Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])C.C(O[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](O)=O)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[OH:5][CH2:4][CH2:6][N:7]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([CH:43]2[CH2:44][CH2:45][N:40]([CH3:38])[CH2:41][CH2:42]2)=[CH:51][CH:50]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)c1
Yield: 45.1 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (18 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[CH:40]=2)[CH2:35][CH2:34]1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)(c1ncc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)s1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (380 mg, 1.13 mmol) in 10 mL THF was cooled to −78° C., then LDA (2.5 mmol, freshly prepared) was added and the resulting mixture was stirred at the same temperature for 30 min. Then a solution of methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.13 mmol) in THF (3 mL) was added and the reaction was warmed to rt over a period of 4 h, then stirred for an additional 15 h at rt. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography to afford racemic methyl 3-hydroxy-3-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate, which was resolved by chiral SFC (Column: Chiralcel OD-H 150×4.6 mm I.D., 5 um; Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL/min; Wavelength: 220 nm) to give each enantiomer. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.
Reaction SMILES: C([O:8][C:9](=[O:58])[C@H:10]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:11][C:12](=[O:50])[CH2:13][CH:14]([O:30][C:31](=[O:49])[CH2:32][NH:33][C:34](=[O:48])[CH2:35][NH:36][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>O1CCCC1.CO>[C:37]([NH:36][CH2:35][C:34]([NH:33][CH2:32][C:31]([O:30][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:58])=[O:8])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:50])=[O:49])=[O:48])(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC(=O)CNC(=O)CNC(=O)CCCCCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC(=O)CNC(=O)CNC(=O)CCCCCCCCC
Yield: 101.3 %

Procedure:
300 mg of the formed ester compound as above was dissolved in a mixture of 20 ml of tetrahydrofuran and 10 ml of methanol. By following the same procedure as in Example 23-(iv), 270 mg of N-[3-(N-decanoylglycylglycyloxy)octadecanoyl]-L-phenylalanine was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][OH:36])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl.C(N(CC)CC)C>[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][O:36][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCO)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCOC(=O)c2cccnc2)cc1
Temperature: 20 °C

Procedure:
A solution of 0.7 gm (4.68 m mol) of nicotinic acid chloride in 20 ml of methylene chloride was rapidly added dropwise to a stirred solution of 2.0 gm (4.56 m mol) of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml (4.81 m mol) of triethylamine. The resulting mixture was stirred at 20° C. for two and one-half hours and then extracted with water, and the organic phase was subsequently dried, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (5:1)].
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:16][CH2:17][C:18]2([OH:28])[CH2:27][CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19]2)[CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.O>[CH3:5][O:4][C:2](=[O:3])[N:15]([C@H:13]([C:10]1[CH:9]=[CH:8][C:7]([Br:6])=[CH:12][CH:11]=1)[CH3:14])[CH2:16][CH2:17][C:18]1([OH:28])[CH2:27][CH2:26][CH2:25][C:20]2([O:21][CH2:22][CH2:23][O:24]2)[CH2:19]1
Reactant: COC(=O)Cl
Reactant: C[C@H](NCCC1(O)CCCC2(C1)OCCO2)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)N(CCC1(O)CCCC2(C1)OCCO2)[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (0.20 mL) is added dropwise to a solution of 7-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-1,4-dioxa-spiro[4.5]decan-7-ol (0.50 g), triethylamine (0.4 mL), and pyridine (0.2 mL) in dichloromethane (10 mL) chilled in an ice bath. The solution is warmed to room temperature and stirred at this temperature overnight. Water is then added and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with water (3×), dried (MgSO4), and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Yield: 0.30 g (50% of theory); Mass spectrum (ESI+): m/z=442/444 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.CCOC(C)=O.O>C(O)(C(F)(F)F)=O>[NH:27]1[CH2:26][CH:25]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])=[N:9]2)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C1CNC1
Yield: 94.9 %

Procedure:
tert-Butyl 3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate (800 mg) in TFA (8 mL) was stirred for 1 hour. To the residue was added EtOAc and 1 water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was evaporated to around 50 ml and washed with 2M HCl. The combined aqueous layer was adjusted with NaOH to pH 8-9, extracted with EtOAc and the combined organic layer washed with brine, and dried over Na2SO4. The solvent was removed to obtain 600 mg of 1-(azetidin-3-yl)-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[N:7]2[CH:3]1[O:4][CH:5]([CH2:15][CH3:16])[CH:6]2[C:10]([O:12][CH2:13][CH3:14])=[O:11].CCO.O.C([O-])(O)=O.[Na+]>[Pd].C([O-])([O-])=O.[Ca+2]>[Cl:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[O:4][CH:5]([CH2:15][CH3:16])[CH:6]2[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(CC)OC2N1C(=O)C2(Cl)Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C(CC)OC2C(Cl)C(=O)N21
Yield: 41 %

