Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[F:48][C:49]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50]1.Cl>CN(C=O)C.O>[F:48][C:49]1([F:54])[CH2:53][CH2:52][N:51]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([B:1]([OH:2])[OH:3])=[CH:5][C:6]=2[F:13])=[O:10])[CH2:50]1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(B(O)O)cc1F)N1CCC(F)(F)C1
Yield: 52.6 %

Procedure:
A solution of 4-borono-2-fluorobenzoic acid (1.00 g, 5.44 mmol), N,N-diisopropylethylamine (2.85 mL, 16.31 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.163 g, 5.69 mmol) and 3,3-difluoropyrrolidine hydrochloride (1.00 g, 6.97 mmol) in DMF (6 mL) was stirred at room temperature for 22 h. Following addition of 1 N HCl (16 mL), the mixture was extracted with ethyl acetate (40 mL). HPLC analysis showed that the aqueous phase still contained product. The aqueous phase was neutralized to pH 7 with solid NaOH and K2CO3 and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to give a thick brown oil. This residue was treated with equal volume of water. The white crystalline solid formed from the mixture was collected by filtration and washed with small amount of ether to give the desired product (0.7811 g). The filtrate was purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-50% solvent B gradient) to give additional product (0.5632 g). The combined yield of the product was 1.344 g (91% yield). MS (ES+) m/z: 274 (M+H); LC retention time: 2.68 min (analytical HPLC Method A).
Reaction SMILES: S([O-])(O)(=O)=O.[K+].C([O:9][C:10]1[O:11][CH2:12][C:13](=O)[C:14]=1C(OCC)=O)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][CH2:30][CH:31]([F:33])[F:32])=[CH:24][CH:23]=1>C(#N)CCC>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:30][CH:31]([F:33])[F:32])[C:13]2[CH2:12][O:11][C:10](=[O:9])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Reactant: FC(F)CNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 93 %

Procedure:
31.2 g of potassium hydrogensulphate are added at room temperature to a suspension of 46 g of ethyl 2-ethoxy-4,5-dihydro-4-oxofuran-3-carboxylate and 39.3 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 705 ml of butyronitrile. The mixture was heated to reflux for 5 hours. Subsequently, it was cooled to room temperature and washed with 890 ml of water. The solvent was removed under reduced pressure. This gave 51 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (this corresponds to a 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][CH3:16])=[C:10]([NH:17][CH2:18][C:19]([OH:21])=O)[CH:9]=1.[CH3:22][CH2:23]N(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N:51]1([C:57]([O:59]C(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][CH3:16])=[C:10]([NH:17][CH2:18][C:19]([N:54]2[CH2:53][CH2:52][N:51]([C:57](=[O:59])[CH:22]=[CH2:23])[CH2:56][CH2:55]2)=[O:21])[CH:9]=1
Reactant: CCN(CC)CC
Reactant: CCc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2CC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
2-((2′,6-dichloro-4-ethyl-[1,1′-biphenyl]-3-yl)amino)acetic acid (150 mg, 0.466 mmol) and Et3N (235 mg, 2.33 mmol) in DMF (5 mL) at 0° C., EDCI.HCl (178 mg, 0.932 mmol) and HOBt (126 mg, 0.932 mmol) were added and the resulting mixture was stirred at 0° C. for 30 min. To this mixture, tert-butyl piperazine-1-carboxylate (123 mg, 0.698 mmol) was added and then stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=50:1) to afford the desired product (45 mg, 21.7% yield). 1H NMR (400 MHz, DMSO-d6) δ: 7.56-7.54 (m, 1H), 7.43-7.41 (m, 2H), 7.32-7.30 (m, 1H), 7.14 (s, 1H), 6.81 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.13 (dd, J=2.4, 16.8 Hz, 1H), 5.71 (dd, J=2.0, 10.4 Hz, 1H), 5.25 (bs., 1H), 3.96 (d, J=4.4 Hz, 2H), 3.56-3.52 (m, 8H), 2.54 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 444.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[O:13](C(C(F)(F)F)=O)[C:14]([C:16]([F:19])([F:18])[F:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][NH:10][C:14](=[O:13])[C:16]([F:19])([F:18])[F:17])=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C(=O)NNC(=O)C(F)(F)F)cc1

