Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: O=S(=O)(Nc1nc(-c2ccccc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine (57 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (64.8 mg) with purity >90%: MS (pos) m/z 453.3, 455.3, 457.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:12][C@H:13]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:14]([CH3:17])([OH:16])[CH3:15].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C@H:13]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:14]([CH3:17])([OH:16])[CH3:15])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)[C@H](N)c1ccc(F)cc1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1SCC2)c1ccc(F)cc1
Temperature: 80 °C

Procedure:
0.533 g (II), 0.850 g (R)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is heated to 80° C. in the microwave for 2 hours and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 0.260 g (III-4) are obtained as a solid. Analytical HPLC-MS (method A): 1.39 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:27]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:4][C:5]([NH:8][S:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[N:6][CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([CH:27]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)(=[O:38])=[O:37])[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:4][C:5]([NH:8][S:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(=O)(=O)Nc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(CCN1CCNCC1)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.3 %

Procedure:
To an ethanol (5 ml) solution of t-butyl 4-[2-[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]ethyl]piperazine-1-carboxylate (72 mg, 0.102 mmol) was added concentrated hydrochloric acid (1 ml). The resulting mixture was stirred at room temperature for 2 days, followed by concentration under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with ether to give the title compound (23 mg, 0.038 mmol, 37%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)=[CH:5][CH:4]=1.[H][H]>O=[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[NH2:14])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(Oc2c[n+]([O-])ccc2[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(Oc2cnccc2N)cc1

Procedure:
To 250 ml ethanol in a 500 ml Parr hydrogenation bottle, were added 3-(4-methoxyphenoxy)-4-nitropyridine-1-oxide (7.9 g) and 0.4 g PtO2. After shaking for two hours at fifty psi of hydrogen, the mixture was filtered and concentrated to 5.8 g of oil.
Reaction SMILES: [C:1]1(N)C(F)=C(F)C(F)=C(N)[C:2]=1F.Cl.Cl.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C@@:27]34[CH2:32][C@@H:31]3[CH2:30][NH:29][CH2:28]4)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.C(I)C>CN(C=O)C.O>[CH2:1]([N:29]1[CH2:30][C@@H:31]2[C@@:27]([C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:26][CH:25]=3)([CH2:32]2)[CH2:28]1)[CH3:2]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: c1cc([C@]23CNC[C@H]2C3)ccc1N1CCOCC1
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C[C@H]2C[C@@]2(c2ccc(N3CCOCC3)cc2)C1
Yield: 47 %

Procedure:
To a solution of dihydrochloride salt of (1R,5S)-(4-morpholin-4-yl-phenyl)-3-aza-bicyclo[3.1.0]hexane (5.0 g, 17.8 mmol) in DMF (20 mL) were added DIPEA (12.7 mL, 71.3 mmol) and ethyl iodide (2.14 mL, 26.7 mmol) at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound as viscous liquid (2.3 g, 47%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[CH2:18][OH:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
Compound 12 (2.64 g, 8.16 mmol) was dissolved in toluene (40 mL), and diisobutylaluminum hydride (1.0 mol/L toluene solution, 24.5 mL) was added to the solution at 0° C. under argon atmosphere, followed by stirring at 0° C. for 1.5 hours. The reaction mixture was added with a saturated aqueous (+)-potassium sodium tartrate tetrahydrate solution to terminate the reaction, and diluted with ethyl acetate, followed by stirring vigorously for 30 minutes. The organic layer was separated from the aqueous layer, and washed with saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:1) to obtain Compound 13 (2.32 g, yield 90%).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[CH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[CH2:33]([O:32][C:30]([CH2:29][O:3][N:4]=[CH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=[O:31])[CH3:34]
Reactant: ON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
0.10 g (2.5 mmol) of sodium hydride was added to a suspension of 0.50 g (1.4 mmol) of 2-hydroxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 25 ml of dimethylformamide. The obtained mixture was stirred. After 30 minutes, 25 ml (2.3 mmol) of ethyl bromoacetate was dropped into the mixture. The mixture thus obtained was stirred at room temperature for several hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reducer pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.52 g of the title compound as a pale-yellow crystal.
Reaction SMILES: FC(F)(OC1C=CC(C(F)(F)F)=CC=1)C(F)(F)F.S(=O)(=O)(O)O.ClS(O)(=O)=O.[F:29][C:30]([F:45])([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)[C:31]([F:34])([F:33])[F:32].S(Cl)([Cl:48])=O>CN(C)C=O>[F:29][C:30]([F:45])([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([Cl:48])=[O:41])=[CH:38][CH:37]=1)[C:31]([F:34])([F:33])[F:32]
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: FC(F)(F)c1ccc(OC(F)(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7.5 parts of p-pentafluoroethoxy benzotrifluoride, 118 parts of 98% sulfuric acid, 11 parts of chlorosulfonic acid (HSO3Cl) and 2 parts of silica gel was heated to 115° C. and maintained thereat for 1.5 hours, then cooled and poured over ice. The resultant crude p-pentafluoroethoxy benzoic acid solid was mixed with 1 part of dimethyl formamide and 25 parts of thionyl chloride. The mixture was stirred for about 45 minutes and an additional 67 parts of thionyl chloride was added. The reaction mixture was then heated at reflux for 2 hours and the product distilled to yield 3.4 parts of p-pentafluoroethoxy benzoyl chloride (b.p. 152° C.-157° C.). ##STR15##
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:28]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:29])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCCC1
Yield: 74 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) was suspended in 1,2-dichloroethane (20 ml), cyclohexylcarbonyl chloride (1.21 g) and pyridine (652 mg) were added, and the mixture was refluxed for 1 hour and 30 minutes. Water (100 ml) was added to the reaction mixture, extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and n-hexane was added to the residue for trituration, collected by filtration, to thereby obtain 2.04 g of the titled compound (Yield: 74.2%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][S:4][C:5]1[NH:10][C:9](=O)[CH:8]=[CH:7][N:6]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:3][C:2]([F:13])([F:12])[F:1])[N:10]=1
Reactant: O=c1ccnc(SCC(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)CSc1nccc(Cl)n1
Yield: 58.8 %