Procedure:
Ethyl 6,6-dichloro-3-ethyl-7-oxo-1-aza-4-oxabicyclo[3.2.0]heptane-2-carboxylate (e21) (25mg, 0.089 m.mole) in EtOH/H2O containing 2 equivalents of NaHCO3 was hydrogenated over Pd/CaCO3 for 45 minutes, extracted into ethyl acetate, dried and evaporated under reduced pressure. Chromatography yielded the title compound (e22) (9 mg, 41%) M+ 247.0612 C10H14ClNO4 requires 247.0611
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(NCc1ccccc1[N+](=O)[O-])C(=O)OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)CC(NCc1ccccc1N)C(=O)OC

Procedure:
A mixture of 2-(2-nitrobenzylamino)succinic acid dimethyl ester [from a) above] (7.6 g, 25.65 mmol) and platinum oxide (349.51 mg, 1.54 mmol) was shaken in methanol on a Parr hydrogenation apparatus under 50 psi of hydrogen gas. After 12 h the mixture was filtered and concentrated to give 6.6 g of the title compound as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (6S)-5′-fluoro-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (200 mg, 0.611 mmol) in THF (4 mL) and water (1 mL) was added 1 N lithium hydroxide (0.733 mL, 0.733 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was acidified to pH 4 by addition of 1 N hydrochloric acid and concentrated to dryness in vacuo to give the title compound. MS: m/z=300.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1H), 8.90 (s, 1H), 8.07 (m, 1H), 7.78 (dd, 1H, J=7.8, 2.7 Hz), 3.87-3.78 (m, 2H), 3.72 (d, 1H, J=17.3 Hz), 3.61 (d, 1H, J=17.6 Hz).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH:25]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[NH:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC.O.O1CCCC1>[C:53]([O:52][C:50](=[O:51])[N:42]([CH2:32][C:29]1[CH:28]=[N:27][C:26]([CH:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:23])=[O:24])[C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])=[CH:31][CH:30]=1)[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc(CO)cn1)c1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
Under a nitrogen atmosphere, diisopropyl azodicarboxylate (128 μl, 0.653 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine (178 mg, 0.435 mmol) obtained in Example 43, di-t-butyl iminodicarboxylate (142 mg, 0.653 mmol) and triphenylphosphine (171 mg, 0.653 mmol). The resulting mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and brine. The resulting organic layer was dried over sodium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (78 mg, 0.128 mmol, 32%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[S:18]([CH3:21])(=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2′-methyl-2-(methylsulfonyl)biphenyl-4-carboxylate (270 mg; 0.89 mmol; 1 eq.) was dissolved in THF (5 mL) and MeOH (5 mL). sodium hydroxide (0.89 mL; 5 M; 4.44 mmol; 5 eq.) was added and the mixture was stirred at RT overnight. Solvents were evaporated and the crude mixture was partitioned between EtOAc and water. Aqueous phase was acidified with HCl 5N solution. The two phases were separated and the organic phase was washed with brine and dried over MgSO4. After filtration and evaporation of the solvents, the title compound was isolated as a beige solid (215 mg, 83%). 1H NMR (DMSO-d6, 300 MHz) δ 13.53 (br s, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.28 (dd, J=1.8, 8.0 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.42-7.23 (m, 4H), 2.90 (s, 3H), 2.02 (s, 3H). LC/MS (Method B): 289.2 (M−H)−. HPLC (max plot) 97.9%; Rt 3.83 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:28][OH:29]
Reactant: NO
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: Cl
Solvent: CO
Product: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde (i.e. the product of Step 2, 1.20 g) in methanol (5 mL) was added hydroxylamine hydrochloride (296 mg) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at 70° C. for 3 h and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4) and evaporated to obtain the title compound (1.2 g, 97%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1)=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cn1cc([N+](=O)[O-])nc1C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])nc1C=O
Yield: 83 %

