Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=[CH:11][CH:10]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)=[CH:13][CH:14]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(=O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
2-Ethyl-3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.5 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.54 g) were dissolved in dichloromethane (10 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.32 g, 64%) as a colorless amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:16]([CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH2:33][CH2:34][CH3:35])C.[Li+].[OH-].O.Cl>C1COCC1>[CH3:32][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=1
Reactant: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Compound 4.5 (32.7 g, 63.0 mmol) was dissolved in THF (250 mL). To the solution was added 4N LiOH (31.5 mL, 126 mmol) and the reaction was stirred at room temperature for 1 h, after which time water (31.5 mL) was added, and the reaction mixture was stirred for 30 min. 2N HCl (70 mL) was then added to the reaction and the THF was removed in vacuo. The residue was diluted with hexane (250 mL) with stirring, and the deposited crystals were collected by filtration and recrystallized from EtOAc-hexane to provide 4 (24.12 g). MS APSI m/e: 489 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.90 (1H, brs); 7.76 (2H, d, J=8.2 Hz); 7.67 (2H, d, J=8.2 Hz); 7.20-7.05 (4H, m); 6.99 (1H, d, J=8.6 Hz); 6.81 (1H, d, J=8.4 Hz); 5.23 (2H, s); 4.68 (2H, s); 2.56-2.47 (2H, m); 2.18 (3H, s); 1.60-1.47 (2H, m); 0.85 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].[CH:23]1([CH:26]([C:33]2[C:38]([F:39])=[CH:37][N:36]=[C:35](O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.[Ag]=O>[CH:23]1([CH:26]([C:33]2[C:38]([F:39])=[CH:37][N:36]=[C:35]([O:11][CH2:10][C:8]3[CH:7]=[CH:6][C:5]([C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[F:20])=[C:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[N:9]=3)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncc1F)C1CC1
Yield: 59.4 %

Procedure:
Silver oxide (327 mg) was added to a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (415 mg) and ethyl 3-cyclopropyl-3-(5-fluoro-2-hydroxypyridin-4-yl)propanoate (300 mg) in toluene (5 mL) at room temperature, and the mixture was heated under reflux for 2 hr. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (379 mg) as a pale-yellow oil.
Reaction SMILES: CN([Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])C.[CH3:17][S:18]([CH3:20])=[O:19].CNC>>[CH3:17][S:18]([CH2:20][Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Reactant: CS(C)=O
Agent: CNC
Product: CCCC[Sn](CCCC)(CCCC)CS(C)=O
Reaction time: 8 h

Procedure:
Dimethylamino tributyltin (33.4 g.; 0.1 moles) and dimethylsulfoxide (100 g.; 1.28 moles) were stirred in a 250 ml reaction flask, under a positive pressure argon atmosphere, for 4.5 hours at 80° C. During the reaction, liberated dimethylamine gas exited from the reaction flask through an open port with the moving argon gas. The reaction stood overnight at ambient temperature. Excess dimethylsulfoxide was distilled at 75° C at 15 mm Hg. The reaction product was distilled through a semi-micro distillation apparatus at 138° C at 0.1 mm Hg. Yield of 25 g (68%) was identified as (methylsulfinylmethyl) tributyltin by 'H NMR and infrared spectra.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].S([O-])(O)(=O)=O.[K+].C(C1C=C(O)C=CC=1O)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(Br)cc(C(C)O)cc1Br
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1

Procedure:
A mixture of 67.6 g (0.02 mole) 1-(3',5'-dibromo-4'-acetoxyphenyl)ethanol, 0.35 g freshly melted and then finely pulverized potassium hydrogen sulfate, and 0.5 g t-butylhydroquinone are heated at 20 Torr to 170°-90° C. The resulting product is distilled off (under vacuum) at a temperature of 140° to 160° C. It is taken up in ether, the ether solution is washed with Na2CO3, dried, and concentrated under vacuum. The remaining product is distilled at 0.02 mbar; the boiling point is 116° C. The isolated product, which is ahighly viscous oil or a white, waxy solid, has a melting point of approximately 75° C. The reaction yield is 27 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1F
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(C=Cc1ccc(Br)cc1F)Nc1ccc(Cl)cc1
Yield: 81.3 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenyl)-acrylic acid (12.7 g, 52 mmol), 4-chloroaniline (9.9 g, 78 mmol), HOBt (10.5 g, 78 mmol) and EDCI (15.0 g, 78 mmol) in 200 mL of dichloromethane was refluxed overnight, and the resulting mixture was washed with 1M NaOH solution, water and brine, dried over Na2SO4, and concentrated. Recrystallization of the residue from EtOAc/Hexane gave 15 g (82%) of white solid. MS: calc'd 354 (MH+), exp 354 (MH+). 1H NMR (CDCl3, 400 MHz), 7.75 (d, 1H, J=15.6 Hz), 7.60 (d, 2H, J=8.8 Hz), 7.48 (s, 1H), 7.32-7.38 (m, 5H, J=7.6 Hz), 6.70 (d, 1H, J=15.6 Hz).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH3:60])([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][C:41]([CH3:60])([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 34.4 %