Procedure:
Synthesis and isolation were same as I-benzoyl-2-trifluoroacetylhydrazine, using 1.8 g (10.8 mmol) of 4-methoxybenzoylhydrazine and 2.0 g (9.5 mmol) of (CF3CO)2O. Yield was 2.4 g (85%). MS (EI, m/e) calcd for C10H9F3N2O3 262, found 262 (M+, 8.0); mp 147-148° C.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[CH3:13][C:14]1[CH:19]=CC(N)=[CH:16][C:15]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1.[CH:30]1(N)CC1>C1COCC1>[CH:9]1([NH:8][C:6]([NH:3][C:2]2[CH:1]=[CH:13][C:14]([CH3:19])=[C:15]([B:21]3[O:22][C:23]([CH3:29])([CH3:28])[C:24]([CH3:26])([CH3:27])[O:25]3)[CH:16]=2)=[O:7])[CH2:10][CH2:30]1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 50 °C

Procedure:
A mixture of CDI (254 mg, 1.57 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (332 mg, 1.42 mmol) under nitrogen was treated with THF (10 mL) and heated to 50° C. for 45 min. The solution was then cooled to RT and treated with cyclopropylamine (113 μl, 1.64 mmol) and again heated to 40° C. for 11 h. The volatiles were then removed in vacuo (rotary evaporator) and the crude solid was purified on the ISCO 40 g column (15-70% EtOAc in hexanes) affording the title compound as a white amorphous solid. MS (ESI, pos.ion) m/z: 317.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[S:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:26][O:27][CH3:28])[C:23]([O-:25])=[O:24].[C:29](=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][N:9]=[C:10]([S:13][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:26][O:27][CH3:28])[C:23]([O:25][CH3:29])=[O:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=S)NOCc1ccccc1
Reactant: COC=C(C(=O)[O-])c1ccccc1CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=NOCc1ccccc1)SCc1ccccc1C(=COC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of N-benzyloxythiopropionamide (1.2 g, 6 mmol) prepared as above, 2-bromomethylphenyl-3-methoxypropenoate (1.7 g, 6 mmol) and potassium carbonate (1 g, 7 mmol) was stirred overnight at room temperature. The reaction mixture was filtered, the solvent was removed by evaporation, and the residue was purified with silica gel chromatography to obtain methyl 2-[2-{(1-benzyloxyiminopropyl)thiomethyl}phenyl]-3-methoxypropenoate (1.6 g, yield: 67%). The proton NMR Spectra: 1.12 t (3H); 2.36 q (2H); 3.67 s (3H); 3.77 s (3H); 3.95 s (2H); 5.12 s (2H); 7.15-7.50 m (9H); 7.59 s (1H) (Solvent: CDCl3).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[CH:3]1.Br[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])=[CH:3]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccccc2[N+](=O)[O-])C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A mixture of 9.5 g (20.2 mmol) of 2-(10,10-dimethyl-10H-indeno[2,1-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4.3 g (21 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenyl phosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 1000 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 5.5 g (58%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.[Br-:19].[Br-:20].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O:40]1CCOCC1>>[Br:19][C:8]1([Br:20])[C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1=[O:40]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1ccc2cnc(Cl)cc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Product: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cnc(Cl)cc21
Reaction time: 2 h

Procedure:
6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (1.53 g, 5.4 mmol) was added as a solution in 1,4-dioxane (10 mL) to a mixture of pyridinium tribromide (8.7 g, 27 mmol) in 1,4-dioxane (10 mL) over 30 min. Following complete addition, the reaction mixture was stirred 2 h and was then quenched with water (25 mL). The resulting mixture was stirred 20 min and was then diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organics were washed with water (2×) and brine (2×), dried over Na2SO4, filtered, and concentrated to afford crude 3,3-dibromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H18Br2ClN2O2Si: 454.92; found: 454.48.
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[NH:15][C:14]=2[CH:23]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27].O>CN(C)C=O>[C:26]([N:15]1[C:14]2[CH:23]=[C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)Nc1nccnc1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2cc(CO[Si](C)(C)C(C)(C)C)ccc2Sc2nccnc21
Reaction time: 0.17 h

