Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]1[C:14](=O)[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([N:24]1[C:14]2[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C1CCC(=O)C(C(=O)c2ccncc2)C1
Reactant: CC(C)(C)NN
Solvent: CCO
Product: COC(=O)C1CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of methyl 3-isonicotinoyl-4-oxocyclohexanecarboxylate (6.3 g, 24.3 mmol) and TEA (10.15 ml) in ethanol was added t-Butyl hydrazine (6.4 g, 73 mmol). The reaction mixture was stirred at room temperature for overnight. The solvent was removed under vacuum and DCM (50 ml) was added, followed by water (50 ml). The organic layer was collected, washed with brine and dried over sodium sulfate. Removal of solvent gave the desired product (6.5 g). LC-MS found 314.2 (M+H)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([N:21]2[CH:29]([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.Cl[C:44]1[C:49]([F:50])=[C:48]([Cl:51])[N:47]=[CH:46][N:45]=1>O1CCCC1.C(OCC)(=O)C.O>[Cl:51][C:48]1[N:47]=[CH:46][N:45]=[C:44]([C:29]2([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22](=[O:42])[N:21]2[C@@H:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH3:20])[C:49]=1[F:50]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncnc(Cl)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Add sodium bis(trimethylsilyl)amide (210 mL, 210 mmol, 1 M THF) drop wise over 60 minutes to an ice cold suspension of 2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (62 g, 144 mmol) and 4,6-dichloro-5-fluoropyrimidine (31 g, 186 mmol) in tetrahydrofuran (620 mL). Stir the solution 60 minutes at 0° C. and then dilute the mixture with ethyl acetate (1 L) and water (1 L). Wash the organic phase with saturated aqueous sodium chloride and evaporate under reduced pressure. Dissolve the residue in 1:1 petroleum ether/ethyl acetate, filter through a pad of silica gel, and evaporate to give the title compound as a yellow foam (83 g, 103%). ES/MS m/z: 562 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].Cl>ClCCl.O1CCOCC1>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A solution containing the product from Example 10B (10 g, 27.7 mmol) in dichloromethane (100 ml) at −5° C. was slowly treated with an HCl solution in dioxane (200 mL, 4 N), stirred at 40° C. for 6 hrs, stirred at 25° C. for 16 hours concentrated to give the title compound as a hydrochloride salt (10 g, quantitative).
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27]CCCC(F)(F)C(F)(F)F)[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:68])([C:64]([F:67])([F:66])[F:65])CCCC(CCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][C:47]([F:68])([F:46])[C:64]([F:67])([F:66])[F:65])[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared in Example 10, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2)=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)=[O:24]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 34.9 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 74 mg of the target compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(C(F)(F)F)c2)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 27% yield; m.p. 195-196° C.; 1H NMR (CDCl3, 300 MHz) δ 8.15 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.40-7.27 (m, 5H), 5.97 (t, J=4.7 Hz, 1H), 4.59 (d, J=5.5 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 420 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>ClCCl>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CN1CCCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
0.35 cm3 (4.174 mmol) of pyrrolidine is added, at a temperature in the region of 20° C., under an argon atmosphere, to 0.5 g (2.087 mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene in solution in 20 cm3 of dichloromethane. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 250 cm3 of dichloromethane, washed with 3 times 200 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 458 mg of 1-(2-nitro-4-trifluoromethylbenzyl)pyrrolidine in the form of an oil;
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C)c(C(=O)Cl)c1

Procedure:
2,5-Dimethylbenzoyl chloride was prepared from reaction of 2,5-dimethylbenzoic acid and thionyl chloride as described in Example 8.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:2]1[S:1][C:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCCc2sccc2C1
Solvent: CC#N
