:49][C:33]([O:34][C:35]2[N:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH:36]=2)=[C:32]([F:51])[CH:31]=1>ClC(Cl)C.CCCCCC.CN(C)C=O.C(OCC)(=O)C>[F:51][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:28])[CH:50]=[CH:49][C:33]=1[O:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[CH:36]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Agent: NC(=O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a suspension of 2-phenylacetamide (905 mg, 6.7 mmol) in dichloroethane (90 ml) was added oxalyl chloride (1.75 ml, 20.1 mmol) under a nitrogen atmosphere, followed by stirring at 110° C. for 12 hrs. The reaction mixture was cooled down to room temperature, and concentrated under a reduced pressure to give a residue, to which hexane (13.4 ml) was added to prepare a solution of phenylacetyl isocyanate in hexane. To a solution of pyrrolidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (40 mg) in N,N-dimethylformamide (1.0 ml) was added the above solution of phenylacetyl isocyanate in hexane (supernatant, 0.948 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which ethyl acetate (1.0 ml) was added to suspend. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (47.1 mg, 78.1%) as pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([CH:31]([NH2:41])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:25][CH2:24]1)=[O:22])[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]([CH:31]([NH:41][C:1]([C:4]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: COC(=O)c1cc(C(=O)O)nc2ccccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCl) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCI (161 mg, 1.2 eq. ), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.CC[O-].[Na+].[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:7][C:12](=[O:19])[CH2:13][C:14](=[O:15])[N:5]2[N:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(N)[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2n(n1)C(=O)CC(=O)N2
Temperature: 25 °C

Procedure:
(prepared in an analogous procedure to that outlined in WO 2004/026229 A2) Step A: 5-Methyl-2H-pyrazol-3-ylamine (2 g, 0.0206 mol) was dissolved in EtOH (60 ml) and NaOEt (11.58 ml of a 21% by wt. solution, 2 eq) was added, followed by diethyl malonate (3.44 ml, 1.1 eq). The mixture was heated at reflux for 3 h. After cooling to rt, the precipitate was collected by filtration, washed with additional EtOH, and dried to give 1.6 g of 2-methyl-4H-pyrazolo[1,5-a]pyrimidine-5,7-dione. Step B: The compound from step A (1.6 g) was dissolved in POCl3 (18 ml) and cooled to 0° C., N,N-dimethylaniline (3.43 ml) was added and the mixture heated at 115-120° C. overnight. After cooling to rt, the POCl3 was removed under reduced pressure, the resulting residue was taken up in CH2Cl2, and poured onto ice. Once the ice melted the mixture was neutralized with NaHCO3 (s) and the organic layer separated. The organic layer was washed with water, dried (MgSO4), concentrated under reduced pressure, and the resulting residue purified by flash chromatography (SiO2, hexane-CH2Cl2) to give 0.734 g of 5,7-dichloro-2-methylpyrazolo[1,5-a]pyrimidine. 1H NMR (CDCl3) δ 6.89 (s, 1H), 6.52 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)cc(-c1ccccc1)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2)cc(=O)c2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To 0.9 gram of methyl 1-methyl-2-phenyl-4-quinolone-6-carboxylate obtained in Example 7 are added 0.5 gram of sodium hydroxide and 40 ml of water and the mixture is stirred at 60° C. for two hours. The mixture is acidified with acetic acid, and crystals which separate out therefrom are collected by filtration, and dried to give 0.5 gram of 1-methyl-2-phenyl-4-quinolone-6-carboxylic acid, colorless powder, melting at above 30° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[NH2:10][C:11](N)=[O:12].Cl>O.C(O)(=O)C>[OH:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][C:2]=1[NH:1][C:11]([NH2:10])=[O:12]
Reactant: Cc1ccc(N)c(O)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(N)=O)c(O)c1
Yield: 86 %

Procedure:
To 13 ml of water, there were added 5.00 g (40.7 mmol) of 6-amino-m-cresol, 9.76 g of (162.6 mmol) of urea, 4 ml of conc. hydrochloric acid and 0.8 ml of a mixture (1:1 (v:v)) of conc. hydrochloric acid and glacial acetic acid, followed by heating under reflux for 1.5 hours. After cooling, 20 ml of water was added. The crystals thus precipitated were filtered and dried to thereby give 5.81 g (35.0 mmol) of N-(2-hydroxy-4-methylphenyl)urea as dark brown crystals. The yield was 86%. After recrystallizing from acetonitrile, 2.00 g of N-(2-hydroxy-4-methylphenyl)urea was obtained as pale purple crystals. The recovering yield was 34%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1>CN1CCCC1=O.[Cu]I>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13]([N:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]3=[O:41])[C:12]=2[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(Br)c32)C1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(-n4ccccc4=O)c32)C1=O
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-4-bromo-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.15 g, 0.28 mmol), copper (I) iodide (27 mg, 0.14 mmol), potassium carbonate (76 mg, 0.55 mmol), and 2-hydroxypyridine (52 mg, 0.55 mmol) in N-methyl-2-pyrrolidinone (2.7 mL) was stirred in an oil bath at 140° C. for 3 hours. The resultant mixture was filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound. ES MS M+1=560
Reaction SMILES: O[CH:2]([CH3:10])[CH2:3][NH:4][C:5]([CH3:9])([CH3:8])[CH2:6]O.[NH3:11]>O>[CH3:9][C:5]1([CH3:8])[CH2:6][NH:11][CH:2]([CH3:10])[CH2:3][NH:4]1
Reactant: N
Reactant: CC(O)CNC(C)(C)CO
Solvent: O
Product: CC1CNC(C)(C)CN1
Yield: 48 %

