Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:14])([O:12]C)[O:10][CH3:11].CN(C)C=O.C(OCC)C>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[C:9](=[O:12])([O:10][CH3:11])[O:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)OCc1ccccc1
Yield: 65 %

Procedure:
Benzyl chloride (31.65 g, 0.25 mole), dimethyl carbonate (90.0 g, 1.0 mole), tetra-n-butylphosphonium bromide (3.39 g, 0.01 mole) and N,N-dimethylformamide (200 ml) are heated to 117° C.-118° C. for 6 hours. After heating is discontinued the reaction mixture is added to 300 ml of diethyl ether and 300 ml of water. The organic layer is washed with 3×100-ml allotments of water followed by 2×100 ml-portions of 10 percent aqueous HCl, 100 ml of saturated aqueous NaHCO3 and 100 ml of a saturated aqueous NaCl solution, and dried over MgSO4. After solvent removal, distillation gives 27.02 g (65 percent yield based on benzyl chloride) of benzyl methyl carbonate, b.p. 110° C.-111° C. (11 torr).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[I:11].[OH-].[Na+]>C(O)(=O)C.O>[I:11][C:4]1[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: CCCc1nc(I)c(CO)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc(I)c(C=O)[nH]1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2-n-propylimidazole in 325 mL of glacial acetic acid at 20° C. was added dropwise over 1 h 290 mL of 1.0N aqueous ceric ammonium nitrate solution. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture then was diluted with water, adjusted to pH 5-6 employing aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to furnish 29.9 g of product as a light yellow solid; mp 141°-142° C. NMR (CDCl3) δ 11.51 (br s, 1H); 9.43 (s, 1H); 2.81 (t, 2H); 1.81 (sext. 2H); 0.97 (t, 3H). ##STR74##
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](C(O)=O)=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:22][CH2:21]1.C([N:38](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(O)(C)(C)C>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([NH2:38])=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:22][CH2:21]1
Reactant: CCN(CC)CC
Reactant: Nn1c(SCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2cc(C(=O)O)ccc2c1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc2c(=O)n(N)c(SCCCN3CCN(c4ccc5ccccc5n4)CC3)nc2c1
Yield: 8.5 %

Procedure:
In 10 ml of tert-butanol, 250 mg of 3-amino-4-oxo-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4-dihydroquinazolin-7-carboxylic acid as synthesized in Example 1-57 was dissolved, to which 52 mg of triethylamine, and further 147 mg of DPPA, were added by the order stated. This mixture was heated under reflux for an overnight. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1). The purified product was added to 8 ml of 4N hydrochloric acid-dioxane solution, stirred for an hour, and an excessive amount of triethylamine was added. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 20 mg (8%) of 3,7-diamino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3H-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17](=[O:20])([O-])[O-].[K+].[K+].[CH2:23]([O:25][C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[C:28]([O:35][CH2:36][CH3:37])[C:27]=1[O:38][CH2:39][CH3:40])[CH3:24]>C(OCC)(=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:17](=[O:20])[C:33]3[CH:29]=[C:28]([O:35][CH2:36][CH3:37])[C:27]([O:38][CH2:39][CH3:40])=[C:26]([O:25][CH2:23][CH3:24])[CH:34]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: CCOc1ccc(C(=O)Cl)c(OCC)c1OCC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OCC)c1OCC
Reaction time: 1 h

