Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.[OH-].[Na+]>CO>[C:18](/[C:17](/[C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:19]
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1
Reaction time: 3 h
Yield: 57.9 %

Procedure:
To a stirred mixture of 4-methoxybenzaldehyde (2 g, 14.69 mmol) and 3-pyridylacetonitrile (1.58 ml, 14.84 mmol) in methanol (30 ml) was added 50% w/v sodium hydroxide (1 ml). The reaction was stirred for 3 hours. The reaction mixture was quenched with water (20 ml), acidified with 2N HCl, then rebasified with dilute NaOH (aq), and the reaction product was extracted successively into dichloromethene (3×20 ml). The organic solutions were dried over anhydrous MgSO4 and the solvent removed. Purification by column chromatography (SiO2, Hexane/Ethylacetate 8:2; 1:1) gave 2.01 g (58% yield) of the title compound as a straw coloured solid: 1H-NMR (CDCl3) 8.80 (d, 1H), 8.50 (m, 1H), 7.80 (m, 3H), 7.45 (s, 1H), 7.25 (m, 1H), 6.90 (m, 2H), 3.80 (s, 3H). 13C NMR (CDCl3) 161.9, 157.6, 157.5, 149.5, 146.9, 143.3, 133.1, 131.4, 130.9, 126, 123.5, 117.7, 114.5, 105.2, 55.4. Mass Spectrum m/e (M+1) 237.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
Add nitric acid (65%, 21.0 g, 0.22 mol) dropwise to a cooled mixture (−10° C.) of (2-bromo-4-fluorophenyl)acetic acid (50 g, 0.22 mol) in concentrated sulfuric acid (250 mL) and stir the resulting mixture at −10-0° C. for 20 min. Pour onto crushed ice, extract with EtOAc (3×200 mL), wash organics with brine (3×100 mL), dry over sodium sulfate, and concentrate in vacuo to give the title compound (50 g, 84% yield). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J=7.6 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 3.87 (s, 2H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:21]=2[N:20]=1>C(O)(C)C>[ClH:2].[ClH:1].[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:21]=3[N:20]=2)[C:9]=1[CH3:10]
Reactant: FC(F)(F)c1ccc2[nH]c(S)nc2c1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
Following the procedure described in Example 12, the reaction of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride with 2-mercapto-5-trifluoromethyl-1H-benzimidazole in isopropanol gives the title compound as a colorless solid; m.p. 173° C (decomp.).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:13]([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:18][CH2:2][CH2:3][N:4]1[CH:13]([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC1c2ccccc2NC(=O)N1CCO
Solvent: ClC(Cl)Cl
Product: CC1c2ccccc2NC(=O)N1CCCl

Procedure:
A mixture of 8 parts of 3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone, 8 parts of thionyl chloride and 90 parts of trichloromethane is stirred and refluxed for 1.50 hours. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 6.6 parts of 3-(2-chloroethyl)-3,4-dihydro-4-methyl-2(1H)-quinazolinone; mp. 126.4° C.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10]>C(O)(=O)C>[CH3:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][N+:3]=1[O-:1]
Reactant: OO
Reactant: Cc1ccc(C)nc1
Solvent: CC(=O)O
Product: Cc1ccc(C)[n+]([O-])c1
Reaction time: 8 h

