Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([C:11]([O:13][CH3:14])=[O:12])[CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(S(C)(=O)=O)c2c1
Reaction time: 0.5 h

Procedure:
A solution of NaN(TMS)2 (1 M) in THF (11 mmol, 11 ml) was added dropwise to a -78° C solution of 6-carbomethoxyindole (876 mg, 5 mmol, prepared according to the procedure of Batcho, et al., Org. Synth. Coll. 7:34) in dry THF (10 ml). After stirring for 30 min, MeSO2Cl (1.47 mL) (Me=CH3) was added. The mixture was allowed to stir overnight then poured onto 100 ml of water. The mixture was extracted with CH2Cl2 (2×75 ml). The extracts were washed with brine, dried (Na2SO4), and the solvent was removed by rotary evaporation to give a light brown solid. The solid was purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to give 510 mg of N-methanesulfonyl-6-carbomethoxyindole.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(CN)O>CCCCCC.C1COCC1>[CH:16]([C:11]1([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([CH:6]=2)[OH:9])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Solvent: NCCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC=CC1(c2cc(O)cc(O)c2)CCCC1
Temperature: 27 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
To a solution of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane (1 equiv.) in dry hexane (0.05M) at 0° C. under an argon atmosphere was added 9-iodo-9-BBN (2.3 equiv., 1M solution in hexane). The mixture was stirred at the same temperature for 3.5 h and then the reaction temperature was raised to 27° C. Stirring was continued at that temperature until completion of the reaction. The volatiles were removed in vacuo, the residual oil was dissolved in diethyl ether, and a solution of ethanolamine (2.4 equiv.) in THF (1.4 M) was added causing spontaneous precipitation of the 9-BBN.ethanolamine adduct. The suspension was stirred for 2.5 h, the white precipitate was filtered off and the filtrate was evaporated under reduced pressure to give an oil. Purification by flash column chromatography on silica gel using 40% diethyl ether—petroleum ether as eluent afforded the title compound in 82% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH:11]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)C.[K+].[Br-]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:11][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:15][CH:16]=1
Reactant: COc1ccc(SC(C)Cl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(SCn2cc(Cl)cnc2=O)cc1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 1-chloroethylthio-4-methoxy benzene [see Preparation 1](10 mmol) in a manner similar to that described in Example 2. The reaction time was 2 h. Yield: 2.46 g (87%) of the N- and O-isomers in the ratio 7:5. The N-isomer was isolated by its lower solubility in methanol; m.p. 140° C. (MeOH). (Found C41.23; H4.00 Calc. for C12H11ClN2O2S: C50.97; H3.93) 1H NMR (DMSO-d6) 3.77 (OMe), 5.12 (CH2), 6.8-7.4 (Ph), 7.90 and 8.56 (H-4 and H-6, respectively, J 4 Hz). IR (KBr): 1660 cm-1 (CO. MS (70 eV, m/z % rel. int.)]: 282/284 (5/2,M), 143/145 (100/33).
Reaction SMILES: [OH:1][C:2]1([C:14]([F:17])([F:16])[F:15])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:18]([C:22](O)=[O:23])([F:21])([F:20])[F:19]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:22]([O:1][C:2]1([C:14]([F:15])([F:16])[F:17])[CH2:6][CH2:5][NH:4][CH2:3]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OC1(C(F)(F)F)CCNC1)C(F)(F)F

Procedure:
tert-Butyl 3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (310 mg, 1.21 mmol) was treated with 20% CF3CO2H in CH2Cl2 for 4 h at room temperature. The volatiles were removed in vacuo to give the subtitled compound (330 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19](=[O:20])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
To a mixture of 4-Bromo-benzylamine (2.00 g), Boc-L-proline (2.01 g), and 4-methylmorpholine (3.26 mL) in DMF (40 mL) was added HATU (3.48 g). Reaction mixture was stirred for 45 minutes, then concentrated, diluted with dichloromethane and washed with 10:1 H2O/saturated sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-(4-Bromo-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g): LCMS-ESI+: calc'd for C17H24BrN2NaO3: 405.29 (M+Na+); Found: 405.0 (M+Na+).