Procedure:
Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (260 mg, 1 mmol) and and potassium carbonate (0.69 g, 5 mmol) in ethyl acetate/water (10 mL/10 mL). Cool in an ice-bath. Add a solution of triethoxy-benzoyl chloride (1.2 mmol) in ethyl acetate (10 mL). After 1 hour, dilute with ethyl acetate and extract with 1M hydrochloric acid solution, 5% sodium bicarbonate solution, and water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.43 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][C:13]1[N:18]=[C:17](SC)[CH:16]=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].[S:26]([O-:30])([O-])(=[O:28])=S.[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[N:18]=[C:17]([S:26]([CH3:1])(=[O:30])=[O:28])[CH:16]=[CH:15][N:14]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (3.92 g, 17.5 mmol) was added to a stirred mixture of 2-chloro-4-(methylsulfanyl)pyrimidine (1.5 g, 7.0 mmol) in dichloromethane (35.0 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1.5 h and then diluted with aqueous sodium thiosulfate. The solution was stirred for 10 min then saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford 2-chloro-4-(methylsulfonyl)pyrimidine as a white solid. MS ESI calcd. for C5H6C1N2O2S [M+H]+ 193. found 193.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](CCCC)(CCCC)[C:82]1[CH:87]=[CH:86][N:85]=[N:84][CH:83]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:18]=[C:17]([C:4]3[C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:6][CH:7]=[C:2]([C:82]4[CH:87]=[CH:86][N:85]=[N:84][CH:83]=4)[CH:3]=3)[N:22]=[C:21]([CH3:23])[N:20]=2)=[CH:27][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccnnc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 110 °C
Yield: 76.9 %

Procedure:
4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (190 mg, 0.325 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (15.51 mg, 0.033 mmol) (Strem Chemicals), tris(dibenzylideneacetone)dipalladium(0) (14.89 mg, 0.016 mmol) (Strem Chemicals) and 4-(tributylstannyl)pyridazine (156 mg, 0.423 mmol) (Synthonix) were weighed in a vial, purged with argon, and then treated with toluene (1.6 mL). The vial was sealed and heated at 110° C. in an oil bath for 21 h. The reaction mixture was treated with water and extracted with EtOAc (2×30 mL), washed with brine (20 mL) and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography using an ISCO Combiflash Companion (12 g column, 20-100% EtOAc in hexanes) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(pyridazin-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (157.1 mg, 0.250 mmol, 77% yield) as a bright yellow crystalline solid. m/z (ESI, +ve ion) 628.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.96 (1H, s); 9.44 (1H, d, J=1.4 Hz); 9.16 (1H, d, J=5.1 Hz); 9.10 (1H, d, J=2.7 Hz); 8.64 (1H, d, J=2.7 Hz); 8.30 (1H, d, J=2.5 Hz); 7.88 (1H, dd, J=8.7, 2.6 Hz); 7.58 (1H, dd, J=5.4, 2.6 Hz); 7.23 (2H, d, J=8.6 Hz); 7.17 (2H, d, J=8.8 Hz); 6.87 (4H, dd, J=12.7, 8.6 Hz); 6.75 (1H, d, J=8.8 Hz); 4.91 (2H, s); 4.83 (2H, s); 3.95 (3H, s); 3.81 (3H, s); 3.78 (3H, s); 2.62 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[N+:21]([O-])([OH:23])=[O:22]>CC(C)=O>[OH:1][C:2]1[C:11]([N+:21]([O-:23])=[O:22])=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc2cc(-c3ccccc3)c(=O)oc2cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(C)=O
Product: COc1cc2cc(-c3ccccc3)c(=O)oc2c([N+](=O)[O-])c1O
Reaction time: 0.33 h

