Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21](Cl)(=O)[O:22]CC.C1C=CC=CC=1>C(N(CC)CC)C>[F:1][C:2]([F:19])([F:20])[CH2:3][N:4]1[C:5]2[C:6](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:14][C:21]1=[O:22]
Reactant: N=C(c1ccccc1)c1ccccc1NCC(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1nc(-c2ccccc2)c2ccccc2n1CC(F)(F)F

Procedure:
To a mixture of 2.8 g of 2-(2,2,2-trifluoroethylamino)-benzophenonimine, 2 ml. of ethyl chlorocarbonate and 20 ml. of benzene was added dropwise 2.0 g of triethylamine, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was absorbed on a silica gel column, eluted with chloroform to obtain 1-(2,2,2-trifluoroethyl)-4-phenyl-2(1H)-quinazolinone, which was recrystallized from ethanol to give colorless crystals, m.p. 181.5°-182.0° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].O>CN(C)C=O>[F:17][C:18]1[CH:19]=[C:20]([O:27][CH2:15][CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]
Reactant: BrCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)cc1F
Temperature: 85 °C
Reaction time: 6 h
Yield: 120.6 %

Procedure:
Potassium carbonate (20.7 g, 150 mmol) and 3-phenylpropyl bromide (18.2 mL, 120 mmol) were added to a solution of 3-fluoro-4-nitrophenol (15.7 g, 100 mmol) in N,N-dimethylformamide (200 mL) at room temperature and the mixture was stirred at 85° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine and dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was dried under reduced pressure to afford 2-fluoro-1-nitro-4-(3-phenylpropoxy)benzene as a brown oil (33.2 g).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH3:10].Cl.C(=O)=O>>[ClH:4].[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:7])=[O:17])[CH3:10]
Reactant: CN(C)CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: O=C=O
Product: CN(C)CCCCCC(=O)Cl
Temperature: 30 °C

Procedure:
Oxalyl chloride (3367.33 g, 26.53 mol) is placed in a 5000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, and argon inlet. 6-(N,N-Dimethylamino)hexanoic acidhydrochloride (1146.00 g, 5.86 mol) is added over 3 h while maintaining the reaction temperature between 25-35 ° C. As reaction takes place, HCl, CO2, and CO are swept away from the mixture with argon. After addition is complete, the mixture is cooled to room temperature over 45 min. Excess oxalyl chloride is removed first by rotary evaporation at 50° C. (water aspirator vacuum) and then by Kugelrohr distillation at 60° C. (0.3 mm Hg) for 3 h. A quantitative yield of 3 is isolated as a dark red oil that solidifies on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15]>>[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[NH2:9])([CH3:16])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: COc1ccc(N)cc1OCCN(C(C)C)C(C)C

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 2-diisopropylaminoethyl chloride hydrochloride, following a procedure similar to that described in Descriptions 1 and 2 (81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30](N(OC)C)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: c1cscn1
Reactant: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(-c2nc(CCC(=O)c3nccs3)cs2)cc1OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution (2 ml) of thiazole (129 mg, 1.5 mmol) in THF was cooled to −70° C., and n-butyllithium (a 2.44M hexane solution) (0.62 ml, 1.5 mmol) was added, and the resulting mixture was stirred at −70° C. for 30 minutes. A solution (4 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide (500 mg, 1.4 mmol) in THF was added to the reaction mixture, followed by stirring at −70° C. for 3 hours. After heating to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 350 mg (yield: 66%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone as colorless needles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[CH:7]([NH:14][S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)c1ccccc1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a stirred solution of tert-butyl-2-amino-2-phenylacetate (1.34 g, 6.45 mmol) and methyl 3-(chlorosulfonyl)benzoate (1.53 g, 6.51 mmol) in tetrahydrofuran (15 mL) was added triethylamine (0.90 mL, 6.45 mmol) in one portion at ambient temperature. The reaction mixture was stirred for 30 minutes, after which time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and 10% citric acid solution (10 mL). The resulting organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield a crude solid. The solid was triturated in diethyl ether (5 mL) and cold methanol (5 mL) to yield the title compound as a white solid (1.13 g, 43%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:27](O)=[O:28])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19]([O:21][CH3:22])=[O:20].ClC(OCC(C)C)=O.[CH3:43][N:44]1CCOCC1.CN.C1COCC1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([C:27]([NH:44][CH3:43])=[O:28])[CH:30]=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19](=[O:20])[O:21][CH3:22]
Reactant: CN1CCOCC1
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)OC)c(Br)c2=O)c1
Reaction time: 0.25 h

