Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([Cl:25])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=2)=[CH:12][C:13]=1[Cl:25]
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate (1.993 g, 0.00368 mol) was added to a solution of 20% trifluoracetic acid in dichloromethane. The mixture was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 mL) and washed with 1.0 M aqueous sodium hydroxide (2×25 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give trans 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.564 g, 0.00355 mol) as a white solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[O:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)CC1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-(3-(5-(1,3-dioxoisoindolin-2-yl)pent-1-ynyl)phenoxy)piperidine-1-carboxylate (10.65 g, 21.8 mmol) in ethanol (100 ml) was added hydrazine (2.1 g, 65.4 mmol). The resulting solution was heated under reflux for two hours, then cooled to room temperature, filtered and concentrated. The residue was dissolved in ethyl acetate (200 ml). The resulting solution was extracted with water twice, brine once, then dried over magnesium sulfate. The resulting solution was filtered and concentrated to yield tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate as a brown oil. MH+ 359.33
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:18][N:19]1[C:27]3[N:26]=[CH:25][NH:24][C:23]=3[C:22](=[O:28])[NH:21][C:20]1=[S:29])=[CH:5][N:6]2C(OC(C)(C)C)=O.C1C(I)=C(OC2C=C(I)C(O)=C(I)C=2)C(I)=CC=1C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:18][N:19]1[C:27]3[N:26]=[CH:25][NH:24][C:23]=3[C:22](=[O:28])[NH:21][C:20]1=[S:29])=[CH:5][NH:6]2
Reactant: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2c(F)cccc21
Agent: O=C(O)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2c[nH]c3cccc(F)c23)c2nc[nH]c12
Yield: 42.3 %

Procedure:
A solution of tert-butyl 4-fluoro-3-[(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl]-1H-indole-1-carboxylate (0.089 g, 0.21 mmol, obtained from Example 11(c)) in CH2Cl2:TFA 4:1 (1 mL) was stirred for 1 h 40 minutes and then evaporated. The crude product was purified by preparative HPLC, giving the title compound (0.028 g, 42%) as a solid.
Reaction SMILES: [CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH:1]1([C:4]([O:12][Si:13]([CH3:16])([CH3:14])[CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5]/[CH:6]=[CH:7]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 85 °C

Procedure:
A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne (Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is heated to 85° C. After the resulting exothermic reaction subsides the mixture is heated at 130° C. for one hour. The crude product is evaporatively distilled to give a liquid, pmr spectrum (CDCl3): δ0.10 (trimethylsiloxy group), 2.33 (doublet, =CHCH2), and 6.02 (vinyl hydrogens).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH2:10][OH:11])=[CH:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:11][CH2:10][C:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC=C(CO)C(C)(C)C1
Product: CC(=O)OCC1=CCC(C)CC1(C)C
Yield: 85.4 %

