Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[O:29][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1cccc(CC(N)=O)c1
Product: COc1cccc(Cc2nc(-c3cc(Br)ccc3OCC(=O)O)co2)c1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(3-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.45 min, m/z 418 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (example 7.1b) in 1.5 mL DMF is added at RT 63 μL (0.77 mmol) pyrrolidine. The reaction mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15])([O-])=O.Cl[Sn]Cl.O>CO.Cl>[F:15][C:14]([F:16])([F:17])[C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of 2-nitro-1,4-bis(trifluoromethyl)benzene (3.3 g, 12.7 mmol) in methanol (15 mL) was added a solution of SnCl2.H2O (8.57 g, 38.1 mmol) in conc. HCl (15 mL) at room temperature, and the mixture was heated to 50° C. and stirred for 4 hours. Methanol was removed, and the aqueous solution was basified with conc. NaOH solution until pH 10. The suspension was diluted with EtOAc (100 mL), and the mixture was stirred at room temperature for 30 minutes and filtered. The solid was discarded, and the filtrate was washed with brine (50 mL), dried over sodium sulfate, and filtered. The solution was concentrated to give 2,5-bis(trifluoromethyl)benzenamine as a yellow oil (2.5 g). MS (ESI): m/z 230 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH:28]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH:28]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)C(O)C(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)C(O)C(c1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.510 mmol) and 1-(6-bromopyridin-2-yl)-3-methyl-1-morpholin-4-ylbutan-2-ol (168 mg, 0.51 mmol) as starting materials.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].N1C=CN=C1.[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O.O.C(OCC)(=O)C>[Si:51]([O:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:4])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) and imidazole (5.6 g) in dry dimethylformamide (45 ml) was treated with t-butyldimethylchlorosilane (6.77 g) at room temperature for 2 hours. The reaction mixture was diluted with cold water (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml). The combined extracts were washed successively with 5% hydrochloric acid solution (80 ml×2) and brine (80 ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and the concentrate was crystallized from isopropanol to give crystals of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 90°-92° C.
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[C:15]2[N:16]([C:20](Br)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])(C)(C)C.CS[C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>>[CH3:13][S:10]([CH2:9][CH2:8][NH:7][C:14]1[C:15]2[N:16]([C:20]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[N:32]=3)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1nccn2c(Br)cnc12
Reactant: C1COCCN1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: CS(=O)(=O)CCNc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
(2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamic acid tert-butyl ester (from Example 5 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and morpholine. LC-MS: [M+H]+ 404.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
L-proline methyl ester hydrochloride (0.300 g, 1.81 mmol) was dissolved in dichloromethane (5 ml). Triethylamine (0.202 g, 1.99 mmol) and 1,1′-carbonylbis-1H-imidazole (0.352 g, 2.17 mmol) were added, and the mixture was stirred at room temperature for five days. Water was added to the reaction solution, followed by extraction with dichloromethane. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, 0.404 g of the title compound was obtained as a colorless oily substance (100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([OH:49])=O)[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50].[F:51][C:52]([F:66])([F:65])[C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1>CN(C=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([N:62]4[CH2:61][CH2:60][N:59]([C:55]5[CH:56]=[CH:57][CH:58]=[C:53]([C:52]([F:65])([F:66])[F:51])[CH:54]=5)[CH2:64][CH2:63]4)=[O:49])[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50]
Reactant: Cc1cc(C2CCc3nc(C(=O)O)cn3C2)ccc1F