Procedure:
21 parts of 2-dichloromethyl-1-methyl-4-nitroimidazole in 80 parts by volume of 10 percent strength by weight sulfuric acid are stirred for 2 hours at 100° C. The solution is cooled, poured onto ice and neutralized with 55 parts of 6 N sodium hydroxide solution. The aqueous phase is extracted with 4 times 50 parts by volume of methylene chloride. The combined extracts are dried and evaporated. 13 parts of 2-formyl-1-methyl-4-nitroimidazole (83% of theory) of melting point 129° C. are obtained.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]Br)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N-:37]=[N+]=[N-].[Na+].P(OCC)(OCC)OCC>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([NH:13][C:14]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][NH2:37])=[C:17]([Br:35])[CH:16]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOP(OCC)OCC
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
To a solution of N-dodecyl-3-bromo-4-(2-bromo-ethoxy)-5-(m-trifluoromethylphenyl)-benzamide (1.431 g, 2.25 mmol, 1 eq) in benzene (2 mL) was added tetrabutyl ammonium bromide (0.053 g, 0.16 mmol, 0.07 eq) and sodium azide (0.216 g, 3.32 mmol, 1.48 eq). The reaction was heated at reflux overnight. Additional tetrabutyl ammonium bromide (0.064 g, 0.20 mmol, 0.09 eq) and sodium azide (0.224 g, 3.45 mmol, 1.53 eq) were required as indicated by TLC. The reaction was cooled to rt and the solids were filtered off. The filtrate was washed with H2O and dried over MgSO4. Triethyl phosphite (0.390 mL, 2.27 mmol, 1.0 eq) was then added to Vie filtrate and the reaction was stirred overnight at rt. Additional triethyl phosphite (0.780 mL, 4.54 mmol, 2.0 eq) was required. After 48 h, HCl gas was bubbled through the reaction mixture and stirred was continued for 72 h. The reaction was then concentrated in vacuo, dissolved in THF and washed with 2 M HCl. The washes were then adjusted pH 10 with 2.5 M NaOH and were extracted with CH2Cl2. All organics were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (7 to 12% MeOH:CH2Cl2) to afford the title compound (0.0738 g, 57%) as a colorless oil. 1H NMR (DMSO-d6) δ8.57 (bt, 1H); 8.12 (d, 11H); 7.90 (m, 3H); 7.80 (d, 1H); 7.73 (dd, 1H); 3.51 (dd, 2H); 3.30 (bs, 2H); 3.23 (dd, 2H); 2.58 (dd, 2H); 1.450 (dd, 2H); 1.25 (m, 18H); 0.83 (t, 3H); IR (film) 3300, 3080, 2920, 2850, 1640, 1600, 1550, 1450, 1330, 1160, 1120, 1080 cm−1; mass spectrum [(+)ESI], m/z 571/573 (M+H)+; Anal. Calcd. for C28H38BrF3N2O2: C, 58.84; H, 6.70; N, 4.90, Found: C, 56.61; H, 6.61; N, 4.71.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17](=[CH2:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].II.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]/[C:17](=[CH:25]\[S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])/[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19]
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Reactant: O=S([O-])c1ccccc1
Agent: II
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a suspension of benzenesulphinic acid sodium salt (7.59 g, 46.2 mmol) and tert-butyl 2-(2-methoxyethoxymethyl)acrylate (10.0 g, 46.2 mmol) in ethyl acetate (50 mL) under a nitrogen atmosphere at room temperature was added, in one portion, iodine (11.3 g, 46.2 mmol) and the mixture stirred for 3 days. An additional 50 mL of ethyl acetate was added after 2 days. The reaction mixture was cooled to 0° C. and triethylamine (9.67 mL, 69.3 mmol) added dropwise. The reaction was stirred at 0° C. for 2 hours and at room temperature for 16 hours and diluted with distilled water (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (25 mL). The combined ethyl acetate extracts were washed with a 1.0M aqueous hydrochloric acid solution and 5% aqueous sodium thiosulphate solution (2×100 mL), filtered to remove solids and the filter pad washed with ethyl acetate. The combined filtrate and washings were washed with distilled water (50 mL), and concentrated under reduced pressure to give a brown oil, (14.85 g). The crude product was purified by chromatography on silica by eluting with hexane/ethyl acetate (2:1) to give, after combination and evaporation of appropriate fractions, the title compound as an oil, (5.09 g, 30.8%) which crystallised on standing, m.pt.=46°-48° C., Rf =0.25 (silica, hexane/ethyl acetate, 2:1), (MH+ 357.05, 1.7%).
Reaction SMILES: C([N:8]1[C:12]([C:13]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(O)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: OC(CCCc1ccc(F)cc1)(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Fc1ccc(CCCC(c2ccc(F)cc2)c2c[nH]cn2)cc1
Temperature: 25 °C

Procedure:
1-benzyl-5-[1,4-bis(4-fluorophenyl)-1-hydroxybutyl]-1H-imidazole (10 g) is dissolved in conc. acetic acid (100 ml). Into the solution is added 0,1 g of palladium on carbon and 0,8 g of ammoniumformate. The mixture is refluxed for an hour and cooled to room temperature. The solution is filtered through silicous earth. The acetic acid filtrate is evaporated, the residue is dissolved in methylene chloride and washed once with 2M aqueous sodium hydroxide solution and once with water. The methylene chloride solution is dried with sodium sulphate and evaporated under reduced pressure. The product is then made to hydrochloride salt with dry hydrogen chloride in diethylether. M.p. 135°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CN(C=O)C>[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[C:4]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCN1CCNCC1
Reactant: CC(=O)N(C)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc(N(C)C(C)=O)c2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a DMF solution (2.5 ml) of N-(3-bromo-phenyl)-N-methyl-acetamide (114 mg) obtained in Step B, palladium acetate (1.1 mg), S-Phos (4.1 mg) and potassium phosphate (212.3 mg), 1-ethylpiperazine (76.2 μl) was added, and then the mixture was degassed under ultrasonic irradiation. This was stirred at 100° C. for 5 hours, followed by addition of water (10 ml), which was extracted with ethyl acetate (10 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=20/1 to 10/1), to obtain the desired compound (104.9 mg, 80%).