Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([OH:12])=O)(=[O:3])[CH3:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([N:65]1[CH2:66][C@@H:67]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@H:63]([N:62]([CH3:74])[C:60](=[O:61])[C:59]([C:51]2[CH:50]=[C:49]([C:48]([F:78])([F:47])[F:77])[CH:54]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:52]=2)([CH3:76])[CH3:75])[CH2:64]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](O)C[C@H]1C(=O)N1C[C@@H](N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Reaction time: 48 h
Yield: 29 %

Procedure:
To a stirred solution of (2S,4R)-1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (commercially available) (7.5 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 7.6 mg (29%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:17]=[N:18][CH:19]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: O=Cc1cncc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(c2cccs2)=NC1=Cc1cncc(F)c1
Temperature: 90 °C
Yield: 68.1 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-fluoro-3-pyridinecarboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[N:9]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.35 g), 1-(bromomethyl)-4-fluorobenzene (0.18 mL) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.057 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.36 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:5][CH:6]=[CH:7][CH:8]=1.Br[C:23]1[N:31]2[C:26]([CH:27]=[N:28][C:29]([S:32][CH3:33])=[N:30]2)=[CH:25][CH:24]=1.CO.C(Cl)Cl>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3]1[C:4]([C:23]2[N:31]3[C:26]([CH:27]=[N:28][C:29]([S:32][CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccnc1-c1ccc2cnc(SC)nn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
3-Methoxy-2-tributylstannanyl-pyridine (1.31 g, 3.29 mmol) was dissolved in N,N-Dimethylformamide (15 mL), 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.504 g, 2.06 mmol) and Tetrakis(triphenylphosphine)palladium(0) (161 mg, 0.139 mmol) were added, and the mixture was degassed under vacuum, then under an atmosphere of Nitrogen, was heated in a block at 80° C. for 8 h, then 110 C overnight. Bis(tri-tert-butylphosphine)palladium (45 mg, 0.088 mmol) was added and heating was continued at 110 C for 8 h. The mixture was cooled, conc. in vacuo and applied to a 25 g Isco cartridge (MeOH:DCM), dried and purified (80 g column, 0-70% EtOAc:Hex) to afford 7-(3-Methoxy-pyridin-2-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.192 g; Yield=34.1%). LCMS (HPLC):0.78 min, m/z=273 (M+H); 1H-NMR (DMSO-d6): 9.04 (s, 1H), 8.29 (d, 1H, J=4.4 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.50 (dd, 1H, J=4.4, 8.4 Hz), 7.12 (d, 1H, J=4.6 Hz), 7.07 (d, 1H, J=4.6 Hz), 3.83 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:38])=[C:28]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=1>>[C:30]([C:28]1[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2C(=O)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-chloro-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.244 g (38%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O5Cl 501.1469, found 501.1474.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:9](=[O:18])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1C(c2ccccc2)=CC(=O)N1C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 0° C. solution of ethyl 2-(N-methyl-3-phenylprop-2-ynoylamino)acetate (prepared according to the procedure described for Intermediate A, 20 g, 82 mmol) in THF (100 mL) was added a solution of Li(SiMe3)2 (1M in THF, 82 mL, 82 mmol). The resulting mixture was stirred for 2 h, then was slowly treated with water (20 mL) and diluted with CH2Cl2 (200 mL). The organic layer was washed with water (150 mL), a 1N HCl solution (150 mL) and water (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient from 0% to 50% EtOAc/hex) to give racemic ethyl 1-methyl-5-oxo-3-phenyl-3-pyrroline-2-carboxylate (14 g, 70%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.13; 1H NMR (CDCl3) δ 1.10 (t, J=7.4 Hz, 3H), 3.03 (s, 3H), 4.12 (m, 2H), 5.13 (s, 1H), 6.46 (s, 1H), 7.39-7.41 (m, 3H), 7.53-7.60 (m, 2H); HPLC ES-MS m/z (rel abundance) 246 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CN(C=O)C.[CH3:30][CH:31]1[O:36][CH:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([N:33]3[CH2:32][CH:31]([CH3:30])[O:36][CH:35]([CH3:37])[CH2:34]3)=[O:20])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: CC1CNCC(C)O1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2nn(-c3ccnc(N)n3)c3cc(Br)ccc23)CC(C)O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride (0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The acid chloride intermediate was suspended in DCM (10 ml), 2,6-dimethylmorpholine (0.55 ml, 4.49 mmol) added. The reaction was stirred at RT for 0.5 hr and then concentrated in vacuo. The residue was diluted with more DCM and water and the organics extracted (2×20 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6). Elution with DCM:methanol 98:2 to 90:10 gave the mixture of cis and trans 2,6-dimethylmorpholin-4-yl compound (200 mg): 1H NMR (500 MHz, CDCl3) delta 1.21 (3H, d, J=6.2 Hz), 1.30 (3H, d, J=6.1 Hz), 2.64 (1H, dd, J=13.1, 10.8 Hz), 2.99 (1H, dd, J=13.2, 10.6 Hz), 4.84-3.26 (6H, m), 5.23 (2H, s), 7.23-7.19 (1H, m), 7.50 (1H, dd, J=8.6, 1.6 Hz), 7.98 (1H, d, J=8.6 Hz), 8.37 (1H, dd, J=5.6, 2.2 Hz), 9.01 (1H, d, J=1.2 Hz); LC-MS: m/z=+430.95/432.85 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[C:7]([O:11][C:12](=[O:15])[CH2:13][NH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:7]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:3](=[O:4])[CH2:2][Br:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CBr