Procedure:
To a solution of 45 (30 mg, 36.3 μmol) in a mixture of MeOH (3.0 mL) and THF (1 mL) was added Pd(OH)2/C (30 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The aromatic chloride was partially cleaved. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 53 (5.8 mg, 34%). 1H NMR (300 MHz, CD3OD) δ 7.50 (s, 1H), 7.00-7.07 (m, 4H), 6.77 (s, 1H), 3.98 (s, 2H), 3.93 (dd, J=2.1, 11.7 Hz, 1H), 3.65-3.82 (m, 3H), 3.55 (dd, J=8.1, 9.6 Hz, 1H), 3.27 (t, J=9.6 Hz, 1H), 2.80 (d, J=11.1 Hz, 1H), 2.57 (q, J=7.5 Hz, 2H), 1.96 (d, J=11.4 Hz, 1H), 1.68 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 447 (M−OH).
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.C(N1C(=O)N(C2SC(C(O)=O)=C(C)C=2)C=N1)C1C=CC=CC=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH2:6]([N:7]1[C:11](=[O:12])[N:10]([C:13]2[S:17][C:16]([C:18]([NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:20])=[C:15]([CH3:21])[CH:14]=2)[CH:9]=[N:8]1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:23][CH:22]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 5-(1-benzyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 89% yield: mp 180-181° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.54 (s, 1H), 7.73 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.43-7.25 (m, 6H), 6.88 (s, 1H), 6.48 (t, J=5.6 Hz, 1H), 5.00 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 150.4, 149.2, 149.0, 140.8, 135.6, 135.3, 134.5, 132.2, 128.8, 128.4, 128.2, 125.1, 120.0, 49.8, 41.4, 16.0; MS (ES+) m/z 406.2 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCC(=O)Cl
Reactant: Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3

Procedure:
An 8.17 gm (0.030 mole) quantity of the compound of Example 9 was added to 3.54 gm (0.035 mole) of triethylamine, 300 mg of 4-dimethylaminopyridine, 3.24 gm (0.035 mole) of propionyl chloride and 50 ml of methylene chloride. This mixture was refluxed for 61/2 hours. The solvent was evaporated. The residue was patitioned between CH2Cl2 and water. The organic layer was washed with water, dried, and evaporated, resulting in a gummy residue. This residue was triturated with ether and hexane, producing a white solid. The solid was filtered and washed with ethane, then treated with benzene and hexane producing crystalline N-(7,8,9,10-tetrahydro-6-(1-piperidinyl)-1,2,4-triazolo [3,4-a]phthalazin-3yl)propanamide; mp 173-174° C. (benzene-hexane).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:44])C(=O)C1>ClCCl>[Br:44][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCCBr
Reaction time: 24 h
Yield: 93.3 %

Procedure:
In a 100 mL two-neck flask with a reflux condenser and magnetic anchor, under a static head of nitrogen, ethyl 12-hydroxydodecanoate (1.65 g, 6.7 mmol) is dissolved in dichloromethane (20 mL). PPh3 (1.93 g, 7.4 mmol) and NBS (1.6 g, 7.0 mmol) are added. The mixture is left stirring under reflux conditions for 24 hours. It is concentrated in the Rotavapor and the product is purified with column chromatography on silica gel with an eluant mixture of petroleum ether/ethyl acetate 5/1. 1.92 g (yield=92%) of ethyl 12-bromododecanoate are isolated as a light yellowish oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[CH3:19][NH:20][CH2:21][CH2:22][OH:23]>O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CNCCO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CNCCO)n1
Temperature: 0 °C
Yield: 70 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 1.6 ml (0.02 mol) of 2-methylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.6 g of yellow powder are obtained, ie a yield of 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:32][CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)[CH:24]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1cccc(-c2ccn3c(-c4ccnc(-c5ccc(F)cc5)c4)cnc3c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc(-c2cc(-c3cnc4cc(-c5cccc(OCCCN6CCCCC6)c5)ccn34)ccn2)cc1
Temperature: 60 °C

Procedure:
3-{3-[2-(4-Fluoro-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-7-yl}-phenol (Ex. 1.102) (1 eq, 0.131 mmol, 50 mg), 1-(3-chloropropyl)piperidine monohydrochloride (2.0 eq, 0.262 mmol, 53.7 mg) and potassium carbonate (3.0 eq, 0.394 mmol, 54.4 mg) are dissolved in DMF (4 ml) and heated at 60° C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with NaHCO3 and brine. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3 to yield 3-[2-(4-fluoro-phenyl)-pyridin-4-yl]-7-[3-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=507
Reaction SMILES: [CH2:1]([N:5](C(=O)[C@@H](C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3]>ClCCl.N1CCCCC1>[CH2:1]([NH:5][NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.67 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethoxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in a mixture of 20 ml of dichloromethane and 5 ml of piperidine was stirred at room temperature for 2 hours. The solution was evaporated and the residue was triturated with hexane/diethyl ether (2:1). The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (5:95) for the elution to give 0.75 g of (E)-2′-(D-alanyl)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11])#[N:31]
Reactant: N#CCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix [1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (4.25 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2,000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.0 Hz, 1H), 7.44 (dd, J=1.2, 7.1 Hz, 1H), 7.26 (s, 1H), 6.75 (dd, J=10.8, 17.6 Hz, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.44 (d, J=11 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 2H), 1.54 (d, J=6.1 Hz, 3H); LC/MS (M+H)+189;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].F[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[O:10][C:16]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:17]=2[C:18](=[O:19])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)oc2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105° C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116–120.1° C. 1H NMR (CDCl3/300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14H8F6O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12].Cl.[C:15](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH3:15])([CH3:12])[OH:13]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C([O-])O
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1N
Temperature: 25 °C

Procedure:
To a 0° C. solution of methylmagnesium bromide (45 mL of a 1.4M solution in toluene, 63 mmol) under nitrogen atmosphere was added a solution of ortho-aminoacetophenone (2.9 g, 21.5 mmol) in THF (20 mL). The mixture was warmed to ambient temperature for 45 min, cooled to 0° C., and poured into ice-water. The mixture was acidified with 6N HCl, adjusted to ca. pH 6 with saturated sodium bicarbonate solution, and then extracted with ether (2×100 mL). The combined ether fractions were dried (MgSO4), filtered and the solvent was removed under reduced pressure to give the oily product, 2-aminophenyldimethyl carbinol.