Procedure:
In this example, a sample of 2,2,5-trimethylpiperazine was prepared by substantially following the procedure set forth in Example II. However, in this example, 120 g of crude N-(2'-hydroxypropyl)-2-amino-2-methyl-1-propanol, 90 g of water, 60 g of a Ni-Cu-Cr catalyst, and 102 g of ammonia were charged. GLC analysis showed that a 48% yield of 2,2,5-trimethylpiperazine was obtained with 55% dialkanolamine conversion.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.CC[N:52](C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[Cl-].[NH4+]>CN(C)C=O.O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([NH2:52])=[O:35])=[CH:37][CH:38]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (30 mg, 0.0468 mmol) obtained in Example 1-D-09 in dimethylformamide (1 ml), Hunig's base (41 μl, 0.234 mmol), HOBt monohydrate (8.3 mg, 0.0468 mmol), WSC hydrochloride (17.6 mg, 0.0702 mmol) and ammonium chloride (5.0 mg, 0.0936 mmol) were added, followed by stirring at 80° C. for 3 hours. To this, water (5 ml) was added, and the solid was filtered off. To this, trifluoroacetic acid (1 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 3 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. The solid was filtered, and subsequently suspended in dichloromethane/hexane=9/1, which was stirred at room temperature for 30 minutes, followed by filtering the solid, to obtain the desired compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C2C=NC(C(OC)=O)=CC=2C2C1=CC=CC=2)C1C=CC=CC=1>C1COCC1.CN(C=O)C>[CH2:21]([N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: COC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Ethyl β-carboline-3-carboxylate 10 (4.8 g, 20 mmol), DMF (100 ml) and THF (100 ml) were respectively added in a 100 ml round-bottom flask, and were stirred at room temperature for 15 minutes, then 60% NaH (2.4 g, 60 mmol) was added and stirred until there were no bubbles formed. Benzyl bromide (15 ml) was added, and the mixture was refluxed for 12 h. Later the mixture was treated in a manner similar to that described for compound 29 to afford white crystals (4.6 g, 70%), mp 126-127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15]([C:18](O)=[O:19])=[CH:14][C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][NH:35][OH:36].C(N(CC)CC)C.Cl>ClCCl.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15]([C:18]([N:35]([OH:36])[CH3:34])=[O:19])=[CH:14][C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2cc(OCc3ccccc3)ccc2OC1
Reactant: CNO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(O)C(=O)C1=Cc2cc(OCc3ccccc3)ccc2OC1