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (173 μl; 212 mg; 0.92 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was purified by column chromatography on silica gel (chloroform). Yield: 166 mg (50%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:13]O)[CH:9]=[CH:8]2.CN(C)C=O.S(Cl)([Cl:22])=O>>[Cl:22][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2ccc(CO)nc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc2ccc(CCl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (8-methoxyquinolin-2-yl)methanol (1.0 g, 5.3 mmol) and N,N-dimethylformamide (39 mg, 0.53 mmol) in sulfurous dichloride (20 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and ice water was added. The pH of the aqueous layer was adjusted to 7 with 10 N sodium hydroxide solution. The mixture was extracted with DCM (30 mL×3). The combined organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.66 g of the product as a yellow solid. MS (ESI): m/z 208.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9](=[S:11])[NH2:10])[CH2:4][CH2:3]1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)(O)[O-].[Na+].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[ClH:12].[Cl:12][CH2:13][C:14]1[N:10]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[S:11][CH:16]=1
Reactant: CN1CCN(CC(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2nc(CCl)cs2)CC1
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethanethioamide (0.438 g, 2.53 mmol), 1,3-dichloroacetone (0.355 g, 2.78 mmol) and sodium bicarbonate (0.236 g, 2.78 mmol) was stirred in chloroform (4 mL) at room temperature for 48 h. The reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate was added dropwise to a cooled (ice bath) solution of thionyl chloride (0.205 mL, 2.78 mmol) in chloroform (2 mL). The solution was stirred at 60° C. for 0.5 h and then cooled to room temperature. The brown mixture was filtered and washed with chloroform to afford 1-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-4-methylpiperazine hydrochloride as a brown solid (0.421 g, 1.49 mmol, 59% yield). 1H NMR (400 MHz; D2O): 2.89 (s, 3H); 3.18-3.43 (m, 4H); 3.56-3.78 (m, 4H); 4.56 (s, 2H); 4.67 (s, 2H); 7.66 (s, 1H); MS (EI) for C10H16ClN3S: 246 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH:19]([OH:21])[CH2:18][NH:17]1)=[O:15])[CH3:12].C(=O)(O)[O-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH:19]([OH:21])[CH2:18][N:17]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CC(O)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(O)CN1c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
4-Fluoronitrobenzene (0.28 mL, 2.65 mmol), 4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (419 mg, 2.65 mmol), and sodium bicarbonate (222 mg, 2.65 mmol) were dissolved in 5 mL dry DMF and heated to 80° C. After 24 h at this temperature, the reaction was cooled and water and ethyl acetate were added. The organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography (65-75% ethyl acetate/hexanes) gave 260 mg (35% yield) of the desired product. 1H NMR (CDCl3, 500 MHz) 8.15 (d, J=9.3 Hz, 2H), 6.54 (d, J=9.3 Hz, 2H), 4.60 (m, 1H), 4.41 (d, J=9.2 Hz, 1H), 4.31 (dq, J=10.8, 7.1 Hz, 1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 3.73 (dt, J=11.0, 1.2 Hz, 1H), 3.70 (dd, J=11.0, 4.2 Hz, 1H), 2.51 (ddd, J=14.2, 9.2, 4.2 Hz, 1H), 2.35 (dd, J=14.2, 1.2 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:8])=[O:4].C1(C)C=CC(S(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[C@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11][C:12]2([O:40][CH2:39][CH2:38][O:14]2)[CH2:13]1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Reactant: OCCO
Agent: Cc1ccc([SH](=O)=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OCc1ccccc1)OCCO2)C(C)C

Procedure:
(S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate (2.45 g, 6.51 mmol) in a round bottom flask was dissolved in anhydrous toluene (200 mL) and p-toluene sulfonic acid monohydride (124 mg, 0.1 mmol) and ethylene glycol (808 mg, 13.02 mmol) were added and the mixture was refluxed for 18 hours, removing the generated byproduct water with a Dean-Stark apparatus. The crude mixture was then diluted with ethyl acetate and washed, respectively, with 10% citric acid, saturated ammonium chloride, 10% sodium carbonate and finally with brine. The organic layers were combined and dried over sodium sulfate and concentrated down on rotovap. The crude residue was then purified on normal phase column chromatography with 5% MeOH/DCM. (2.3 g, 84%)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl>C(N(CC)CC)C.O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: NCCS(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 36.7 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H, s), 8.58 (1H, s), 8.23 (1H, d), 7.77-7.88 (3H, m), 7.30-7.52 (5H, m), 7.26 (2H, s), 7.20 (1H, d), 7.08 (2H, d), 6.81 (1H, d), 5.14 (2H, s), 4.44 (2H, s), 3.34-3.60 (2H, m), 3.25-3.45 (2H,obscured by water); m/z (M+1+) 530.
