Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10]([Cl:15])(=O)[CH:11]([CH3:13])[CH3:12]>CCCCCC>[ClH:15].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: NNc1ccc(Br)cn1
Solvent: CCCCCC
Product: CC(C)c1nnc2ccc(Br)cn12
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 ml three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top to a nitrogen bubbler and a thermometer, was charged with 5-bromo-pyridin-2-yl-hydrazine (43.4 g, 0.231 moles) and isobutyryl chloride (218 ml, 2.08 moles). The mixture was gently refluxed for 3 hours. The heating source was then replaced with an ice-water bath and the slurry cooled to room temperature. Hexane (220 ml) was added and the slurry stirred at room temperature for 15 minutes and filtered. The cake was washed with hexane (3×70 ml) and then dried in a vacuum-oven (35° C.) for 48 hours. The title compound was obtained as an off-white powder (58.96 g, yield 92.3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]3[CH:24]=[CH:23][C:13]4[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=4[CH:11]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrC1CCCC1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OC4CCCC4)cc3)cc2o1
Yield: 25 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (40.0 mg, 0.123 mmol) obtained in Example 165 and bromocyclopentane (0.147 mL, 1.85 mmol) and in the same manner as in Example 158, the title compound was obtained (11.9 mg, yield 25%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:14])[F:13].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(CC)CC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:17]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:13])[F:14])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1ccccc1SCC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccccc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-aminomethyl-(2,2,2-trifluoroethylthio)benzene hydrochloride (500 mg, 1.94 mmol) in CH2C2 (20 mL) were added successively (BOC)2O (465 mg, 2.13 mmol), DMAP (23.7 mg, 0.194 mmol) and Et3N (0.27 mL, 1.94 mmol). The reaction mixture was stirred overnight at room temperature and was then diluted with EtOAc and washed successively with 10% aqueous citric acid, brine, and water. The organic layer was dried over MgSO4 and concentrated at reduced pressure. Silica gel chromatography (isocratic elution with 20% EtOAc-hexanes) afforded the title compound as a colorless oil:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[Cl-].[OH:17][NH3+:18].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=[N:18][OH:17]
Reactant: [NH3+]O
Reactant: Cc1cc(C)c(C(=O)C(F)(F)F)c(C)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(=NO)C(F)(F)F)c(C)c1
Temperature: 0 °C
Yield: 28.3 %

Procedure:
6.3 g (0.029 mol) of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone are dissolved in 30 ml of ethanol at 80° C. To the solution are added dropwise 2.0 g (0.029 mol) of hydroxylammonium chloride and 4.1 g (0.050 mol) of sodium acetate dissolved in 15 ml of water. The reaction mixture is refluxed overnight, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from 20 ml of hexane, yielding 1.9 g of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone oxime in the form of white crystals, mp. 119-125° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13](O)=[O:14])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13]([Cl:26])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetic acid (8-a) (0.94 g), toluene (anhydrous) (3.0 ml) and dimethylformamide (anhydrous) (0.2 ml) were added under a nitrogen atmosphere and the internal temperature was raised to about 50° C. Thionyl chloride (0.45 ml) was added thereto and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure, and azeotropically distilled with toluene to give 0.96 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([CH:25]5[CH2:27][CH2:26]5)[CH2:29][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NC1CCN(C2CC2)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C4CC4)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropylpiperidin-4-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (d, J=6.06 Hz, 2H) 0.82 (br. s., 2 H) 1.79 (d, J=10.86 Hz, 2 H) 1.97 (d, J=10.86 Hz, 2 H) 2.43 (s, 4 H) 2.88-3.14 (m, 2 H) 3.35-3.34 (m, 2 H) 4.00 (d, J=6.57 Hz, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.79 (d, J=8.08 Hz, 1 H) 8.16 (s, 1 H) 8.35-8.50 (m, 2 H) 8.66 (d, J=7.07 Hz, 1H) 8.92 (t, J=1.52 Hz, 1 H) 11.41-12.67 (m, 1 H). MS m/z [M+H]+ 443.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.Cl[CH2:18][C:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([NH:30][C:31](=[O:47])[C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]=3[F:46])[CH:28]=2)[NH:23][CH:22]=1)=[O:20]>CCO>[F:46][C:33]1[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:41])=[O:42])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:31]([NH:30][C:27]1[CH:28]=[C:29]2[C:21]([C:19](=[O:20])[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH:11]([F:10])[CH2:12]3)=[CH:22][NH:23][C:24]2=[N:25][CH:26]=1)=[O:47]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: FC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN4CCCC(F)C4)c3c2)c1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Hunig's base (0.0196 mL, 0.106 mmol) and 3-fluoropiperidine (0.0148 g, 0.106 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.0106 mmol) in EtOH (0.2 mL), which was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified via column chromatography (5% to 10% MeOH/DCM) to provide 2,6-difluoro-N-(3-(2-(3-fluoropiperidin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (3 mg, 52.6%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.92 (m, 1H), 8.62-8.63 (m, 1H), 8.60 (s, 1H), 7.63-7.69 (m, 1H), 7.13-7.16 (m, 1H), 4.60-4.80 (m, 1H), 3.76 (s, 2H), 3.08-3.15 (m, 2H), 2.86-2.94 (m, 1H), 2.59-2.79 (m, 4H), 2.50-2.55 (m, 1H), 1.80-1.93 (m, 4H), 1.57-1.71 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=538.1.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1.[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(#N)C.C(Cl)Cl>[F:18][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)C(=N)S1