Product: CCOC(=O)N1CCCc2sc(Br)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of Compound 1050 (1.53 g, 6.79 mmol) in acetonitrile (70 mL) at 0° C. was slowly added NBS (1.69 g, 9.48 mmol). The reaction was stirred at room temperature for 30 minutes, at which point HPLC analysis indicated disappearance of starting material. The reaction was quenched by addition of saturated sodium bicarbonate (50 mL) and stirred for one hour. The mixture was extracted with diethyl ether (3×100 mL), the volatiles removed under reduced pressure, and the residue purified by silica chromatography (0-30% ethyl acetate in hexanes) to give ethyl 2-bromo-7,8-dihydro-4H-thieno[3,2-c]azepine-5-carboxylate as a pale yellow oil (Compound 1051, 2.07 g, 86% yield); 1H NMR (300 MHz, CDCl3): δ 6.84-6.70 (m, 1H), 4.30 (d, J=15.4 Hz, 2H), 4.02 (q, J=6.7 Hz, 2H), 3.63 (s, 2H), 2.78 (dd, J=4.6, 5.7 Hz, 2H), 1.80 (s, 2H) and 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: N#N.C[Si](C)(C)[S:5][Si](C)(C)C.C[O-].[Na+].[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]#[N:28])=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1>CN(C=O)C.O>[CH3:15][C:16]1([C:21]2[O:25][C:24]([CH2:26][C:27]([NH2:28])=[S:5])=[CH:23][CH:22]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC1(c2ccc(CC#N)o2)OCCO1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc(CC(N)=S)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethyldisilthiane (9.45 mL, 45.07 mmol) was added dropwise to a solution of NaOMe (2.51 g, 45.07 mmol) in dry DMF (40 mL) and the reaction mixture was stirred at rt for 15 min. This dark blue solution was then added to a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-acetonitrile (3.48 g, 18.03 mmol) in DMF (30 mL) and the reaction mixture was stirred for 16 h at rt. Water (300 mL) was then added and the mixture was extracted twice with EA (300 mL). The combined org. phases were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.18. LC-MS-conditions 02: tR=0.74 min, [M+H]+=228.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])(=[O:19])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1ccc(F)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
4-Fluoro-1-methylsulfonyl-2-nitrobenzene can be obtained in the following way: 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene in 15 ml of dichloromethane are added dropwise to a suspension, stirred at a temperature in the region of −5° C. under argon, of 1.5 g of 3-chloroperoxybenzoic acid in 15 ml of dichloromethane. The reaction mixture is then stirred at a temperature in the region of 0° C. for 30 minutes and is then left to reheat to a temperature in the region of 20° C. It is then filtered through sintered glass and the solid is washed with dichloromethane. The filtrate is washed with an aqueous sodium hydrogencarbonate solution then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a column of 125 g of silica (particle size 40-63 μm), eluting with pure dichloromethane. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.2 g of 4-fluoro-1-methylsulfonyl-2-nitrobenzene are thus obtained in the form of a yellow foam (Rf=0.43, silica gel thin layer chromatography, eluent: dichloromethane)).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])[CH2:25][CH:26]=3)[CH:18]=[N:19][CH:20]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(C3=CCNCC3)c2)c(F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CC=C(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-5-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 167, triethylamine (42.3 uL, 0.30 mmol) and cyclopropanesulfonyl chloride (12.8 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(#N)C.[OH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN1CCCC1=O>[C:21]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(OCCOCCO)c1ccc(O)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C=C(C)C(=O)OCCOCCOC(=O)c1ccc(O)c(Cl)c1

Procedure:
A 500-ml eggplant type flask was charged with 50 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 285 g of diethyleneglycol and further with 2.5 g of PTS (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was heated with stirring on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. Thereafter, excess diethylene glycol therein was removed by means of vacuum distillation. The residue therein was poured into ice water and the precipitated crystals were recrystallized using benzene/ethanol to obtain 49 g of 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]-ester (melting point: 77.5° to 78° C.). To 100 ml of an acetonitrile solution containing 30 g of the 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]ester, 57.2 g of N-methylpyrrolidone and further 36 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred for 8 hours at 40° C. to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water, and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethyl acetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid [2-(2-methacryloyloxyethoxy)ethyl]ester (melting point: 57° to 58.5° C.).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.Br.C(O)(=O)C.C(=O)(O)[O-].