Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC[NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].C(N([CH2:15][CH3:16])CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[C:17]([CH2:15][CH2:16][CH:7]=[C:6]([CH3:8])[C:5]([NH2:4])=[O:9])([CH:18]=[CH2:19])=[O:20]
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: C=C(C)C(=O)NCCO
Solvent: ClC(Cl)Cl
Product: C=CC(=O)CCC=C(C)C(N)=O
Reaction time: 16 h

Procedure:
To a stirred solution of N-(2-hydroxyethyl)methacrylamide (10 mmol, 1.3 g) and triethylamine (11 mmol, 1.5 cm3) in chloroform (40 cm3), was added dropwise, a solution of acryloyl chloride (11 mmol, 0.9 cm3) in chloroform (20 cm3) at room temperature under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred for a further 16 h. The usual work-up as for example 1 then gave the crosslinking monomer, 2-acrylethylmethacrylamide (Rf 0.54) as a clear, colorless oil (0.6 g, 32%). δH (400 MHz; CDCl3) 6.45 (1H, br m), NH; 6.38 (1H, dd, J 17.8, 2.0 Hz), ROOCH═CHaHb; 6.08 (1H, dd, J 17.8, 8.9 Hz), ROOCH═CHaHb; 5.82 (1H, dd, J 8.9, 2.0 Hz), ROOCH═CHaHb; 5.66 (1H, s), RHNOC(H3C)C═CHcHd; 5.29 (1H, s), RHNOC(H3C)C═CHcHd; 4.25 (2H, t, J 4.9 Hz), CH2OCO; 3.57 (2H, td, J 4.9, 4.7 Hz), CH2NHCO; 1.94 (3H, s), CH3. δC (75.4 MHZ; CDCl3) 168.52, HNC═O; 166.22, OC═O; 139.60, RHNOC(H3C)C═CH2; 131.34, ROOCH═CH2; 127.83, ROOCH═CH2; 119.69, RHNOC(H3C)C═CH2; 63.07, CH2OC═O; 38.97, CH2NHC═O; 18.43, CH3. Found: M+. 183.22.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[N:12]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1
Reactant: [H][H]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccccc2N)co1

Procedure:
Combine 5-[4-(2-nitro-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.5 g, 8.2 mmol) with 5% Pd/C (300 mg) and Pd/black (50 mg) in THF and react with hydrogen (init. 39 psi) in a Parr® apparatus. When reduction is complete, filter the mixture through, Celite® and concentrate the filtrate. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 2.05 g (91%) of 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester. MS (ES): (M+1)+ 275.1, 276.2 m/z.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1.O>C1COCC1>[F:29][C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(Nc1ncc(Br)s1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ncc(F)s1)C(F)(F)F
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
NEt3 (63.4 mL, 455 mmol) was added to a stirred suspension of 5-bromothiazol-2-ylamine hydrobromide (102.7 g, 379 mmol) in CH2Cl2 (1.5 L). After 1 h, TFAA (64.2 mL, 455 mmol) was added dropwise at 0° C. over 15 min. The mixture was allowed to warm to 20° C. over 1 h, before being stirred for an additional 2 h. H2O (600 mL) was added and the resulting precipitate was collected. The aqueous layer of the filtrate was separated and extracted with CHCl3 (3×300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The collected precipitate and residual solid were combined and triturated with EtOAc-n-C6H14 to give N-(5-bromothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.45 (1H, s), 13.05 (1H, br). n-BuLi (253 mL of a 1.58M solution in hexanes, 403 mmol) was added dropwise over 50 min to a stirred solution of the above amide (50.0 g, 183 mmol) in anhydrous THF (1.3 L) at −78° C. After 1.5 h, a solution of N-fluorobenzenesulphonimide (86.0 g, 275 mmol) in anhydrous THF (250 mL) was added dropwise over 30 min. The mixture was stirred for 3 h, before being warmed up to −30° C. H2O (300 mL) was added and the mixture was filtered through a Celite pad. The solid collected and Celite were washed with Et2O (400 mL) and H2O (400 mL). The organic layer of the filtrate was separated and extracted with water (2×400 mL). The combined aqueous layers were washed with Et2O (400 mL), before being acidified to pH 6.5 with 2M HCl and extracted with EtOAc (2×400 mL). The combined organic extracts were washed with H2O (2×400 mL) and brine, before being dried (MgSO4), filtered and concentrated. Column chromatography (EtOAc-n-C6H14, 1:3 to 1:2) gave N-(5-fluorothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.13 (1H, d). AcCl (12.6 mL, 175 mmol) was added dropwise to a stirred solution of this amide (15.7 g, 73 mmol) in MeOH (300 mL) at 0° C. The mixture was stirred at 20° C. for 30 min, heated under reflux for 1 h, and finally concentrated in vacuo. The residual solid was triturated with THF to give the title compound: δH (D2O): 7.00 (1H, d).
Reaction SMILES: C([NH:3][CH:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:5])=O.C(N)=O>>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([C:6]2([CH:4]([NH2:3])[CH3:5])[CH2:9][CH2:8][CH2:7]2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: NC=O
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Product: Cl

