Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][C:46]([N:52]=[C:53]=[S:54])=[CH:47][CH:48]=3)[CH:43]=2)(=[O:41])=[O:40])=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([NH:1][C:53]([NH:52][C:46]4[CH:47]=[CH:48][C:49]5[C:44](=[CH:43][C:42]([S:39]([NH:38][C:35]6[CH:36]=[CH:37][C:28]([Cl:27])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=6)(=[O:40])=[O:41])=[CH:51][CH:50]=5)[CH:45]=4)=[S:54])=[CH:3][CH:4]=3)[CH:9]=2)(=[O:14])=[O:13])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(NC(=S)Nc4ccc5ccc(S(=O)(=O)Nc6ccc(Cl)c(C(=O)OC)c6)cc5c4)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
To 3.0 g (7.68 mmol) of compound 134 was added a solution of 4.0 g (9.24 mmol) of compound 135 in 200 mL of dichloromethane. The reaction was allowed to stir at ambient temperature for 48 hours. The fine, white solid was collected to give 5.2 g of compound 157.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14](COCC[Si](C)(C)C)[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:4]([C@H:34]([OH:36])[CH3:35])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[C:4]([C@H:34]([OH:36])[CH3:35])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2ccccc2-c2ccc(F)cc2[C@@H](C)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccc(F)cc2[C@@H](C)O)cc1
Yield: 65.9 %

Procedure:
N-{4′-Fluoro-2′-[(R)-1-hydroxyethyl]-1,1′-biphenyl-2-yl }-4-methoxy-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.28 g, 0.51 mmol) was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.76 mL, 0.76 mmol) was added. The solution was heated at reflux for six hours. The solution was concentrated in vacuo and the mixture was dissolved in ethyl acetate and washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The product was passed through a silica gel plug (5:1 hexane: ethyl acetate followed by 1:1 hexane:ethyl acetate) to yield the title compound as a solid (0.135 g, 66% ), m.p. 137-138° C. The NM spectrum of the title compound was consistent with rotamers. The peaks attributed to individual rotamers in the 1H NMR spectrum coalesced at 90° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.CN([Si](C)(C)C)C(=O)C(F)(F)F.Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[S:34][C:33]3[N:35]=[CH:36][CH:37]=[N:38][C:32]=3[NH:31][C:30]=2[CH:39]=1>C(#N)C>[N:38]1[C:32]2[NH:31][C:30]3[CH:39]=[C:26]([CH2:25][N+:1]45[CH2:8][CH2:7][C:4]([C:9]([O-:11])=[O:10])([CH2:5][CH2:6]4)[CH2:3][CH2:2]5)[CH:27]=[CH:28][C:29]=3[S:34][C:33]=2[N:35]=[CH:36][CH:37]=1
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: O=C([O-])C12CC[N+](Cc3ccc4c(c3)Nc3nccnc3S4)(CC1)CC2
Reaction time: 2 h
Yield: 14.3 %

Procedure:
0.620 g of 1-azabicyclo[2.2.2]octane-4-carboxylic acid was dissolved in 40 ml of acetonitrile. After adding 3.98 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide, the resulting mixture was stirred for 2 hours. Next, 0.998 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was added thereto and the resulting mixture was heated under reflux for 4 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in methanol/dichloromethane. After adding diethyl ether, the mixture was filtered and the residue was purified by High-porous gel chromatography (CHP20P, mfd by Mitsubishi Chemical Industries, 75-150μ) (eluted with methanol/water) to thereby give 0.21 g of the title compound as a yellow powder.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH:38]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CO.C(Cl)(Cl)Cl>[CH:38]1([N:44]2[CH2:49][CH2:48][N:47]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]4)=[O:3])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: C1CCC(N2CCNCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N1CCN(C2CCCCC2)CC1
Reaction time: 5 h
Yield: 49.8 %

Procedure:
Into 200 ml of chloroform were added 5 g of 6-(3-carboxypropoxy)carbostyril and 3.2 g DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, the reaction mixture was further stirred for 1 hour, then 3.7 g of N-cyclohexylpiperazine was added dropwise at a room temperature, and the reaction was continued for 5 hours. After the reaction was completed, the reaction mixture was washed with 1% NaOH aqueous solution and water, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=30:1) to obtain elute. The elute was concentrated and the residue was recrystallized from water-containing methanol to obtain 4 g of 6-[3-(4-cyclohexyl-1-piperazylcarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals. Melting point: 184.5°-186° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])=[CH:20][C:19]=1[Cl:30].CC(=O)OCC>CN(C=O)C>[Cl:30][C:19]1[CH:20]=[C:21]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (397 mg, 1.66 mmol) and 1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (400 mg, 1.66 mmol) in DMF (5 mL) at rt was added TEA (168 mg, 1.66 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound 5-(5-(3,4-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (180 mg; yield 24.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.83-7.60 (m, 5H), 4.45 (d, J=18.8 Hz, 1H), 4.26 (d, J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.8% at 220 nm and 97.5% at 254 nm; MS: m/z=444.3 (M+, ESI+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1.CCCCCC>[CH:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1)=[O:24]