Procedure:
77.8 g (385.5 mmol) of α-bromoacetic acid bromide is added in drops at 0° C. to 50 g (296.5 mmol) of glycine-tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this cases the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum The residue is recrystallized from diisopropyl ether/n-hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CO.[OH-].[Na+].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)Cc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Temperature: 25 °C

Procedure:
To a flask charged with methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 5 mmol) was added MeOH (1.5 mL), H2O (0.5 mL), followed by NaOH (2 mL, 6 M, 12 mmol) to generate a yellow solution, which was capped and maintained at rt for 18 h. The solution was acidified with conc. HCl to pH=3 and poured into CH2Cl2. The layers were separated and the organic layer was extracted with CH2Cl2 (2×10 mL), followed by EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to produce a colorless solid, which was of sufficient purity for use in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][NH:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:15]([CH3:16])[CH3:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Reactant: CNC
Product: COC(=O)c1ccc(CN(C)C)c(Br)c1
Yield: 70 %

Procedure:
By following essentially the procedure of Example 137, Part B, the title compound was prepared from methyl 3-bromo-4-bromomethylbenzoate (Example 137, Part A) and dimethylamine (40%), in 70% yield. The flash chromatography was carried out by eluting with a gradient of hexanes(100-80%)/EtOAc(0-20%).
Reaction SMILES: [C:1]([C:5]1[Se:6][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S1(=O)C=CC=C[CH2:17]1.C[Mg]Br.[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].[H+]>O1CCCC1.CCOCC>[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].[C:1]([C:5]1[CH:10]=[C:9]([CH3:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[Se+:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(=O)cc(C(C)(C)C)[se]1
Reactant: O=S1C=CC=CC1
Agent: C[Mg]Br
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 76 %

Procedure:
2,6-Di-tert-butylselenopyran-4-one, compound E, (27.1 grams, 0.100 mole) was dissolved in 250 mL of dry tetrahydrofuran. To this solution was added 40 mL of a 3.0 M solution of methylmagnesium bromide (0.12 mole) in ether. After addition was complete, the reaction mixture was heated at reflux for 1 h and was cooled to ambient temperature. The reaction mixture was slowly added with stirring to 1 L of a cold solution of 10% hexafluorophosphoric acid. The solid was collected by filtration and the filter cake was washed with water (2×250 mL) and ether (3×250 mL). The crude white solid was recrystallized from acetonitrile-ether to give 28.0 g (76% of theoretical) of 2,6-di-tert-butyl-4-methylselenopyrylium hexafluorophosphate, compound F: Melting point 203-204° C.; 1H NMR (deuteriochloroform) d 8.34 (s, 2 H), 2.83 (s, 3 H), 1.66 (s, 18 H). Anal. Calculated for C14H23Se-PF6: C, 40.50; H, 5.58. Found: C, 40.51; H, 5.35.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](/[C:22](=[CH:12]/[C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[C:6]3[CH3:11])/[C:23]#[N:24])=[O:25])=[CH:19][CH:20]=1
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Product: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(Cl)cc3)cc12

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 500 mg (2.81 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 566 mg (3.09 mmol) 3-(4-chlorophenyl)-3-oxopropanenitrile to yield 830 mg (66% of th.) of the crude product (76% purity) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8](Cl)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.N1C=CC=CC=1.O>CC(C)=O>[CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: c1nc[nH]n1
Reactant: CCCCCCCCC(CCCCCC)C(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC(CCCCCC)C(=O)n1cncn1
Yield: 118 %