Procedure:
6-Benzyloxy-2H-1-benzopyran-3-carboxylic acid (362 mg, 1.33 mmol) and DMF (97 mg, 1.33 mmol) are dissolved in 5 ml of dichloromethane. To this is added oxalyl chloride (0.38 g, 2.99 mmol) and the mixture is stirred until no further gas evolution is observed (2 hours). This acid chloride solution is slowly added to a mixture of N-methylhydroxylamine hydrochloride (0.44 g, 5.32 mmol) and triethylamine (0.81 g, 7.98 mmol) in THF/water (4.1 ml/0.99 ml). The resultant mixture is stirred at room temperature for 1 hour, and poured onto 100 ml of 2N aqueous HCl. The mixture is extracted twice with dichloromethane and the organic phase is dried (MgSO4). Evaporation followed by trituration of the residual solid with ethyl acetate/hexane gives 6-benzyloxy-N-hydroxy-N-methyl-2H-1-benzopyran-3-carboxamide, m.p. 143°-146° C., as a pale yellow solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][N:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccnc2cccnc12
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5cccnc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1,5-naphthyridine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 9.09-9.08 (m, 1H), 8.95-8.87 (m, 1H), 8.44-8.39 (m, 1H), 8.00 (s, 1H), 7.73-7.70 (m, 1H), 7.67-7.64 (m, 1H), 5.00-4.96 (m, 1H), 4.56-4.53 (m, 1H), 4.33-4.29 (m, 1H), 3.34 (t, J=8.3 Hz, 1H), 3.19 (d, J=9.5 Hz, 1H), 2.91-2.82 (m, 2H), 2.47-2.43 (m, 1H), 2.12 (t, J=8.3 Hz, 1H), 1.48 (dd, J=9.9. 6.6 Hz, 6H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z=404.2).
Reaction SMILES: [CH2:1]([Si:4]([CH2:29][CH:30]=[CH2:31])([CH2:26][CH:27]=[CH2:28])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:13][CH2:14][CH2:15][Si:16]([CH2:23][CH:24]=[CH2:25])([CH2:20][CH:21]=[CH2:22])[CH2:17][CH:18]=[CH2:19])([O:11][CH3:12])OC)[CH:2]=[CH2:3].[C:32]([Li])([CH3:35])([CH3:34])[CH3:33]>CCCCC>[CH2:1]([Si:4]([CH2:29][CH:30]=[CH2:31])([CH2:26][CH:27]=[CH2:28])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:13][CH2:14][CH2:15][Si:16]([CH2:17][CH:18]=[CH2:19])([CH2:20][CH:21]=[CH2:22])[CH2:23][CH:24]=[CH2:25])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH3:12])[CH:2]=[CH2:3]
Reactant: [Li]C(C)(C)C
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)OC
Solvent: CCCCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, bis{3-(triallylsilyl)propyl}dimethoxysilane (29′) (1.0 g, 2.097 mmol) was cooled down to −78° C., then n-pentane solution of 1.61M t-butyllithium 1.954 mL (3.145 mmol) was added dropwise, then stirred at −78° C. for 17 hours. The reacted mixture was cooled down to 0° C., quenched with water, saturated ammonium chloride aqueous solution was added. The obtained organic layer was separated. The obtained water layer was extracted with diethyl ether and the collected organic layer was each washed with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining a crude product. The crude product was purified through short silica gel column chromatography (eluent: hexane/ethyl acetate=20/1), obtaining bis({3-(triallylsilyl)propyl}(tert-butyl)methoxysilane (30) (yield: 0.902 g, yield (%): 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:45])[C:33]=1[O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:5][C:6]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1)(C(OCC=C)=O)[C:7]([O:9]CC=C)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]([CH:6]([CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:33]([O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[C:32]([F:45])[CH:31]=1)[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=1)([OH:9])=[O:8]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CCC(Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)C(=O)O)cc1
Temperature: 100 °C

Procedure:
9.2 g (14.27 mmol) of diallyl 2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate, 64 mg (0.29 mmol) of palladium(II) acetate and 262 mg (1 mmol) of triphenylphosphine are stirred in 300 ml of dioxane under argon. Then a solution of 4.76 g (47.08 mmol) of triethylamine and 1.64 g (35.67 mmol) of formic acid in 200 ml of dioxane is added dropwise, and the mixture is heated at 100° C. for 2 h. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 3.69 g (49% of theory) of the title compound are obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.[F:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O1CCCC1.O.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:43][C:44]1[CH:49]=[C:48]([C:21]2[N:29]3[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:32]=4)=[N:28]3)=[CH:23][CH:22]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: Brc1ccc2cnc(Nc3cccc(N4CCOCC4)c3)nn12
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Fc1cccc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
Palladium Acetate (0.029 g, 0.00013 mol) and Triphenylphosphine (0.042 g, 0.00016 mol) were dissolved in Tetrahydrofuran (2.0 mL) and the mixture was allowed to stir at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(3-morpholin-4-yl-phenyl)-amine (0.240 g, 0.000641 mol) was then added and the reaction was again allowed to stir for 10 minutes. 3-fluorophenylboronic acid (0.179 g, 0.00128 mol) was added followed by 0.9 M of Sodium carbonate in water (2 mL) and Ethanol (2.0 mL). The reaction mixture was then heated at 80° C. and was allowed to stir overnight. The reaction mixture was poured over saturated sodium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Gilson prep HPLC to afford 40.32 mg of [7-(3-Fluoro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as a lyophilated powder. (M+H)=390.14. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.93 (m, 1H), 7.83 (m, 1H), 7.35-7.55 (m, 5H), 7.18 (m, 3H), 6.99 (m, 1H), 3.92 (m, 4H), 3.26 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:15]=3)[N:10]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:20])[CH:15]=3)[N:10]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(/C=C/C(=O)O)cc12
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(/C=C/C(=O)N3CCC3)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 85, with the exceptions that (E)-3-(1′-acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)acrylic acid was used instead of 2-(5-chloro-1′-(methoxycarbonyl)spiro[indoline-3,3′-pyrrolidin]-1-ylcarboxamido)thiazole-4-carboxylic acid, and that azetidine hydrochloride was used instead of dimethylamine hydrochloride.