Procedure:
To a solution of 4.0 g of 8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in 50 ml of N,N-dimethylformamide was added 0.73 g of sodium hydride (60%) and the resulting mixture was stirred for 10 minutes. After adding 1.4 ml of acetyl chloride thereto, the resulting mixture was reacted at room temperature for 10 minutes. After adding water followed by extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting with ethyl acetate/hexane) to thereby give 2.5 g of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:41])[CH2:39][CH3:40].[Na]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:41])[CH2:39][CH3:40])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Na]
Product: CCC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using propanoyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1H2O Calc. C 66.61; H 5.42; N 4.71 Found C 66.87; H 5.45; N 4.69.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[O:20]([CH2:27][CH2:28][NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:29][CH2:28][CH2:27][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCOc1ccccc1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: Clc1nc(SCc2ccccc2)nc2nc(NCCOc3ccccc3)sc12

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-phenoxyethylamine.
Reaction SMILES: [F:1][C:2]([C:10]([F:13])([F:12])[F:11])([CH:7](O)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.FC(C(F)(F)F)(C(OS(C(F)(F)F)(=O)=O)C)C(OC)=O.N12CCCN=C1CCCCC2>ClCCl.N1C=CC=CC=1>[F:1][C:2]([C:10]([F:11])([F:13])[F:12])([CH:7]=[CH2:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(C(C)O)C(F)(F)F
Agent: COC(=O)C(F)(C(C)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC(F)(C(=O)OC)C(F)(F)F
Reaction time: 2 h

Procedure:
Methyl 2-fluoro-2-trifluoromethyl-3-hydroxybutanoate (1 g) and pyridine (440 μl) in dichloromethane (5 ml) were stirred at -10° C. under nitrogen. Trifluoromethanesulphonic anhydride (900 μl) in dichloromethane (5 ml) was added dropwise and the resulting mixture stirred for 2 hours. The solution of methyl 2-fluoro-2-trifluoromethyl-3-trifluoromethylsulphonyloxybutanoate prepared in Step 1 was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 ml) and heated under reflux for 1 hour. Further DBU (1.5 ml) was added and the mixture left to stand at room temperature overnight. The red solution was washed with 5% aqueous HCl, saturated aqueous sodium bicarbonate (twice), dried (MgSO4) and concentrated at atmospheric pressure to give a red oil which was distilled using a Kugelrohr apparatus. The fraction distilling at 50° C. (air bath temperature) and at 100 mmHg was shown by NMR to be the desired product; 1H NMR (270 MHz; CDCl3) δ 3.92 (3H,s), 5.65(1H,dd), 5.81(1H,d), 6.08(1H,ddd) ppm. ##STR1##
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3]O.N1C=CC=CC=1.P(Br)(Br)[Br:28].O>CCOCC>[Br:28][CH2:3][C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH2:1]
Reactant: C=C(CO)CCCCCCCCCCCCCCCC
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(CBr)CCCCCCCCCCCCCCCC
Temperature: -15 °C

Procedure:
A mixture of 20 g of 2-methylene-1-octadecanol, 150 ml of ether and 12.6 ml of pyridine is cooled to -15° C. in an ice-methanol bath. A solution of 7.3 ml of phosphorous tribromide in 50 ml of ether is added slowly over 1 hour, and the mixture is allowed to warm to room temperature overnight. The mixture is recooled to 0° C., 1.9 ml of water added and then allowed to warm to room temperature over 6 hours. The mixture is washed, filtered and evaporated, to give 19.2 g of the desired compound as a clear oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13]Br>>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: Fc1ccccc1CCBr
Product: CC(CCc1ccccc1F)c1ccncc1
Yield: 34.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.90 g (9.35 mmol) of 2-fluorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified, to obtain 0.74 g of desired compound (yield: 39.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[CH:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1.C(Cl)Cl.CO>[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N4CCCC4)nn3C)nc2n1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.1 %