Procedure:
2-Hexyldecanoyl chloride (25 g) was added during 10 minutes to a stirred solution of 1,2,4-triazole (14 g) and pyridine (10 ml) in acetone (50 ml). During addition the temperature rose from 20° to 38°. The mixture was drowned into water and extracted with toluene, and the toluene solution was washed with water and then distilled yielding 1-(2'-hexyldecanoyl)-1,2,4-triazole (33 g), b.p. 156°-160° at 0.15 mm of mercury. This compound was evaluated as an extractant for copper using the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][CH2:12][CH3:13])[CH3:2].[Br:14]N1C(=O)CCC1=O.CCCCCC>C(#N)C>[Br:14][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:11][CH2:12][CH3:13])[C:6]=1[F:10]
Reactant: CCOc1cccc(F)c1OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CC#N
Product: CCOc1ccc(Br)c(F)c1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 1,2-diethoxy-3-fluorobenzene (150.00 g, 814 mmoL) in acetonitrile (900 mL), a solution of N-bromosuccinimide (NBS) (153.72 g, 864 mmoL) in acetonitrile (1.5 L) was added dropwise under ice cooling and stirred overnight at room temperature. After evaporation of the solvent, ethyl acetate was added to the residue, followed by washing with water. The resultant aqueous layer was re-extracted with ethyl acetate, and the extract was mixed with the previously obtained organic layer. The organic layer was washed with water, saturated saline and water in this order and then dried over anhydrous magnesium sulfate. The resultant solution was concentrated to obtain an oily material. Hexane was added to the oily material, and the crystals deposited were removed by filtration. The solution was re-concentrated to obtain an oily material, which was distilled under reduced pressure to give 205.65 g of the captioned compound (yield: 96%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH3:39].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:48](=[O:49])[CH2:47][N:44]3[C:45]([CH3:46])=[C:41]([Cl:40])[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH3:39]
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.74 (s,1H), 6.56 (d, 1H), 5.39 (s, 2H), 3.82 (s, 3H), 3.63 (m, 4H), 3.30 (m, 2H), 3.19 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=451.1, found 451.0.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[NH:20][C:19](=O)[CH2:18][O:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14]>CCOCC.C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[NH:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C1COCC(c2ccc(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(C2COCCN2)cc1F

Procedure:
To a suspension of LiAlH4 (6.0 mmol, 0.23 g) in 25.0 mL of Et2O was added a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (2.0 mmol, 0.42 g) in 20.0 mL Et2O and 5.0 mL THF at room temperature. The resulting suspension was heated to reflux for 2 hours and was then quenched with water and aq. NaOH solution. The solid was filtered off and the filtrate was dried over Na2SO4. The filtrate was then decanted and the solvent was removed in vacuo to obtain 5-(3,4-difluoro-phenyl)morpholine as a viscous oil. It was converted to its hydrochloride salt for its analysis. Yellow powder. M.P.=171-173° C.; Mass spec. 200 (M+1, 100%). Analysis calculated for C10H12NOF2Cl.0.5 acetone: C, 51.96; H, 5.61; N, 5.41. Found: C, 51.98; H, 5.70; N, 5.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br.[NH:22]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:27][NH2:28]>Br.C(O)CC>[ClH:1].[NH:24]1[CH2:25][CH2:26][N:22]=[C:23]1[NH:27][N:28]=[C:10]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NNC1=NCCN1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Agent: Br
Solvent: CCCO
Product: Cl
Product: Clc1ccc(C=CC(C=Cc2ccc(Cl)cc2)=NNC2=NCCN2)cc1
Temperature: -10 °C

Procedure:
A mixture consisting of 6 grams of 1,5-bis(p-chlorophenyl)- 1,4-pentadien-3-one, 3.6 grams of 2-imidazolin-2-ylhydrazine hydrobromide, 10 drops of 48 percent aqueous hydrobromic acid and 80 ml. of n-propanol is stirred and heated at reflux for two hours. The reaction mixture is then concentrated to about one-half its volume and cooled at -10° C. The yellow crystalline precipitate is collected, washed with ether, and then added to a slight excess of aqueous 2N sodium hydroxide. The resultant free base is collected, dried, dissolved in ether and treated with a slight excess of 7.2 N n-propanolic hydrogen⟦,⟧ chloride, yielding the title compound melting at 239°-240° C. If the original hydrobromide salt is recrystallized from methanol, a product containing one mole of methanol of crystallization is obtained, melting at 206.5°-208.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[C:4]([CH:15]=O)=[CH:3]1.C[C:18]1[NH:19]C2C(C=1C=O)=CC=CC=2>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[C:4]([CH2:15][NH:19][CH3:18])=[CH:3]1
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: COC(=O)c1cccc2c(C=O)cn(C)c12
Product: CNCc1cn(C)c2c(C(=O)OC)cccc12
Yield: 92 %

Procedure:
According to the procedure of Preparation 12, except substituting 1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the 2-methylindole-3-carboxaldehyde, the title compound (1.7 g, 92%) was obtained as an oil: MS (ES) m/e 233.2 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([O:12]C)=[O:11])=[O:6].[OH-].[Li+]>O1CCCC1.CO>[OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC[C@H](NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1)C(=O)O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
The product of step 11B is dissolved in tetrahydrofuran/methanol (1:1) and treated with excess 3N aqueous lithium hydroxide. The reaction is followed by HPLC for disappearance of starting material. The reaction is concentrated, diluted with additional water, and purified by passage down an-acidic ion exchange column. The product fractions are lyophilized to afford the product as a solid.