Procedure:
The solution of 2-(2,2,2-trifluoro-ethylsulfanyl)-3H-pyrimidin-4-one (25 g, crude) in POCl3 (250 mL) was stirred and refluxed for 5 hours. After most POCl3 was removed, the residue was dropped into ice and the pH was adjusted to 8-9, extracted with ethyl acetate, dried over MgSO4 and the crude material was purified by column chromatography on silica gel to give 4-chloro-2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidine (14.6 g, 58.8%) as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10]1.Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C:13]1[N:9]([CH3:8])[CH:10]=[N:11][CH:12]=1)=[O:16]
Reactant: Cn1cncc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cncn1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (5.51 mL, 39.646 mmol) was added slowly to a mixture of 1-methyl-1H-imidazole-5-carboxylic acid (2 g, 15.86 mmol), N,O-dimethylhydroxylamine hydrochloride (1.55 g, 15.86 mmol), and EDCI (3.65 g, 19.03 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture was stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([CH3:25])=[CH:17][C:18]([NH2:22])=[CH:19][C:20]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N)cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3,5-dimethylnitrobenzene (2.24 g) in a mixture of ethanol (30 ml) and tetrahydrofuran (10 ml) was added palladium on carbon (0.20 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.94 g, yield 95%) as a pale rose solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), imidazole (1.70 g), potassium carbonate (2.80 g) and N,N-dimethylformamide (15 ml) was stirred at 130° C. for 2.5 hours. Water was added to the reaction mixture. The pH was then adjusted 6 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolepropionic acid (1.35 g, 85%). This was recrystallized from methanol to give colorless needles. mp 194-195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[O:12]1[CH2:13][CH2:14][CH:10]([O:9][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11]1
Reactant: OC1CCOC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 3-hydroxytetrahydrofuran by the method of Example 10 (b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[N:5]([CH2:7][C:8]1[CH:15]=[C:11]2[O:12][CH2:13][CH2:14][N:10]2[N:9]=1)[CH3:6].F[C:21](F)(F)S(OC)(=O)=O.[I-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.CC([O-])(C)C.[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH2:7][C:8]2[N:9]([CH3:21])[N:10]([CH:14]=[CH2:13])[C:11](=[O:12])[CH:15]=2)[CH3:6])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CN(Cc1cc2n(n1)CCO2)c1cc(Cl)cc(Cl)c1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [I-]
Solvent: CC#N
Product: C=Cn1c(=O)cc(CN(C)c2cc(Cl)cc(Cl)c2)n1C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 36 (200 mg, 0.67 mmol) in anhydrous acetonitrile (6 mL), methyl trifluoromethanesulfonate (85 uL, 0.75 mmol) was added, and the solution was stirred for 2 h before the addition of sodium iodide (195 mg, 1.3 mmol) and TsOH (127 mg, 0.67 mmol). After conversion to the iodinated intermediate by overnight stirring, KOtBu (188 mg, 1.7 mmol) was added to the mixture, which was further stirred for 1 h. After evaporation of the volatiles, the residue was purified on a silica gel column, eluting with a mixture of MeOH and dichloromethane (4% MeOH) to afford 37 as a yellow liquid (115 mg, 55%). 1H NMR (CDCl3, 500 MHz): δ=6.85 (dd, J=9.0, 16.0 Hz, 1H), 6.77 (t, J=1.5 Hz, 2H), 6.56 (d, J=1.5 Hz, 2H), 5.37 (s, 1H), 4.88-4.80 (m, 2H), 4.31 (s, 2H), 3.17 (s, 3H), 2.99 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ=165.4, 159.2, 150.3, 136.0X2, 126.3, 118.0, 111.3X2, 101.1, 99.5, 49.6, 39.0, 37.3 ppm.
Reaction SMILES: COCCCO[C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1C)[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl.[O:31]1CCC[CH2:32]1>O>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][O:12][CH2:10][C:9]1[CH:8]=[C:7]([CH2:32][OH:31])[CH:20]=[CH:19][CH:18]=1
Reactant: COCCCOC(=O)c1ccc(C)c(OCCCOC)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: COCCCOCc1cccc(CO)c1
Temperature: 25 °C