Procedure:
To a solution of 7-hydroxy-6-methoxy-3-phenyl-chromen-2-one (1.34 g) in acetone (40 ml) was added nitric acid (0.22 ml in 5 ml of CH2Cl2) and the resulting mixture stirred for 20 minutes. After evaporation of the solvents the product was recrystallized from ethanol. Yield: 0.85 g.
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]>C(Cl)Cl>[CH2:1]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=C1CCCC1=O
Solvent: ClCCl
Product: CCCCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 20 h
Yield: 101.3 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 270 mg (0.16 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 5 g (32 mmole) of 2-pentylidenecyclopentanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 60 kg/cm2 for 20 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 5 g (percent yield: 100%) of 2-pentylcyclopentanone as a clear yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4]([NH:8][CH2:9][CH3:10])[N:3]=1.[I:11][Cl:12]>CO>[ClH:12].[NH2:1][C:2]1[N:7]=[C:6]([I:11])[CH:5]=[C:4]([NH:8][CH2:9][CH3:10])[N:3]=1
Reactant: ClI
Reactant: CCNc1ccnc(N)n1
Solvent: CO
Product: CCNc1cc(I)nc(N)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 2-amino-6-ethylaminopyrimidine (98 g, 0.64 mol) in methanol (1.6 L) was added ICl (115.0 g, 0.71 mol) in a small portion at 15° C. Then the reaction mixture was stirred at room temperature for 3 h (monitored by LC/MS). After evaporation of solvent by rotary evaporator, the residue was triturated with acetone. 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 93% isolated yield) was obtained by vacuum filtration and drying. 1H NMR (400 MHz, CD3OD) δ 3.58 (q, 2H), 2.14 (s, 3H), 1.11 (t, 3H); MS (EI) for C7H11N4ClI: 279.1 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]([O:1][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.23 g (0.54 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 4 ml of dry CH2Cl2 was added 0.06 ml of triethylamine (0.81 mmol). The solution was flushed with nitrogen and then 0.12 g (0.81 mmol) of chlorotrimethylsilane was slowly added by syringe. The mixture was stirred at room temperature (flushed with nitrogen) for 30 minutes, concentrated in vacuo to an oil and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=O.B(F)(F)F.CCOCC>>[NH2:9][C:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:12]([O:11][CH3:10])=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]=2[N:1]=[C:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COc1cccc2c1CCCC2=O
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Solvent: CCOCC
Product: COc1cccc2c1CCc1c-2nc2ccccc2c1N

Procedure:
2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 3, 4-dihydro-5-methoxy-[2H)-napthalen-1-one) (Aldrich Chemicals) (8.1 g, 46.0 mmol) and boron trifluoride diethyl etherate (1M, 5.7 ml, 46.6 mmol) were treated according to general procedure described herein to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])C(=O)[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.[CH3:17][O-:18].[Na+].[CH:20]([C:22]([CH2:24][CH3:25])=[O:23])=[CH2:21]>C(O)C.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:17](=[O:18])[C:6]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:21][CH2:20][C:22](=[O:23])[CH2:24][CH3:25])[CH2:5]2
Reactant: CCCCC1Cc2cc(N)c(F)cc2C1=O
Reactant: C[O-]
Reactant: C=CC(=O)CC
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCCC1(CCC(=O)CC)Cc2cc(N)c(F)cc2C1=O
Temperature: 70 °C
Yield: 217.4 %

Procedure:
A solution of 5-amino-2-butyl-6-fluoro-1-indanone (0.81 g, 3.84 mmol) in ethanol (18 mL) was treated with sodium methoxide (0.5M solution in MeOH, 1.54 mL, 0.768 mmol) and ethyl vinyl ketone (0.572 mL, 5.76 mmol). The resulting solution was stirred under a nitrogen atmosphere and heated in an oil bath at 70° C. over night. After cooling to room temperature, the mixture was diluted with CH2Cl2 and filtered through a pad of silica gel. The product washed off with EtOAc and the filtrate was evaporated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 4:1 to 3:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide to afford 5-amino-2-butyl-6-fluoro-2-(3-oxopentyl)-1-indanone(0.51 g, 45%) as a yellow foam.
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:24])[C:9]=1C(OCC)=O)([CH3:3])[CH3:2].[OH-].[K+]>CS(C)=O.O>[CH:30]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10](=[O:24])[CH:9]=1)([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1c(NCCN(C(C)C)C(C)C)c2ccccc2n(-c2ccccc2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N(CCNc1cc(=O)n(-c2ccccc2)c2ccccc12)C(C)C
Temperature: 0 °C
Yield: 71.5 %