Reaction SMILES: C1(C2NC(=O)C(C)NC2=O)CC1.Cl.C[O:15][C:16](=O)[CH:17]([NH:21][C:22](=[O:27])[CH:23]([NH2:26])[CH2:24][CH3:25])[CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH:17]2[NH:21][C:22](=[O:27])[CH:23]([CH2:24][CH3:25])[NH:26][C:16]2=[O:15])[CH2:20][CH2:19]1
Reactant: CCC(N)C(=O)NC(C(=O)OC)C1CC1
Agent: CC1NC(=O)C(C2CC2)NC1=O
Agent: Cl
Product: CCC1NC(=O)C(C2CC2)NC1=O

Procedure:
Following the procedure for the preparation of 3-cyclopropyl-6-methylpiperazine-2,5-dione but substituting methyl[(2-aminobutanoyl)amino](cyclopropyl)acetate hydrochloride and making non-critical variations provided the title compound as a solid: 1H NMR (DMSO-d6) δ 0.29–0.48, 0.79–1.20, 1.69, 3.20, 3.93, 8.05.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[CH:36]1([CH2:41][C:42](Cl)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:42](=[O:43])[CH2:41][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC1CCCC1

Procedure:
In 10 ml of dichloromethane are dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one and 0.2 ml of N,N-dimethylaniline and, with stirring, 0.3 ml of cyclopentylacetyl chloride is added. The mixture is stirred at room temperature (15°-25° C.) overnight and 150 ml of ethyl acetate is added. The mixture is washed with 10% H3PO4, water, 10% aqueous NaHCO3, water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off and the residue is subjected to column chromatography. Following passage of 80 ml of diisopropyl ether-n-hexane (1:10), elution is carried out with 80 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.1 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[O:40][CH3:41]>N1C=CC=CC=1>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[O:8])=[C:12]([O:40][CH3:41])[CH:13]=3)[C:25]=12
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc(C)on1
Reaction time: 5 h

Procedure:
5-methyl-3-isoxazolecarbonyl chloride (20 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was purified by preparative HPLC (Hypersil BSD C18, 5 um, 100×21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partitioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore™ high performance extraction disk cartridge (C18-SD octadecyl) to give cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide (14 mg, 38%). 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 2.53 (s, 3H), 2.76 (m, 3H), 3.37 (bm, 8H), 3.99 (s, 3H), 4.93 (m, 1H), 6.74 (s, 1H), 7.36 (m, 2H), 8.26 (m, 1H), 9.48 (s, 1H); LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+=546.4, Rt=1.82 min.
Reaction SMILES: [C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)#[N:2].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)#[N:2]
Reactant: N#C/N=C(/Nc1ccc(F)c(F)c1)Oc1ccccc1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 85 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)carbamimidate (286 mg, 1.05 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (369 mg, 277 μL, 1.57 mmol) in DMF (10.5 mL) was added at room temperature under an atmosphere of nitrogen potassium carbonate (289 mg, 2.09 mmol). The suspension was heated to 85° C. over night. Additional 2-(3-bromopropoxy)tetrahydro-2H-pyran (140 μL, 0.8 mmol) and potassium carbonate (145 mg, 1.05 mmol) were added and the reaction was heated for 5 hours to 85° C. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow viscous oil (202 mg, 46%) after column chromatography on silica gel using a gradient of heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3].[H-].[Na+].[H][H].[CH2:20](Br)[CH:21]=[C:22]([CH3:24])[CH3:23]>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3]
Reactant: [H][H]
Reactant: C=CCOc1ccc2c(c1)CCC(=O)N2
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCC(=O)N2CC=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
10.2 Grams of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 100 ml of dimethyl-formamide (DMF), then at room temperature, 2.2 g of 60% oily sodium hydride was added little by little thereto, and the reaction mixture was stirred at 25° to 40° C. until generation of hydrogen was stopped. The reaction mixture was cooled to room temperature, 9.1 g of prenyl bromide was added thereto and stirred at room temperature for 8 hours. After the reaction was completed, water was added, and the reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with water and an aqueous solution saturated with sodium chloride in this order, then thus washed extract was dried with anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and concentrated. Thus obtained oily residue was subjected to refining and separating by means of a silica gel flush column chromatography by using mixed solvent of ethyl acetate:n-hexane (1:10 to 1:2) as an eluent to obtain 10.2 g (59.7%) of 6-allyloxy-3,4-dihydro-1-prenyl-2-(1H)-quinolinone.