Procedure:
A mixture of 4,6,6-trimethyl-1-cyclohexene-1-methanol (3 g, 19.5 mmole) and acetic anhydride (2.4 g, 24 mmole) was heated to 70° during 3 h, then distilled at a bath temperature of 70°/0.5 hPa, to obtain 3.27 g (86%) of the desired product.
Reaction SMILES: CC(C)N=C=NC(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=O.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([C:14]([C:13]2[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:11]([F:10])[CH:12]=2)=[O:16])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(F)c(F)c(F)c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
DIC (1.34 g, 10.2 mmol) was added drop wise to a stirred solution of 3,4,5-trifluoro benzoic acid (1.5 g, 8.5 mmol) in THF (10 mL) and the resulting mixture was maintained for 30 minutes at room temperature. Mono benzyl piperazine (1.64 g, 9.35 mmol) was then added and the mixture heated to reflux at 70° C. overnight, under an atmosphere of nitrogen. The resulting solid precipitate was filtered and the filtrate was washed with water and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (12% ethyl acetate in hexane) to afford 1.7 g (60%) of (4-benzyl-piperazin-1-yl)-(3,4,5-trifluoro-phenyl)-methanone. 1H NMR: (CDCl3): δ 7.32 (m, 5H), 7.06 (t, 2H), 3.75 (bs, 2H), 3.54 (s, 2H), 3.44 (bs, 2H), 2.46 (bs, 4H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 g, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.0065 mole), and dimethylsulfate (0.76 g, 0.006 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.13 g, yield: 89.6%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Mg]Cl)C.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:7]2[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccnc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Br)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 10 g (42 mmol) 2,3-dibromopyridine in 210 ml dry tetrahydrofuran at room temperature were added 22 ml (44 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was stirred for 1 h at room temperature. A solution of 7.9 g (44 mmol) 1-benzyl-4-piperidone in 40 ml tetrahydrofuran was added, and stirring was continued for 16 h. The reaction mixture was quenched with water, basified to pH 9 with aqueous 2 M sodium hydroxide solution and extracted with tert-butyl methyl ether (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (3.4 g, 23%) as an orange amorphous solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25](OCC)=[O:26])[CH:20]=4)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH2:17][CH2:18]3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: OCc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a cooled solution of 2.5 g (6.25 mmol) of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-ethoxycarbonylphenyl)piperazine (prepared by path II), is added, under argon, 0.36 g (9.36 mmol) of lithium aluminum hydride. The suspension is stirred overnight at room temperature. Hydrolysis is performed at 0° C. by slow addition of 0.35 mL of water, 0.35 mL of 15% aqueous sodium hydroxide solution and 1.0 mL of water. The slurry is stirred for 15 minutes at room temperature then magnesium sulfate is added. The mixture is filtered and the salts are washed with ethyl acetate. The filtrate is concentrated under reduced pressure to give 2.0 g (89%) of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-hydroxymethylphenyl)piperazine as a solid.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:23]=4)[C:18]([S:33][CH3:34])=[CH:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)(=O)C.ClCCl>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:23]=4)[C:18]([S:33]([CH3:34])=[O:1])=[CH:17]3)=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1cn(-c2ncc(-c3ccnc(C)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen peroxide (30%, 0.4 mL, 3.595 mmol, 4.0 eq) was added to a stirred solution of (1-(5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (400 mg, 0.898 mmol, 1.0 eq, synthesized analogously to procedure 1d) in acetic acid (10 mL). The reaction mixture was stirred for 1 h at room temperature and then diluted with dichloromethane (20 mL). The mixture was washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated under vacuum. The remnant was purified by preparative silica gel TLC [dichloromethane with 3% methanol]. White solid. Yield: 250 mg
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]([C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:49])OC2C=CC=CC=2)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[NH2:32]>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:36]4[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=4)[C:31]([NH2:32])=[O:33])=[O:49])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Reactant: NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccc(C(N)=O)c4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 4 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4% yield.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O.O>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][C:10]1[N:11]([CH2:16][CH2:17][CH3:18])[C:12](=[O:15])[C:13]2[NH:14][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7][C:8]=2[N:9]=1)[CH3:21]
Reactant: CCOC(=O)CN
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1c(NCC(=O)OCC)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 130 °C
Yield: 48.4 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.10 g, 0.357 mmol) in N-methylpyrrolidone (2 ml) was added glycine ethyl ester (0.074 g, 0.532 mmol) followed by diisopropyl ethylamine (0.18 ml, 1.07 mmol). The resulting reaction mixture was heated at 130° C. overnight. To the reaction mixture was added ethyl acetate followed by water. The layers were separated. The ethyl acetate layer was washed thrice with water. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 5% methanol in dichloromethane as the solvent system to give the product (0.060 g, 48%) as an off white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][C:8](=[O:14])[NH:9]3)[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[Br:15][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2c(cccc2C2CC2)N1
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2C2CC2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-cyclopropyl-3,4-dihydroquinolin-2(1H)-one (147-5; 0.5 g, 0.00267 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.47 g, 0.0026 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated and diluted with ice cold water (100 mL) with constant stirring, the solid residue obtained was filtered and dried to obtain the title compound. MS (M+1): 266.1.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.[CH2:33](Br)[CH:34]=[CH2:35]>CN(C=O)C>[CH2:35]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH2:2][CH3:3])=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)[CH:34]=[CH2:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: C=CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CC1
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3carboxylic acid hydrochloride (0.18 g), triethylamine (0.12 g), allyl bromide (0.09 g), and DMF (3 ml) was heated with stirring at 90° for 3 hours and the solvent was evaporated. The residue was dissolved in 2N sodium hydroxide solution. The alkaline solution was adjusted to pH 7 with aqueous acetic acid and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 7-(4-allyl-1-piperazinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.055 g), mp 227°-230° C. (decomp.).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[N:17]4[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]4=[N:15][C:14]=3[CH3:28])=[C:10]([CH3:29])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.C1C[O:33][CH2:32][CH2:31]1.C([Li])CCC.CON(C)C(=O)C>CCOC(C)=O>[CH2:23]([CH:22]([C:21]1[C:16]2[N:17]([C:13]([C:11]3[S:12][C:8]([C:6]4[N:7]=[C:2]([C:32](=[O:33])[CH3:31])[CH:3]=[CH:4][CH:5]=4)=[CH:9][C:10]=3[CH3:29])=[C:14]([CH3:28])[N:15]=2)[N:18]=[C:19]([CH3:27])[CH:20]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: C1CCOC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(Br)n4)cc3C)c(C)nc12
Agent: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C(C)=O)n4)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 13 %