Procedure:
Dissolved in 50 ml of dimethylsulfoxide were 1.31 g (3 mmol) of ethyl 4-(2-diisopropylaminoethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate (Compound No. 7), followed by the addition of a solution of 0.68 g (10 mmol) of potassium hydroxide in 6 ml of water. They were reacted at 60° C. for 4 hours. The reaction mixture was poured into ice water, and the resulting precipitate was collected by filtration, washed with water and then dried. The resulting powder was dissolved in chloroform, purified by chromatography on a silica gel column, and then recrystallized from isopropyl ether, whereby 0.78 g of 4-(2-diisopropylaminoethylamino)-1-phenyl-1,2-dihydroquinolin-2-one (Compound No. 43) was obtained (yield: 71.6%).
Reaction SMILES: Cl.Cl.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3SC(CN5CCNCC5)=CC=3)=CC=CC=4)C)N=C(C3C=C(O)C=C(F)C=3)C=12.[CH3:46][N:47]([CH3:71])[CH2:48][CH:49]=[CH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60](=[O:67])[O:59][C:58]=2[CH:68](O)[CH3:69])=[CH:53][CH:52]=1.[CH2:72]([O:79][C:80]1[CH:81]=[C:82]([C:87]2[C:95]3[C:90](=[N:91][CH:92]=[N:93][C:94]=3[NH2:96])[NH:89][N:88]=2)[CH:83]=[C:84]([F:86])[CH:85]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>>[NH2:96][C:94]1[N:93]=[CH:92][N:91]=[C:90]2[N:89]([CH:68]([C:58]3[O:59][C:60](=[O:67])[C:61]4[C:66]([C:57]=3[C:54]3[CH:53]=[CH:52][C:51]([CH:50]=[CH:49][CH2:48][N:47]([CH3:46])[CH3:71])=[CH:56][CH:55]=3)=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH3:69])[N:88]=[C:87]([C:82]3[CH:83]=[C:84]([F:86])[CH:85]=[C:80]([O:79][CH2:72][C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[CH:81]=3)[C:95]=12
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)cc1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)cc1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Yield: 28.6 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 4-(4-(3-(dimethylamino)prop-1-en-1-yl)phenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B45, 220 mg, 0.630 mmol) and 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 0.63 mmol, 211 mg) to give 3-(1-(4-amino-3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(3-(dimethylamino)prop-1-en-1-yl)phenyl)-1H-isochromen-1-one (120 mg, 0.18 mmol, 43.1% yield) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]([CH:26]=1)=[N:23][O:24][N:25]=2>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[C:22]([CH:26]=2)=[N:23][O:24][N:25]=3)[C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccc2nonc2c1
Product: N#Cc1ccc(N(Cc2ccc3nonc3c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 5-bromomethylbenzofurazane
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][NH2:27].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:1].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][NH:27][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccccn3)n2)n[nH]1
Product: Cl
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(pyridin-2-yloxy)ethylamine (674 μl) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(pyridin-2-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (68 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[CH3:7])[N:3]=[CH:2]1.[C:17]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][C:33](=[O:34])[CH:25]([NH:24][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:7])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1c(CO)cccc1[C@H](C)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1c(COC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cccc1[C@H](C)c1c[nH]cn1

Procedure:
The title compound was prepared from (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCl (671 mg, 3.5 mmol) and DMAP (427 mg, 3.5 mmol) according to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][OH:29])=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][O:29][C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N=C(NO)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N=C(NOC(=O)Cc1ccc(F)cc1)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
The product of example 20 (200 mg, 0.51 mmol) and 4-fluorophenylacetyl chloride (0.073 mL, 0.53 mmol) were dissolved in THF (5 ml). To this solution was added TEA (0.14 mL, 1.02 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then poured into water (30 ml). The crude product was obtained by filtration. It was recrystallized from CH2Cl2/PE to give the titled product (261 mg, yield 97.0%)