Procedure:
400 ml of 30% hydrogen peroxide were added dropwise at room temperature to 321.5 g of 2,5-lutidine (2,5-dimethylpyridine) in 1800 ml of glacial acetic acid. The solution was stirred at 80° overnight, then cooled to 40° , treated once more with 400 ml of 30% hydrogen peroxide and heated to 80° for a further 24 hours. After evaporation in vacuo the residue was dissolved in 300 ml of water. The solution was made basic with concentrated sodium hydroxide solution while cooling, saturated with sodium chloride and extracted three times with 1 1 of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. There was obtained 2,5-dimethylpyridine 1-oxide in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.C(Cl)(=O)C(Cl)=O.C1COCC1.C[N:41](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:41])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a stirred suspension of 4-[4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (0.5 g, 1.24 mmol) in THF/DMF (9.0 mL; 8:1) was added oxalyl chloride (0.33 mL, 3.7 mmol) and the mixture stirred for 18 hours. The solvent was concentrated and the residue co-evaporated with toluene. To the residue was added a solution of ammonia in dioxane (0.5 M, 20 mL) and the mixture stirred for 18 hours. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and absorbed onto silica. The crude product was chromatographed by flash column chromatography (3% MeOH in DCM) to give the product as pale yellow solid (0.278 g, 55.7%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH:34]([C:36]#[N:37])[CH2:33][NH:32][C:31]=4[CH:38]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH:34]([C:36]#[N:37])[CH2:33][NH:32][C:31]=2[CH:38]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC(C#N)O4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CC1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (430 mg) in THF:Methanol:water (2:1:1 mixture, 4 mL) was added lithium hydroxide (20 mg). After stirring at room temperature overnight, the reaction mixture was concentrated. The resulting residue was taken up in 50% methanol in ethyl acetate then filtered through celite bed. The filtrate was concentrated, and the residue was purified by preparative HPLC to furnish 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: O=C1CNCCN1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCNC(=O)C4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 71.7 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.200 g) was dissolved in 2-methoxyethanol (6 ml) and piperazine-2-one (0.821 g) was then added and the mixture heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.162 g) as a white powder, NMR Spectrum: (d6-DMSO) 2.10 (quin, 2H), 2.66 (m, 4H), 3.12 (s, 2H), 3.33 (m, 2H), 3.44 (s, 3H), 4.01 (s, 3H), 4.24 (t, 2H), 4.34 (s, 2H), 6.09 (s, 2H), 7.04 (, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.77 (s, 1H), 8.46 (s, 1H), 9.04 (s, 1H); Mass Spectrum: M+H+ 554/556.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[C:6]([OH:8])=[O:7])=[O:10])=[CH:20][CH:19]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a solution of 4-bromophthalic anhydride (50 g, 220 mmol) in fluorobenzene (300 mL) was added aluminum chloride (60 g, 450 mmol) by small portions under ice-cooling. The-obtained mixture was stirred at room temperature for 15 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether and the precipitated crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give a solid of a mixture (9:1)(7 g, 10%) of 2-(4-fluorobenzoyl)-4-bromobenzoic acid and 2-(4-fluorobenzoyl)-5-bromobenzoic acid. (2-(4-fluorobenzoyl)-4-bromobenzoic acid: 1H-NMR(CDCl3) δ: 7.06–7.17 (2H, m), 7.50 (1H, d, J=2.0 Hz), 7.69–7.79 (3H, m), 7.95 (1H, d, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1O>>[F:18][C:17]1[C:12]2[N:11]=[C:4]([C:3]3[C:2]([NH2:1])=[N:10][CH:9]=[CH:8][CH:7]=3)[O:6][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1c(O)cccc1F
Reactant: Nc1ncccc1C(=O)O
Product: Nc1ncccc1-c1nc2c(F)cccc2o1
Temperature: 200 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
PPA (10 ml) at 50° C. was added to a stirred mixture of 2-aminonicotinic acid (2 g) and 2-amino-3-fluoro-phenol (1.841 g). The resulting suspension was stirred at 200° C. for 16 hours. The mixture was cooled and quenched with ice and water (100 ml) and the pH was adjusted to 12 with an aqueous solution of sodium hydroxide (6N then 2N). The resultant solid was filtered and washed with water. The solid was dried under reduce pressure with phosphorus pentoxide. The solid was adsorbed on silica gel with methylene chloride (100 ml) and methanol (10 ml) and purified by flash chromatography on silica gel eluting with 20 to 30% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (2.060 g) as a solid. NMR Spectrum: (CDCl3): 6.78 (dd, 1H), 6.97 (bs, 2H), 7.09 (dd, 1H), 7.31 (ddd, 1H), 7.38 (d, 1H), 8.30 (d, 1H), 8.33 (bs, 1H); Mass spectrum: M+H+ 230
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:8].CN(C)C=O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:24]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:18])(=[O:26])[CH3:25]
Reactant: O=C(Cc1cccs1)C1C(=O)Nc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)N1C(=O)C(C(=O)Cc2cccs2)c2ccccc21
Reaction time: 0.02 h
Yield: 4.4 %

Procedure:
A stirred mixture of 1.29 g (5.0 mmole) of 3-([2-thienyl]acetyl)-2-oxindole, 1.22 g (10.0 mmole) of 4-(N,N-dimethylamino)pyridine and 15 ml of N,N-dimethylformamide was cooled in an ice-bath, and then 562 mg (5.5 mmole) of acetic anhydride was added dropwise, with stirring, during 1 minute. Stirring was continued for 3.25 hours at ice-bath temperature, and then the reaction mixture was filtered. The filtrate was poured onto a mixture of 3N hydrochloric acid and water, which caused formation of a solid and a gum. The solid was recovered by filtration and the gum was recovered by decantation. The gum was triturated under isopropanol-water giving further solid material, which was also recovered by filtration. The two solids were combined and extracted with hot benzene, leaving a dark, gummy residue. The benzene solution was cooled and evaporated in vacuo, and the residue was recrystallized from toluene to give 66 mg of the title compound, m.p. 136°-137° C. The mother liquors from the recrystallization were evaporated in vacuo and the latter residue was recrystallized from hexane to give a second crop, 90 mg, of the title compound, m.p. 135°-136° C. The second crop was submitted to elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][CH2:44][NH:43][C@H:42]([CH3:46])[CH2:41]1)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[N:20]=[C:19]([CH2:21][N:43]5[CH2:44][CH2:45][NH:40][CH2:41][CH:42]5[CH3:46])[O:18][N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2noc(CN3CCNCC3C)n2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 70 °C
Yield: 39.5 %