Procedure:
The solution of 7.70 g of 3-methoxypropyl 3-(3-methoxypropoxy)-4-methylbenzoate in 20 ml of tetrahydrofuran is added dropwise at 20-60° C. to the stirred mixture of 1.02 g of lithium aluminium hydride in 20 ml of tetrahydrofuran. The reaction mixture is stirred at reflux over 3 hours and subsequently cooled to room temperature. 2 ml of water, 2 ml of 2N NaOH and once again 2 ml of water are successively added dropwise. The suspension is stirred at room temperature over 14 hours. The reaction mixture is poured onto 250 ml of 2N HCl (cold) and extracted with ethyl acetate (2×200 ml). The organic phases are washed successively with 2N HCl (100 ml), water (100 ml) and brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:1 EtOAc-heptane); Rt=3.59.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.C(Cl)[Cl:26]>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([Cl:26])=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1
Reactant: ClCCl
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Oxallylchloride (285 mg, 2.24 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carboxylic acid 35 (250 mg, 0.75 mmol) in CH2Cl2 (15 mL) followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 12 h. The volatiles were concentrated and the crude residue was dissolved in CH2Cl2. The solvent was evaporated and the crude product dried under vacuum and used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH2:7])=[O:26])=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccccc2N)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 1 L round-bottom flask, were added tert-butyl(2-(4-acetamidobenzamido) phenyl)carbamate (31.8 g, 86.2 mmol), DCM (160 mL) and TFA (95 mL). The reaction mixture was stirred for 2 hours before concentrating in vacuo. EtOH (95 mL) was added and concentrated in vacuo to further reduce the amount of residual TFA. MTBE (320 mL) was added, and the suspension was stirred for 2 hours. The solids were filtered, washed with MTBE (2×60 mL), and dried at 40° C. in vacuo for 18 hours to get 4-acetamido-N-(2-aminophenyl)benzamide trifluoroacetate salt (32.6 g, 99% yield, 92.2% HPLC purity).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.F[C:30](F)(F)C(O)=O>C([O-])([O-])OCC>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[NH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH3:30])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[O:14])=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CCOC([O-])[O-]
Product: CNc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(OC)cc3)[nH]2)cc1

Procedure:
To 2-(4-aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.35 g) obtained in Example 48 were added ethyl orthoformate (40 ml) and trifluoroacetic acid (0.5 ml) and the mixture was refluxed under heating for one day. The reaction mixture was concentrated and to the residue were added tetrahydrofuran (40 ml) and ethyl alcohol (25 ml). Sodium borohydride (1.2 g) was added to the mixture with stirring. The mixture was stirred at room temperature for 1 hr and refluxed under heating for 2 hr. The reaction mixture was extracted with ethyl acetate, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to give 5-(4-methoxyphenyl)-2-(4-methylaminophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.6 g). This compound was dissolved in ethyl acetate and ether—hydrochloric acid was added to allow precipitation of the crystals of hydrochloride. The precipitated crystals were collected by filtration and recrystallized from methyl alcohol to give 5-(4-methoxyphenyl)-2-(4-methylaminophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride dihydrate (240 mg), melting point 193-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(CN(c2ccc(Cl)cc2)c2nc(=O)c3cccnc3s2)c1
Yield: 22.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 2.681 g (9.25 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 162 mg of lithium hydride, 1.50 g of 3-methoxybenzyl chloride and 40 ml of DMF were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform). As a result, 2.288 of 2-[N-(4-chlorophenylimino)-2,3-dihydro-4H-3-(3-methoxybenzyl)pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ethanol) was obtained as a low polarity substance, and 843 mg of 2-[N-(4-chlorophenyl)-N-(3-methoxybenzyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ethyl acetate and diisopropyl ether) was obtained as a high polarity substance.