Solvent: CC#N
Solvent: ClCCl
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2ccnc2)S1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylenethiazolidin-2-imine (Example 115, 0.2 g, 0.74 mmol) and carbonyldiimidazole (0.14 g, 0.92 mmol) in dry acetonitrile (5 mL) was stirred at 70° C. for 16 hours. After cooling down, the mixture was diluted with 150 mL of CH2Cl2 and washed successively with saturated sodium bicarbonate (75 mL), water (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed over silica using 100% CH2Cl2 to CH2Cl2:MeOH 95:5 as mobile phase to give the titled compound. 1H NMR (CD3OD) δ ppm 5.00 (2H), 5.40 (1H), 5.50 (1H), 6.90 (1H), 7.35 (2H), 7.44 (1H), 7.50 (1H), 8.05 (1H); MS (ESI) m/z 365(M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:20]CN(C(C)C)C(C)C.CI.O>CN(C=O)C>[CH3:20][O:10][C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)s1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Esterification. To a solution of (S)-3-(5-bromo-thiophen-2-yl)-2-ter t-butoxycarbonylamino-propionic acid in DMF (50 mL) was added DIEA and methyl iodide. The reaction mixture stirred at rt for 2.5 h and was poured onto EtOAc and water. The organic layer was washed with 1 N HCl and 10% sodium carbonate, dried over sodium sulfate and concentrated to furnish (S)-3-(5-bromo-thiophen-2-yl)-2-tert-butoxycarbonylamino-propionic acid methyl ester. This product was used without further purification.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[I:21]I.S(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([I:21])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(F)nc1
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Fc1cc(I)c(F)cn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
n-BuLi 2.5M in hexanes (4.9 mL, 12.25 mmol) was added to a solution of diisopropylamine (1.7 mL, 12.20 mmol) in tetrahydrofuran (22 mL) at −20° C., under nitrogen atmosphere, over a period of 10 minutes. The solution was stirred at −20° C. for 30 min and then it was cooled to −78° C. A solution of 2,5-difluoropyridine (1.33 g, 11.5 mmol) in tetrahydrofuran (3 mL) was added over a period of 30 min and the mixture was stirred at −78° C. for 4 hours. After this time, a solution of iodine (3.20 g, 12.6 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred at −78° C. for 1 hour. Water (1 mL) and tetrahydrofuran (3 mL) were added and the temperature was allowed to raise until room temperature, then water (25 mL) and aqueous sodium bisulphite 40% p/v (3 mL) were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×50 mL), the combined organic layers were washed with brine, dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by silica flash chromatography (5% diethyl ether in hexanes) to yield the title compound (1.35 g, 48%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C([O-])(=O)C.[Na+].[Br:18]Br>CCCCCC>[Br:18][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:12]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 2',3',4'-trichloroacetophenone (21.4 g, 0.0958 mole), anhydrous sodium acetate (8.0 g), and n-hexane (50 ml) was heated under reflux while treated with a solution of bromine (15.3 g, 0.096 mole) in 25 ml of n-hexane in five portions, decolorizing before each new addition. The mixture was then filtered while hot and the insoluble residue was triturated twice with 50 ml of boiling n-hexane. Enough additional n-hexane was added to the combined filtrates to avoid oiling out of product at 40°. The solution was then seeded and cooled at -10° for 18 hours. Product was collected and air dried to give 17.9 g (62%), mp 44°-46°.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:4].[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:19][CH:18]=1>>[CH3:4][CH:3]([NH:2][C:23](=[O:24])[C:22]([O:21][C:20]1[CH:28]=[CH:29][C:17]([Cl:16])=[CH:18][CH:19]=1)([CH3:27])[CH3:26])[CH:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)CC(c1ccccc1)C(C)N
Agent: Cl
Product: CC(C)CC(c1ccccc1)C(C)NC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
2-Amino-5-methyl-3-phenylhexane hydrochloride salt from Reference Example 26 (30 mg) was reacted with the acid chloride prepared from of 2-(4-chlorophenoxy)-2-methyl-propionic acid (37 mg) according to the procedure described in Example 62-63 to afford the title compound after purification by preparative TLC on silica gel eluted with 20% EtOAC-hexane. 1H NMR: (500 MHz, CDCl3): δ 0.83 and 0.85 (2d, 6H), 0.96 (d, 3H), 1.34 (m, 1H), 1.45 (m, 1H), 1.53 (s, 3H), 1.59 (s, 3H), 2.73 (m, 1H), 4.24 (m, 1H), 6.41 (d, 1H), 6.8-7.4 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[CH2:31][NH2:32])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][C@H:27]2[CH2:28][CH2:29][CH2:30][N:26]2[CH2:25][CH:22]2[CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NC[C@H]1CCCN1CC1CC1
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 17] and [(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methylamine [see WO 9839295 A1], to afford the product as a orange oil (100%).