Procedure:
The preparation of N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (m.p. 124°-125° C.) (Example 1(a) Formula I R1 =Me; R2 =H; R3 =H; R4 =CHO; R5 =4--Cl and R6 =3--Cl) described above was repeated and the product isolated by cooling the reaction mixture and collecting the solid produced by filtration. The formamide was then hydrolysed by concentrated hydrochloric acid in industriral methylated spirit to give the hydrochloride salt of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 46.1 %

Procedure:
15.23 g of 5-acetyl-8-hydroxycarbostyril and 15.7 g of benzyl chloride are added to a mixture of 200 ml of acetone and 90 ml of water, and 10.35 g of potassium carbonate are added thereto. The mixture is refluxed for 12 hours under stirring. Then, the mixture is evaporated under reduced pressure to remove acetone, and the residue is extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove chloroform. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 10.14 g of 5-acetyl-8-benzyloxycarbostyril are obtained as prisms. 1.58 g of said product are further recovered from the mother liquor.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1>C(COC)OC>[CH2:1]([N:8]([CH2:24][C:21]1[CH:20]=[N:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2ccc(Cl)nc2)CO1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.1 g of sodium hydroxide are added and, at 40° C. 25.5 g of a 20% solution of 2-chloro-5-(chloromethyl)pyridine in dimethoxyethane are metered in. The mixture is stirred at 50° C. for a further 6 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 8 g of 4-{benzyl[(6-chloropyridin-3-yl)methyl]amino}furan-2(5H)-one are obtained (this corresponds to 85% yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.[F:30][C:31]([F:39])([F:38])[CH2:32][CH2:33][C:34]([NH:36][NH2:37])=[O:35].CN1CCOCC1>ClCCCl.O>[F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:37][NH:36][C:34](=[O:35])[CH2:33][CH2:32][C:31]([F:39])([F:38])[F:30])=[O:11])=[C:8]([C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: O=C(Cl)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: NNC(=O)CCC(F)(F)F
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a stirred solution of (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoyl chloride (143 mg, 0.288 mmol) in DCE (3 mL) were added 4,4,4-trifluorobutanehydrazide (45 mg, 0.29 mmol), and 4-methylmorpholine (63.4 μL, 0.577 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with aqueous 1M HCl (−1×30 mL), saturated aqueous NaHCO3 (1×30 mL), and brine. The resulting organic solution was dried over Na2SO4 and concentrated under reduced pressure. Purification by automated flash column chromatography (SiO2, hexanes and EtOAc) afforded the title compound as a beige solid (78 mg, 42%): 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.85 (s, 1H), 7.70-7.62 (m, 1H), 7.55 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.41 (s, 2H), 6.59 (d, J=15.9 Hz, 1H), 6.44 (dd, J=15.9, 7.8 Hz, 1H), 4.19-4.05 (m, 1H), 2.51 (dd, J=9.0, 6.6 Hz, 2H), 2.37-2.18 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −59.46, −67.07, −68.59; ESIMS m/z 615 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][NH2:21])=[CH:18][C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=O)C.[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[C:19]([N:20]2[C:25](=[O:24])[CH:27]3[C:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)=[N:21]2)=[CH:18][C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NNc1cc2c(cc1F)OCC(=O)N2Cc1ccccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1COc2cc(F)c(N3N=C4CCCCC4C3=O)cc2N1Cc1ccccn1
Yield: 60.8 %