[Na+]>>[C:31]1([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([S:13][C:7]4[CH:8]=[CH:9][N:10]=[C:11]5[C:6]=4[N:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[CH:19][CH:18]=3)=[N:22][N:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1cnc2c(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A reaction vial was charged with N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine (40 mg, 82 μmol), HBr (891 μl, 16408 μmol), and acetic acid (939 μl, 16408 μmol). The vial was sealed, and the reaction mixture was stirred at 85° C. for 2 hrs. Upon cooling, LC/MS analysis showed a mass ion peak corresponding to N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine (40 mg, 82 μmol). The reaction mixture was poured into an ice-cooled aqueous solution of sodium bicarbonate. Extraction of the product was attempted with DCM. However, the product seemed insoluble in DCM and was present in both the aqueous and organic layers, so all liquid was removed in vacuo. The resulting white solid was taken up in water and filtered. The filtrate was washed several times with water, and the resulting yellow solid was analyzed by LCMS. LCMS analysis showed clean 8-(4-(4-phenylphthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-3-ol. The crude material was carried forward.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C:14]2[N:22]([CH3:23])[C:21]3[C:20](=[O:24])[N:19]([CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH3:29])[C:16]=3[N:15]=2)=[CH:10][CH:9]=1)=[O:5])C.O.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:4]([CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C:14]2[N:22]([CH3:23])[C:21]3[C:20](=[O:24])[N:19]([CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH3:29])[C:16]=3[N:15]=2)=[CH:10][CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc(/C=C/c2nc3c(c(=O)n(CC)c(=O)n3CC)n2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCC(=O)O)cc3)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
Compound 189 (200 mg, 0.47 mmol) obtained in Reference Example 186 was dissolved in a mixed solvent of 4 ml of tetrahydrofuran, 4 ml of ethanol, and 2 ml of water. To the solution was added 98 mg (2.34 mmol) of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for one hour. To the reaction solution was added 2N hydrochloric acid, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol/acetic acid) to give 40 mg (yield 21%) of Compound 190 as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2ccc(OC)cc12
Reactant: CN(C)C=O
Product: COc1ccc2[nH]c(=O)n3c(=O)[nH]nc3c2c1
Temperature: 25 °C

Procedure:
3.0 g (0.011 mol) of ethyl 2-hydroxy-6-methoxy-quinazoline-4-yl-carbazate in 70 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with methanol and dried in a vacuum. There were obtained white crystals which were recrystallized from methanol/acetone. Yield: 1.16 g (46%) of 9-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as beige crystals; m.p. >350° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[CH2:40][NH:39][CH2:38][CH2:37]2.C1(NC(N)=O)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]([N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:43]([O:44][CH3:45])=[C:34]([O:33][CH3:32])[CH:35]=3)[CH2:40]2)=[O:31])[CH2:27][CH2:28]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(=O)NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
DCC (2.16 g, 0.011 mol), a catalytic amount of DMAP (0.098 g, 8 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.04 g, 0.009 mol) were added to a solution of 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.31 g, 0.008 mol) in dichloromethane (30 ml). The clear solution soon deposited a white solid corresponding to the cyclohexyl urea formation. The crude was stirred for 2 hours at room temperature. The solid was filtered and the crude was washed with water and dried over Na2SO4. The solvent was vacuum concentrated and the residue was purified by flash chromatography using a gradient consisting of different mixtures of dichloromethane/methanol to give pure tert-Butyl-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-1-carboxy-late as yellow solid (3.8 g, 85% yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A suspension of N-(4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (80 mg, 0.170 mmol) in DCM (3 mL) was cooled to 0° C. and treated with trifluoroacetic acid (3 mL, 40.4 mmol). The yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3-MeOH in DCM to give N-(4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (20 mg, 0.052 mmol, 30.5% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.47-13.72 (m, 1H); 12.82 (s, 1H); 10.10 (s, 1H); 9.78 (s, 1H); 8.59 (s, 1H); 8.33 (d, J=3.20 Hz, 1H); 7.75 (d, J=76.46 Hz, 2H); 7.58 (d, J=8.53 Hz, 2H); 6.94-7.03 (m, 1H); 2.87 (s, 3H); 1.72-1.82 (m, 1H); 0.72-0.84 (m, 4H). m/z (ESI, +ve ion) 386 (M+H)+.