Reaction SMILES: Br.[Br-].[NH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C([Li])CCC.[Cl:36][C:37]1[CH:51]=[CH:50][C:40]2[CH:41]=[CH:42][N:43]3[CH:49]=[CH:48][CH:47]=[C:44]3[C:45](=O)[C:39]=2[CH:38]=1>CCCCCCC.O>[Cl:36][C:37]1[CH:51]=[CH:50][C:40]2[CH:41]=[CH:42][N:43]3[CH:49]=[CH:48][CH:47]=[C:44]3[C:45](=[CH:6][CH2:5][CH2:4][NH2:3])[C:39]=2[CH:38]=1
Reactant: O=c1c2cc(Cl)ccc2ccn2cccc12
Reactant: NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: NCCC=C1c2cc(Cl)ccc2C=Cn2cccc21
Reaction time: 0.5 h

Procedure:
Anhydrous 3-aminopropyltriphenylphosphonium bromide hydrobromide, 9.0 g., is suspended in 30 ml. dry tetrahydrofuran and 0.038 moles of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 3.44 g. of 9-chloro-11H-pyrrolo[2,1-b][3]benzazepin-11-one is added to the deep red solution and the reaction is maintained at reflux for 10 hours. Water, 500 ml., is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 100 ml. benzene is added. After stirring, the benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with 3 × 50 ml. portions of benzene. The benzene extracts are washed, then dried with anhydrous sodium sulfate and concentrated in a vacuum leaving a residue of 9-chloro-11-(3-aminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: C(Cl)(=O)C.[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([CH3:25])([N+:22]([O-])=O)[CH3:21]>CO.[Zn]>[NH2:22][C:20]([CH3:25])([CH3:21])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:29])[F:30])=[CH:13][C:12]=1[C:7]1[N:8]([CH3:11])[N:9]=[CH:10][C:6]=1[Br:5]
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)C(F)(F)F)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)Cl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C(F)(F)F)ccc1OCC(C)(C)N
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Acetylchloride (1.36 mL, 19.1 mmol) was added slowly to a well-stirred solution of N-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)-2,2,2-trifluoroacetamide (889 mg, 1.91 mmol) in methanol (10 mL). Zinc dust (1.25 g, 19.1 mmol) was added in small portions, and the mixture was stirred at 55° C. After 2 h, the solvent was removed under reduced pressure, and residue was suspended in 1M HCl (10 mL) and covered with ethyl acetate. The mixture was cooled on an ice bath, and ammonium hydroxide was added until all precipitate dissolved. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with sodium sulfate, filtered and evaporated to dryness to yield N-(4-(2-amino-2-methylpropoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl)-2,2,2-trifluoroacetamide as a white powder (693 mg, 1.59 mmol, 83%). LCMS m/z (%)=437.3 (M+H 81Br 9.0%), 435.2 (M+H 79Br 14.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COC(=O)[C:56](Cl)([F:58])[F:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH:56]([F:58])[F:57])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(OC(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 75 °C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg), cesium carbonate (55 mg) and 2-chloro-2,2-difluoroacetic acid methyl ester (44 mg) are dissolved in N,N-dimethylformamide (1 ml) and stirred at 75° C. for 17 hours. The reaction solution is cooled to room temperature, and thereto are added an aqueous citric acid solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-difluoromethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (101 mg). MS (m/z): 705 [M+H]+
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH2:36]([Mg]Br)[CH3:37].O1CC[CH2:42][CH2:41]1>>[C:29]1([S:26]([N:25]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])([CH2:36][CH3:37])[CH2:41][CH3:42])=[CH:5][CH:6]=2)=[CH:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)(=[O:27])=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-benzoic acid methyl ester (330 mg, 0.68 mmol) in dry tetrahydrofuran (20 mL) at 0° C. was added an ethylmagnesium bromide solution in tetrahydrofuran (3.0 M, 1.14 mL, 3.4 mmol) dropwise. After stirring at 0° C. for 1 h, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 3-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-pentan-3-ol (220 mg, 63%) as a white solid: LC/MS m/e calcd for C31H34N2O3S [M+H]+ 515.69, observed 515.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][O:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11])(=[O:6])=[O:5].[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:48](OCC)(=[O:50])C>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]([O:9][CH2:8][CH2:7][S:4]([CH2:3][CH2:2][O:1][C:48](=[O:50])[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:6])=[O:5])=[O:11])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(NCCCN)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OCCS(=O)(=O)CCO)Oc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C(NCCCNC(=O)OCCS(=O)(=O)CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 18 (0.68 g, 2.13 mmol) and (3-aminopropyl)[(4-methoxyphenyl)diphenylmethyl]amine (0.89 g, 2.56 mmol) was stirred at 40° C. for 30 min. p-nitrophenyl chlorofornate (0.62 g, 3.08 mmol) was added and stirring was continued for an additional 2 h. The solution was diluted with ethyl acetate (350 ml), washed with water (300 ml) and then dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 40-100% ethyl acetate in hexane. The pure product fractions were evaporated affording a foam: 351 mg of 20 (35%) yield; 1H NMR (DMSO-d6) δ 8.32 (2H, d, J=9.2 Hz, aromatic), 7.56 (1H, d, J=9.2 Hz, aromatic), 7.37 (4H, d, J=7.4 Hz, aromatic), 7.29-7.15 (8H, m, aromatic), 6.83 (2H, d, J=8.9 Hz, aromatic), 4.61 (2H, t, J=5.5 Hz, CH2), 4.29 (2H, t, J=6.0 Hz, CH2), 3.71 (3H, s, methoxy), 3.67 (2H, t, J=5.7 Hz, CH2), 3.51 (2H, t, J=5.8 Hz, CH2), 3.07 (2H, m, CH2), 1.93 (2H, m, CH2), 1.59 (2H, m, CH2).