Procedure:
A mixture of 5,7-dimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine (65 mg, 200 μmol, Eq: 1.00) and palladium on carbon 10% (42.6 mg, 40.1 μmol, Eq: 0.2) in methanol (10.0 ml) was stirred for 14 hours at 25° C. under hydrogen atmosphere. TLC (CH2Cl2/MeOH 19:1/UV 254 nm) showed complete reaction (spot to spot). palladium was filtered off and the filtrate was evaporated and dried under high vacuum to give 5,7-Dimethyl-2-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine (34 mg, 52%) as viscous oil
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)cc1

Procedure:
N-Bromosuccinimide (1.51 g, 8.509 mmol) was added to a solution of 1-methyl-4-nitrobenzene (1.2 g, 7.735 mmol) in carbon tetrachloride. 70% benzoyl peroxide (cat. 120 mg) was added to the mixture at room temperature. The mixture was refluxed. After 24 h the mixture was extracted with ethyl acetate, dried over magnesium sulfate. Evaporation of the ethyl acetate and purification by column chromatography yielded 1-(bromomethyl)-4-nitrobenzene.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:20][C:19]1=[O:30])[CH3:17])=[O:5])[CH3:2].CI.[C:35](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:35])[CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:20][C:19]1=[O:30])[CH3:17])=[O:5])[CH3:32]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cn(C)c12
Yield: 29.1 %

Procedure:
A solution of 3-{(2 R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]propyl}-1H-indole-7-carboxylic acid diethylamide (10 mg, 0.022 mmol), methyl iodide (21 μL, 0.33 mmol), potassium carbonate (90 mg, 0.66 mmol) in acetone (2 mL) is refluxed for 24 hours. After cooling, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by preparative TLC (silica gel, 0.5 mm, 20×20 cm, methanol/chloroform=1/30) to give 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg). A solution of 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg, 0.0064 mmol) and potassium hydroxide (0.6 g) in water (1 mL) and ethanol (1 mL) is stirred at 70° C. for 7 hours. After cooling, ethanol is removed by distillation, and water is added thereto. The mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (60, 2 g, a saturated ammonia solution in chloroform) to give 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (2 mg, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][NH:10][CH2:11][C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:24](=[O:26])[N:10]([CH2:11][C:12]([F:14])([F:15])[F:13])[CH2:9][C:3]=12
Reactant: Nc1ncnc(Cl)c1CNCC(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Combine 6-chloro-5-((2,2,2-trifluoroethylamino)methyl)pyrimidin-4-amine (9.57 g, 39.78 mmol), triethylamine (5.50 mL, 2.0 eq), and dichloromethane (795 mL). Cool to 0° C. under nitrogen. Add a solution of triphosgene (11.85 g, 1.0 eq) in dichloromethane (228 mL). Stir at 0° C. for 30 min, and allow to warm to room temperature. Heat the reaction mixture to 40° C. overnight. Add aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 9:1 dichloromethane:methanol, to give the title compound (4.50 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.41 (s, 1H), 4.20 (m, 2H), 3.25 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:22](Br)([CH3:24])[CH3:23]>CN(C=O)C>[CH:22]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1)([CH3:24])[CH3:23]
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To a solution of 1-(piperidin-4-yl)-indole (0.5 g, 2.5 mmol) in dry DMF (3 m) was added anhydrous potassium carbonate (360 mg, 2.6 mmol). After stirring for 15 minutes at ambient temperature, i-propyl bromide (0.84 mL, 9 mmol) was added. The reaction mixture was refluxed for 2 days with stirring, quenched with water, extracted with ethyl acetate (2×), dried, and evaporated. The remaining residue was chromatographed on silica gel eluting with a toluene/acetone gradient (90:10 to 70:30). Evaporation of the eluting solvent gave the title compound as an oil. (220 mg, 36% yield).