Procedure:
To a −78° C. solution of 3-[5-(6-bromo-pyridin-2-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine) (0.26 g, 0.55 mmol), and THF (5 mL), is added 1.34 M n-Bu-Li (0.43 mL, 0.58 mmol). After 30 minutes N-methoxy-N-methyl-acetamide (0.065 mL, 0.61 mmol) is added and the solution warmed to ambient temperature. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (25 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15-20% EtOAc/hexane gradient) furnish the title compound (0.030 g, 0.069 mmol, 13%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.19 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 2.77 (s, 3H), 3.30-3.40 (m, 1H), 6.69 (s, 1H), 7.59 (s, 1H), 7.77-7.85 (m, 2H), 7.87 (dd, J=6.8, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C25H28N4OS (M+H)+: 433.3; found: 433.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:8][CH:9]=1)=O.CS(O)(=O)=O.FC1C=CC=CC=1C1OC(C([NH:36][C:37]([NH2:39])=[NH:38])=O)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[F:16][C:12]1[CH:11]=[C:10]([C:7]2[O:6][C:5]([C:3]([NH:38][C:37]([NH2:39])=[NH:36])=[O:2])=[CH:9][CH:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(-c2cccc(F)c2)o1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)c1ccc(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
5-(3-fluorophenyl)furan-2-carboxylic acid methyl ester (250 mg, 1.14 mmol) was dissolved in DMF (3 ml), to which 2 M guanidine solution (3.4 ml, 6.8 mmol) prepared in Example 1 was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane), to give 252 mg of a title compound (yield: 89%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CSc1ncnc2c(N3CCSCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methylthio-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 165°-167° C.) and piperazine at room temperature.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([CH:25]=[C:26]([C:28]2[NH:29][C:30]([C:33]3[O:34][C@@H:35]([CH3:38])[CH2:36][N:37]=3)=[CH:31][CH:32]=2)[CH:27]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])=[CH:12][N:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:38][C@@H:35]1[O:34][C:33]([C:30]2[NH:29][C:28]([C:26]3[CH:27]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)=[O:17])=[CH:12][N:11]=4)[CH:25]=3)[O:5][C@@H:4]([CH3:39])[CH2:3][OH:2])=[CH:32][CH:31]=2)=[N:37][CH2:36]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4cnc(C(=O)N5CCN(C)CC5)cn4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reaction time: 3 h
Yield: 25 %

Procedure:
2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazine (259 mg, 0.48 mmol) synthesized in Example (131d) was dissolved in methylene chloride (15 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.81 mL, 0.81 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 3 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-8%) to afford the desired compound (62.4 mg, yield 25%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([OH:28])(=[O:27])[C:21]([CH2:23][C:24](O)=[O:25])=[CH2:22].C(CN)O>>[CH2:1]([N:19]1[C:24](=[O:25])[CH2:23][CH:21]([C:20]([OH:28])=[O:27])[CH2:22]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: NCCO
Product: CCCCCCCC/C=C\CCCCCCCCN1CC(C(=O)O)CC1=O
Yield: 117 %

Procedure:
265 g of oleylamine, 130 g of itaconic acid and 61 g of monoethanolamine were used to obtain 440 g of N-oleyl-5-oxopyrrolidine-3-carboxylic acid monoethanolammonium salt with
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[S:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][CH:6]=1)(=[O:10])(=[O:11])[NH2:12]
Reactant: O=S(=O)(O)Cl
Reactant: NS(=O)(=O)CCc1ccccc1
Product: NS(=O)(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
1.3 g (7.3 mmol) of 2-phenylethanesulfonamide was added to 2.4 g (36.5 mmol) of chlorosulfonic acid under ice-cooling over 20 minutes, followed by stirring at room temperature for further 90 minutes. The reaction mixture solution was poured into ice-water, and then extracted with ethyl acetate. The extract was successively washed with an aqueous saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1.6 g of the title compound.