Procedure:
A mixture of 7-fluoro-6-hydrazino-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (1.49 g), 2-ethoxycarbonyl-cyclohexanone (0.9 g) and ethanol (20 ml) was admixed with a catalytic amount of sodium ethoxide, and heated under reflux for 5 hours. The reaction mixture was distilled to remove the ethanol therefrom, admixed with toluene (30 ml), heated under reflux for 10 minutes, cooled to a temperature of 0° to 10° C., and filtered. The solid portion thus obtained was washed with n-hexane, and dried, so that the aimed compound, i.e. 7-fluoro-6-(3,3a,4,5,6,7-hexahydro-2H-indazole-3-on-2-yl)-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (1.24 g) was obtained. m.p. 216°-219° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH3:16])[N:9]=2)[S:5][C:6]=1[CH3:7].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:14][C:13]3[C:8]([C:4]4[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=4)=[N:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 9 h
Yield: 22.1 %

Procedure:
2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-ol (200 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (768 mg), 4-dimethylaminopyridine (313 mg), and cesium carbonate (313 mg) were suspended in dimethyl sulfoxide (4 ml), and the mixture was stirred at 130° C. for 9 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (94 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)[C:6]=1[CH3:7]
Reactant: C1=COCCC1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c(C(F)(F)F)nn1C1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A solution of 4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazole (1.00 g, 4.37 mmol) and p-toluenesulfonic acid monohydrate (80 mg, 0.4 mmol) in CHCl3 (3.5 mL) was cooled to 0° C. and dihydropyran (480 μL, 5.2 mmol) was added dropwise. The reaction was stirred at 0° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by column chromatography to obtain the desired product (1.18 g, 86%). 1H NMR (400 MHz, CDCl3): δ 5.35 (dd, 1H), 3.98 (m, 1H), 3.65 (m, 1H), 2.40 (m, 1H), 2.37 (s, 3H), 2.12 (m, 1H), 1.96 (m, 1H), 1.64 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:24][C:25](=[O:31])OC(C)(C)C)[S:5][C:6]=1[C:7](=O)[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[S:15]C(=S)N(CC)CC.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(CC)C(SC1C=NC=CC=1NC(C1SC(N)=NC=1Br)=O)=S)C.C(O)=O>C([SiH](CC)CC)C>[Br:1][C:2]1[N:3]=[C:4]([NH:24][CH:25]=[O:31])[S:5][C:6]=1[C:7]1[S:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(NC(=O)OC(C)(C)C)nc1Br
Agent: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(N)nc1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: O=CNc1nc(Br)c(-c2nc3ccncc3s2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-bromo-5-((3-(diethylcarbamothioylthio)pyridin-4-yl)carbamoyl)thiazol-2-ylcarbamate (1.0 g, 1.8 mmol) and a 1:1 mixture of TFA (0.14 mL, 1.8 mmol) and DCM (0.12 mL, 1.8 mmol) with a few drops of triethylsilane. The solution was then stirred at room temperature. LCMS indicated that the reaction was complete after about 1 hour. The solvents were removed, and the resulting oil was used without further manipulation. To a 100 mL round-bottomed flask was added 4-(2-amino-4-bromothiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (0.82 g, 1.8 mmol) and formic acid (0.070 mL, 1.8 mmol), and the mixture was heated at 100° C. for about 2 hours. LCMS indicated no remaining starting material, so the solvent was removed and 2 N ammonia in MeOH was added. An orange precipitate formed which was filtered and determined to be the product N-(4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)formamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:10]=2)[CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(OCCN3CCCCC3)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Synthesized from 2-(3′-benzyloxy-5-methoxybiphenyl-2-yl)-6-methoxynaphthalene (205 mg) according to an analogous synthetic method to Example 22, 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (176 mg) was obtained. To a solution of 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (276 mg) in N,N-dimethylformamide (7 ml) were sequentially added potassium carbonate (220 mg) and 1-(2-chloroethyl)piperidine (280 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (319 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1.[C-:28]#[N:29].[Na+].[N+:31]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[N+:31]([C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:11]2([C:28]#[N:29])[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:3][C:2]=3[F:1])[CH2:9][C:10]2([CH3:15])[CH3:16])=[CH:36][CH:35]=1)([O-:33])=[O:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc([N+](=O)[O-])cc4)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 51 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[3-fluoro-4-(4-oxo-3,3-dimethylpiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 4-nitroaniline the compound was obtained in 51% yield.
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].CO[C:21](OC)([N:23](C)C)[CH3:22]>>[C:9]1([SH:6]2(=[O:7])[CH:5]=[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=3)[N:23]=[C:21]([CH3:22])[NH:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(C)(OC)N(C)C
Reactant: N=S(=O)(C=Cc1ccccc1N)c1ccccc1
Product: CC1=NC(c2ccccc2)=C[SH](=O)(c2ccccc2)N1