Reactant: CC(C)[C@H]1COC(c2ccc(Br)cc2)=N1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(c2ccc(C=O)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g of (S)-2-(4-bromophenyl)-4-isopropyl-2-oxazoline in 20 ml of absolute tetrahydrofuran is treated drop-wise with 5 ml of 1.6M butyllithium in hexane at -78° C. and while gassing with nitrogen, stirred at this temperature for 2 hours, then treated dropwise with 2 ml of absolute N,N-dimethyl-formamide and then warmed slowly to room temperature. The reaction mixture is poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases are washed twice with 100 ml of saturated sodium chloride solution each time, dried over magnesium sulphate, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) yields 0.8 g of pure (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.07, 6.82, 5.12, 4.41, 2.82, 2.56, 2.15-1.71, 1.68-1.40, 1.28, 0.92; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1123.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=O)C>>[CH3:15][O:9][C:8]([CH2:7][C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Product: COC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-cyclohexanediacetic acid (5.0 g) in acetic anhydride (8.0 mL) was stirred under reflux for 5 hours. The solution was then concentrated under reduced pressure and distilled with toluene azeotropically. To a solution of the resulting residue in methanol (15.2 mL) was added boron trifluoride diethyl ether complex (1.58 mL) at room temperature. The solution was stirred at room temperature for 2 hours. Saturated aqueous sodium carbonate solution was added to the solution and it was washed with diethyl ether. The aqueous layer was neutralized by addition of conc. hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (4.21 g).
Reaction SMILES: [O:1]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[S:14][C:15]([Sn](CCCC)(CCCC)CCCC)=[CH:16][N:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.Br[C:34]1[S:38][C:37]([C:39](=[O:41])[CH3:40])=[CH:36][CH:35]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:2]([O:1][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[S:14][C:15]([C:34]3[S:38][C:37]([C:39](=[O:41])[CH3:40])=[CH:36][CH:35]=3)=[CH:16][N:17]=2)=[CH:31][CH:32]=1)([CH3:3])[CH3:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(Oc3ccccc3)cc2)s1
Reactant: CC(=O)c1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 60 °C
Yield: 84.8 %

Procedure:
To a degassed solution of Example 2A (550 mg, 1.05 mmol) in N,N-dimethyl formamide (10 mL) at room temperature, was added 1-(5-bromothiophen-2-yl)ethanone (269 mg, 1.31 mmol) followed by dichlorobis(triphenylphosphine)palladium(II) (45 mg, 0.064 mmol). The reaction mixture was heated at 60° C. overnight. The solvent was evaporated under vacuum and the product was purified via silica gel column chromatography using a gradient of 15 to 35% ethyl acetate in hexane to give the desired compound (320 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (d, J=4.04 Hz, 1H) 7.43 (s, 1H) 7.15-7.24 (m, 2H) 7.02 (d, J=4.04 Hz, 1H) 6.88-6.97 (m, 2H) 4.44-4.62 (heptet, J=5.88 Hz, 1H) 2.54 (s, 3H) 1.36 (d, J=5.88 Hz, 6H). MS (ESI) m/z 360 (M+1)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1
Reactant: CC(=O)OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole (1556 g, 2.23 mol), 2N-aqueous sodium hydroxide solution (2.4 L, 4.8 mol) and activated carbon (47 g) were added to methanol (4.7 L), and the mixture was refluxed under stirring for 1 hour. The activated carbon and the insoluble material were removed by filtration under pressurization. The residue was washed with methanol/water (2:1) (470 ml). The washing solution was combined with the filtrate and the mixture was refluxed. Water (3.3 L) was added at the same temperature. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (4.7 L) and dried under reduced pressure to give 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (568.5 g, 2.11 mol, yield 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N+:13]2[O-])=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccc(NC)nc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a −70° C. solution of 7-(ethoxycarbonyl)quinoline 1-oxide (1.67 g, 7.70 mmol) in dichloromethane (80 mL) was added trifluoromethanesulfonic anhydride (1.43 mL, 8.47 mmol) dropwise, under a nitrogen atmosphere. The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (21 mL, 42 mmol, 2.0 M) was added dropwise at −70° C. The mixture was stirred for 5 minutes and then the reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (720 mg, 41%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.42 (s, 1 H), 7.84-7.82 (m, 2 H), 7.63-7.61 (m, 1 H), 6.72-6.70 (m, 1 H), 4.92 (br. s., 1 H), 4.44-4.38 (m, 2 H), 3.12-3.11 (m, 3 H), 1.44-1.40 (m, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)C.C(OCC)(=O)C.[ClH:26]>>[ClH:26].[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (6.0 g) in concentrated hydrochloric acid (10 ml) was heated at 100° C. for 8 hours and then evaporated to give an oil which solidified on trituration with ethyl acetate. The solid was crystallised twice from aqueous acetonitrile to give 4-(1-imidazolylmethyl)phenoxyacetic acid hydrochloride (4.84 g), m.p. 107°-110° C. Found: C, 50.24, H, 5.31, N, 9.83. C12H12N2O3.HCl.H2O requires: C, 50.28, H, 5.23, N, 9.77%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[CH:35]=[C:36]([C:43]([OH:45])=O)[S:37][C:38]=2[C:39]([F:42])([F:41])[F:40])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:43]([C:36]3[S:37][C:38]([C:39]([F:40])([F:41])[F:42])=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:35]=3)=[O:45])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([CH3:8])[O:10][CH3:11])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Pyridine (4.40 mL, 54.2 mmol) was added dropwise to N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) dissolved in CH2Cl2 (100 mL) at RT. The reaction mixture was stirred for 30 min, and 4-bromobenzoyl chloride (5.95 g, 27.1 mmol) dissolved in CH2Cl2 (50 mL) was added dropwise. The mixture was stirred for 24 h and the volatiles were removed under reduced pressure. Water (200 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed successively with 5% aqueous HCl (200 mL), 5% aqueous NaHCO3 (200 mL), water (200 mL), and brine (200 mL). The mixture was dried over MgSO4 and concentrated to afford 6.35 g (74%) of 80 as a colorless oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 3.35 (s, 3H), 3.53 (s, 3H), 7.54 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH2:35][CH:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH2:35][CH:36]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and compound (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (322 mg, 1.29 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 51 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][N:18]([CH3:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15]1)=[O:13])[CH3:10].Cl>ClCCl>[C:1]([C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:19][N:18]([CH3:20])[C:17]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CN(C)c2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1CN(C)c2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 mmol (0.1 ml) of acetyl chloride and 4 mmol (545 mg) of aluminum chloride are added to a solution of 1.6 mmol (355 mg) of 2-ethoxycarbonyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 18 ml of dichloromethane at -10° C. The reaction mixture is stirred at room temperature for 1 hour before being hydrolysed by a cooled aqueous solution of 2 M hydrochloric acid. The mixture is extracted with dichloromethane and the organic phase is washed with a saturated solution of NaHCO3, dried over magnesium sulphate, concentrated and purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (7/3) as eluant to yield the expected product.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.O>[CH3:6][C:7]1[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: Cc1c(C=O)cccc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(CC(C#N)C#N)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a mixture of malononitrile (2.352 g, 35.6 mmol) in 95% Ethanol (50 mL) was added 2-methyl-3-(trifluoromethyl)benzaldehyde (6.7 g, 35.6 mmol). The reaction was stirred at rt for 18 h. Additional EtOH (20 mL) was added and the mixture was stirred for 20 minutes and cooled to 0° C. in an ice bath. Sodium borohydride (0.364 g, 9.61 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 77%). To a mixture of {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 27.3 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.68 mL, 54.6 mmol). The reaction mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (eluting with MeOH/DCM: 0˜10%) to give the product (3.5 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.47 (s, 3H) 3.69 (s, 2H) 7.11-7.37 (m, 2H) 7.51 (d, 1H); LC/MS: MS (ES+) m/e 271.2 [M+H]+.