Reaction SMILES: Cl[C:2]1C=N[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S.[CH3:33][N:34](C)C=O>[Cu]Br>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:31][CH2:30][CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:29][CH2:28]3)=[N:34][CH:33]=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Agent: [Cu]Br
Agent: S
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper (1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeON, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide (g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH:6]1([CH2:12][N:13]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)P(OC)(OC)=O)[C:14](=[O:16])[O-:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:30]([C:32]1[S:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1)=O>CCCCCC.O1CCCC1>[CH:6]1([CH2:12][N:13]([C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:30][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[C:14](=[O:16])[O:15][CH2:1][CH3:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: COP(=O)(OC)C(c1ccccc1)N(CC1CCCCC1)C(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N(CC1CCCCC1)C(=Cc1ccc(-c2ccccc2)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere n-butyllithium (1.3 mL of a 2.5M solution in hexane) was added to a stirred, cold (-78° C.) solution of 1.15 gram (0.00293 mole) of N-cyclohexylmethyl-N-[phenyl(dimethoxyphosphinyl)methyl]carbamate in approximately 20 mL of tetrahydrofuran. This mixture was stirred for about 30 minutes at -78° C. after which 2-formyl-5-phenylthiophene (0.51 gram, 0.0027 mole) was added. The mixture was allowed to gradually warm to room temperature and stir for four hours. The reaction mixture was quenched with dilute hydrochloric acid and was then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and filtered through celite. The filtrate was evaporated under reduced pressure to yield 0.6 gram of ethyl N-cyclohexylmethyl-N-[1-phenyl-2-(5-phenyl-2-thienyl)ethene-1-yl]carbamate as a red gel.
Reaction SMILES: F[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][CH3:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[OH2:19].[OH-].[Li+:21].C(=O)=O.[OH-].[Li+]>O>[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][CH3:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([O:19][Li:21])(=[O:4])=[O:3]
Reactant: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Reactant: O
Reactant: [Li+]
Agent: O=C=O
Agent: [OH-]
Product: [Li]OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC
Temperature: 25 °C

Procedure:
FSO2(CF2)4OCH3 (35.8 g, 0.114 mole) was treated with lithium hydroxide monohydrate (12 g, 0.285 mole) in deionized water (150 g) at 75° C. for six hours. After cooling to room temperature, two small pieces of solid carbon dioxide (Dry Ice) were added to neutralize the excess lithium hydroxide. The water was removed by using a rotary evaporator and the residue extracted with alcohol as described in Preparation of Precursor 1 above to yield LiO3S(CF2)4OCH3.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)on2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)on2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Lithium hydroxide monohydrate (73.5 mg) was added to a solution of methyl E-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyrate (412 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyric acid (320 mg, yield 80%) as colorless crystals. m.p. 100-101° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[O:16][C:15]([CH3:17])=[N:14][C:13]=12)=[O:7])C.Cl>CO>[CH3:17][C:15]1[O:16][C:12]2[C:13](=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][CH:11]=2)[N:14]=1
Reactant: CCOC(=O)c1cccc2oc(C)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(C(=O)O)cccc2o1
Reaction time: 0.5 h

Procedure:
At 0° C. an aq. KOH solution (1.0M, 2.40 mL) is added to a solution of 2-methyl-benzooxazole-4-carboxylic acid ethyl ester (0.98 mmol) in MeOH (5.0 mL) and stirred for 30 min. The mixture is allowed to reach rt, stirred for additional 60 min and made acidic by addition of aq. hydrochloric acid (2.0 M). After removal of MeOH under reduced pressure the obtained precipitate is filtered off to give the desired product which is dried in vacuo. 1H-NMR (DMSO-d6): δ=2.64 (s, 3H); 7.41 (t, J=8.0 Hz, 1H); 7.83 (d, J=7.8 Hz, 1H); 7.88 (d, J=8.0 Hz, 1H); 12.8 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:7]=[O:8])[CH3:2]
Reactant: OCCCCCCCl
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(C=O)ccc1OCCCCCCO
Yield: 84 %

Procedure:
3-ethoxy-4-[(6-hydroxyhexyl)oxy]benzaldehyde is prepared starting from 3-ethoxy-4-hydroxybenzaldehyde and 6-chlorohexan-1-ol according the same procedure following for example 7 in 84% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.