Procedure:
Using the procedure of Step B of Example 1, the S-(2-aminostyryl)-S-phenyl-sulfoximine of Example 1 Step A was reacted with dimethyl acetamide dimethyl acetal to obtain 1,5-diphenyl-3-methyl-1H-1,2,4-thiadiazine-1-oxide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].C(N(CC)CC)C>C(OCC)C>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)c1cccs1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)c1cccs1
Reaction time: 60 h
Yield: 99 %

Procedure:
12 g of 3-chloro-1-(thiophen-2-yl)propan-1-one) prepared in Example 1a are solubilized in ethyl ether (180 mL). Triethylamine (10.2 g; 100 mmoles) is added at room temperature. The mixture is left under stirring for 60 hours, then washed with a HCl 10% solution and extracted with ethyl ether (2×20 mL). The organic phase is anhydrified with sodium sulphate, filtered and the solvent removed under vacuum. 9.4 g of 1-(thiophen-2-yl)-prop-2-en-1-one are obtained (yellow oil, yield 99%). Rf=0.74 (ligroin/ethyl acetate 8/2 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.76 (m, 1H, ArH), 7.68 (m, 1H, ArH), 7.10 (m, 2H, ArH), 6.49 (m, 1H, CH2), 5.87 (m, 1H, CH2); 13C NMR (CDCl3) δ (ppm): 182.4, 144.6, 134.4, 132.5, 131.9, 129.4, 128.3; FT-IR (film) νmax: 3094.5, 1645.1, 1409.7, 1240.2, 850.4, 716 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N([OH:23])N=NC=2C=1.N1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>Cl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([N:2]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(F)cn1
Reactant: C1COCCN1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1ccc(F)cn1)N1CCOCC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 203.1 %

Procedure:
2-Cyano-5-fluoropyridine (1.00 g, 8.19 mmol) was dissolved in hydrochloric acid (37% aqueous, 1.0 mL) and heated to 60° C. for 18 h and then evaporated in vacuo. The residue was suspended in DMF (40.0 mL) and EDC (1.89 g, 9.83 mmol), HOBt (111 mg, 0.82 mmol), morpholine (787 μL, 9.00 mmol) and triethylamine (1.25 mL, 9.00 mmol) were added and the reaction stirred for 18 h. The reaction was partitioned between water (200 mL) and EtOAc (100 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-8% [2M NH3 in MeOH] in DCM, to give the title compound (350 mg), contaminated with a single impurity (˜10% by NMR integration). The product was used in the next step without further purification. LCMS (Method 1): Rt 1.88 min, m/z 211 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH3:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([N:15]([CH3:14])[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CNc1cccc2ccccc12
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Product: CCc1cccc(N(C)C(=N)N(C)c2cccc3ccccc23)c1
Reaction time: 14 h

Procedure:
In a 5 ml round bottom flask was placed N-(3-ethyl phenyl)-N-methylcyanamide (340 mg, 2.18 mmol), N-methyl -1-naphthyl amine hydrochloride (440 mg, 2.28 mmol) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath and allowed to stir under N2 for 14 h. The resultant brown glass was dissolved in methanol (5 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (25 ml) and extracted with CHCl3 (5×20 ml) to yield a brown oil upon drying (540 mg). A TLC of this brown oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/EtOH 2:1 (TLC Rf=0.09, CHCl3 :EtOH, 1:1) to afford a pale yellow oil, 380 mg (56%). IR (neat) 3323 (--NH), 1690-1570 (broad, --C=NH). 1H-NMR (CDCl3) δ1.02 (t, 3H, J=7.5), 2.35 (q, 2H, J=7.5), 2.96 (s, 3H), 3.27 (s, 3H), 5.70 (broad s, 1H), 6.45-7.73 (m, 11H, H-aromat). 13C-NMR (CDCl3)CN3, 163.4; Ar, 145.9, 144.4, 142.5, 134.0, 129.7, 128.2, 127.8, 125.9, 125.5, 125.3, 125.1, 123.6, 123.1, 123.0, 122.5, 120.8; NCH3, 40.1;N'CH3, 39.4; CH2, 28.2; CH3, 15.0. Mass Spec. m/e calcd for C21H23N3, 317.1892, Found, 317.1881.