Procedure:
To a solution of 2-(4-chlorobenzyl)-5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2,3-dihydroisoindol-1-one (37 mg, 0.0952 mmol) in MeCN (4 mL) was added K2CO3 (39 mg, 0.286 mmol) and (3R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (38 mg, 0.190 mmol). The mixture was heated at 70° C. overnight, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH 9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) to provide 2-(4-chlorobenzyl)-7-methyl-5-[5-(2-methylpiperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one as a yellow oil (17 mg). 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.93 (s, 1H), 7.33 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.29 (s, 2H), 4.17 (d, 1H), 4.06 (d, 1H), 2.83-3.04 (m, 4H), 2.83 (s, 3H), 2.50-2.61 (m, 3H), 1.19 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:13]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:24]=3)[N+:12]=2[O-])=[CH:7][CH:6]=1)[CH3:3].P(OCC)(OCC)OCC>CN(C)C(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:24]=3)=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:15]=2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(-c2[nH]c(-c3ccc(F)cc3)c(-c3ccnc(Oc4ccccc4)n3)[n+]2[O-])cc1
Agent: CCOP(OCC)OCC
Solvent: CC(=O)N(C)C
Product: CN(C)Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccnc(Oc4ccccc4)n3)[nH]2)cc1
Temperature: 95 °C
Yield: 30.6 %

Procedure:
To a solution of 2-[4-(N,N-Dimethylaminomethyl)phenyl]-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl)imidazole-N-oxide (0.32 g, 0.66 mmol) in 5 mL of N,N-dimethylacetamide was added triethyl phosphite (0.34 mL, 2.0 mmol) and the solution was heated at 95° C. overnight. The solution was concentrated to a small volume under reduced pressure and H2O was added. The mixture was extracted thrice with 20 mL of CH2C2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by silica gel chromatography using 5-15% CH3OH/CH2Cl2 to give the title compound as a yellow foam (0.094 g, 30%). ES(+)MS m/e=466 (MH+)
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1csc(N2CC(O)C2)n1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (2.20 g, 4.29 mmol) (obtained as described in Reference Example 32(1)) in anhydrous tetrahydrofuran (110 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (5.15 ml, 5.15 mmol) in an ice bath, and then the mixture was stirred for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-hydroxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.18 g, yield 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:49][CH2:48]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H46N6O5SCl2 [(M+H)+] 769.2700, observed 769.2697.
Reaction SMILES: Br.N=[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][S:4]1.C([O-])(=[O:17])C.[Na+].C(O)(=O)C.N([O-])=O.[Na+]>O>[C:9]1([CH2:8][N:7]2[CH2:6][CH2:5][S:4][C:3]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N=C1SCCN1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1SCCN1Cc1ccccc1
Yield: 42.3 %

Procedure:
To a solution of 2.73 g (0.01 mol) of 2-imino-3-phenylmethylthiazolidine hydrobromide in 10 ml of water 1.36 g of anhydrous sodium acetate and 0.62 ml of glacial acetic acid are added, then 0.75 g of sodium nitrite dissolved in 3 ml of water is dropped to the above mixture at 5° C. under stirring, then the mixture is stirred at 5° C. for additional 3 hours. After standing in a refrigerator overnight, the solution is stirred at room temperature for 3 hours. After rubbing, a precipitate appears which is filtered off, washed with water, dried and then refluxed with five volumes of n-butanol for 2 hours. After evaporating the solvent, the residue is thoroughly rubbed with diisopropyl ether and the product is filtered off. Thus, 0,81 g (42.3%) of the title product is obtained, m.p.: 49°-50° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([OH:23])=O)[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[CH3:25][NH2:26].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([NH:26][CH3:25])=[O:23])[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(CC(=O)O)n1nnc(-c2cccc(Cl)c2)n1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)CC(C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Oxalylchloride (2 mL, 3.9 mmol) was added during 5 minutes to 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butanoic acid in DCM (40 mL) and DMF (5 drops) under argon. The mixture was stirred at r.t. for 3 h and then was MeNH2 (2M in THF, 3.6 mL, 7.2 mmol) added and the resulting mixture was stirred o.n. Saturated NaHCO3 (75 mL) was added and the mixture was extracted with CHCl3 (3×100 mL). The combined organic phases were dried (MgSO4) and concentrated. The crude was purified by flash column chromatography (SiO2, Heptane-EtOAc 1:2) to give 0.74 g (74%) of the title compound.