Reaction SMILES: NC1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])CC=2)C=1Br.[Cl:35][C:36]1[C:37]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[N:38][C:39]2[N:40]([N:43]=[CH:44][C:45]=2[C:46]2[CH:47]=[N:48][C:49]3[C:54]([CH:55]=2)=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:41]=1[NH2:42].BrC1C(C2CCNCC=2)=NC2N(N=CC=2C2C=NC3C(C=2)=CC=CC=3)C=1N>>[NH2:42][C:41]1[N:40]2[N:43]=[CH:44][C:45]([C:46]3[CH:47]=[N:48][C:49]4[C:54]([CH:55]=3)=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:39]2[N:38]=[C:37]([N:56]2[CH2:57][CH2:58][N:59]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:60][CH2:61]2)[C:36]=1[Cl:35]
Reactant: Nc1c(Br)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: Nc1c(Cl)c(N2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Nc1c(Cl)c(N2CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
(4-(7-Amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)(thiophen-2-yl)methanone was synthesized in a manner similar to the synthesis of (4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone, but with 6-chloro-5-(piperazin-1-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. The reaction was purified via reverse-phase preparatory HPLC to yield (4-(7-amino-6-chloro-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)(thiophen-2-yl)methanone as yellow solid. (M+H=490.19, retention time=3.75 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:40]=2)[CH2:14][N:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
(1-{5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-phenyl-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (90 mg) was dissolved in m-xylenes (3 mL) and heated at 135° C. Solid ammonium acetate (100 mg, 1.29 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product {1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40.2 mg, 0.0764 mmol): LCMS-ESI+: calc'd for C25H28BrN5O3: 526.4 (M+). Found: 526.4/528.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:12]([O:14]CC)=O)=[O:10].S(=O)(=O)(O)[OH:30].[OH-].[Na+]>C(O)C>[CH2:17]([C:11]1[C:12](=[O:14])[C:4]2[C:3]([C:8](=[O:30])[C:9]=1[OH:10])=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCC(C(=O)Cc1ccccc1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2c(C)cccc2C1=O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
Four parts of crude ethyl 2-[(2-methylphenyl)acetyl]tetradecanoate obtained in Example 3 was combined with 12 parts of cold concentrated sulfuric acid and stirred at room temperature for 66 hours. The mixture was poured into ice water and made slightly basic by the addition of 50% aqueous sodium hydroxide. Enough ethanol was added to dissolve the organic matter and air was then bubbled through the solution for 3 hours. The resulting solution was extracted with 100 parts petroleum ether (twice), acidified with hydrochloric acid and re-extracted with diethylether. The ether extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was taken up in acetonitrile and filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum ether to give 0.2 g of 2-dodecyl-3-hydroxy-5-methyl-1,4-naphthoquinone, m.p. 92°-93° C.
Reaction SMILES: C(OC([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:7]=1)=O)C.[CH3:22][Mg]Br.C([O:27][CH2:28][CH3:29])C.S(=O)(=O)(O)O>C(OCC)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:7]=[C:6]([C:28]([OH:27])([CH3:29])[CH3:22])[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Product: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 20 °C
Reaction time: 2 h
Yield: 63250.6 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid ethyl ester (150 mg, 0.5 mmol) in diethyl ether (3 mL) was added at 0° C. 3 M methylmagnesium bromide/diethyl ether (0.37 mL, 1.1 mmol). The mixture was stirred at 20° C. for 2 h and then poured into 10% aqueous sulfuric acid. The mixture was extracted with AcOEt and the organic layer was washed with H2O, dried (Na2SO4) and evaporated in vacuo. The residue was triturated with cyclohexane to give 2-[5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (91 g, 63%). Off-white solid. MS (ISP) 288.1 [(M+H)+]; mp 113–115° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C.O1CCOCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1ccc2nnc(Cl)n2n1

Procedure:
The 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine was prepared according to the method described in Example 16b, but using 1 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 1.71 g of a solution at 21% of sodium ethoxide in ethanol and 30 cm3 of dioxane, after reaction at reflux for 5.5 h. 874 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a whitish powder, the characteristics are as follows:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([CH2:17][N:18]=[C:19]=[O:20])=[CH:15][CH:14]=1.C([O:25]CC)C>>[CH2:1]([N:8]1[C:9](=[O:25])[S:10][N:18]([CH2:17][C:16]2[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:19]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: CCOCC
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(Cn2sc(=O)n(Cc3ccccc3)c2=O)cc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), p-metoxybenzyl-isocyanate (6.5 mmol, 0.92 mL) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: solvent evaporation. Purification: silica gel column chromatography (AcOEt/hexane, 1:4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:9]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3,4-dichloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 220–223° C.