Procedure:
To a cooled (−10° C.) solution of 3-[3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (0.07 g, 0.13 mmol) in DMF (2.0 mL) was added isobutyl chloroformate (0.02 mL, 0.16 mmol) and 4-methylmorpholine (0.02 mL, 0.16 mmol). After 15 min, 2.0M methylamine in THF (0.01 mL, 0.20 mmol) was added. Solvent removed by distillation after 30 min. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a white foam, (0.061 g, 86%). 1H NMR (CD3OD/400 MHz) δ7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 546.0987 and 548.1018 (M+H calculated for C25H26BrFN3O5 requires 546.1034 and 548.1018).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[CH2:7]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=O)[CH2:23][C:24](=O)[CH3:25])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[C:24]([CH3:25])[N:3]=[C:4]([NH2:6])[N:5]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)CC(=O)C1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C2CCCN2C(=O)OCc2ccccc2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
Sodium (550 mg, 25.0 mmol) was added portionwise to a stirred solution of anhydrous ethanol (30 mL) under nitrogen at room temperature. When all the sodium had dissolved, to the solution was added a solution of guanidine hydrochloride (2.28 g, 25.0 mmol) in ethanol (20 mL). The resulting mixture was stirred for 20 minutes. The precipitated sodium chloride was removed by filtration and to the clear filtrate was added 2-(3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester (6.87 g, 23.7 mmol). The flask was then fitted with a Dean-Stark Tube and 20 mL of distillate was removed as the solution was heated to reflux under nitrogen for 12 h. The mixture was allowed to cool to room temperature, then was gradually cooled to −5° C. The resulting solid was collected by filtration and air dried to give 3.37 g (46%) of 2-(2-amino-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid benzyl ester as cream colored crystals. [M+H]+ 312.88.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][CH2:20][CH2:21][C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: COCCC(=O)O
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 13.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (37 mg, 1.1 eq, 0.16 mmol) was added to a solution of 3-methoxypropionic acid (15.5 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 1.0 eq, 0.16 mmol), 1-hydroxybenzotriazole (20 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and solvent was removed in vacuo. The resultant solid was washed with water and purified by semi-preparative HPLC to yield the title compound as a white solid (5.8 mg, 0.02 mmol, 12%). LCMS: [M+H]+=313, Rt=1.35 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O.[C:22](O)(=O)[CH3:23]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:3]3[CH2:4][CH2:5][NH:8][CH2:22][CH:23]=3)=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CNC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc2c(c1)c(C1=CCNCC1)cn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide (3) (12.3 g) in a mixture of acetic acid (60 mL) and trifluoroacetic acid (15 rnL) was added during 0.5 h to a refluxing solution of 4-piperidon, HCl, H2O (36.6 g) in a mixture of acetic acid (50 mL) and trifluoroacetic acid (100 mL). The reaction mixture was refluxed for 1h, cooled to room temperature and the solvents were removed in vacuo. Water was added and pH was adjusted to 10 by addition of aqueous NaOH. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over MgSO4. Evaporation of the solvents in vacuo afforded the title compound as a foam.Yield 16 g. 1H-NMR (DMSO) 2.48 (s, broad, 2H), 2.80 (d. 3H), 2.98 (t, 2H), 3.50 (d, 2H), 6.40(s, 1H) 7.45 (t, 2H), 7.50 (d, 1H), 7.65 (dd, 2H), 7.70-7.80 (m, 2H), 8.40 (s, 1H), 8.45 (q, broad, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH3:2].[OH-].[Na+].[CH2:14](O)[CH3:15].BrCC>ClCCl>[CH2:14]([O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[O:3][CH2:1][CH3:2])[CH3:15]
Reactant: CCO
Reactant: CCOc1c(O)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCBr
Solvent: ClCCl
Product: CCOc1cccc(F)c1OCC
Temperature: 10 °C
Yield: 75 %

Procedure:
To a 250 ml reactor were added 12.5 (0.08 mol) of 2-ethoxy-3-fluorophenol [F1], 3.2 g (0.08 mol) of sodium hydroxide and 20 ml of ethanol. After cooling to around 10° C., 20 ml of an ethanol solution of 9.6 g (0.088 ml) of bromoethane was slowly added. After the termination of the addition, they were reacted under a reflux temperature for 3 hours and, after the termination of the reaction, dichloromethane was added, followed by extraction. The extraction liquid was washed with water and dried, and the solvent was removed by distillation to obtain 11.0 g of an oily product [G1]. The process yield was 75%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=O.[C:24](=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=[CH2:24]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 43.6 %

Procedure:
2.83 g (8.0 mmol) of 2-(2,2,2-trifluoroethylthio)-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound No. V-275 of the present invention) prepared in the same-manner as in Example 8 (9), 2.85 g (8.0 mmol) of methyltriphenylphosphonium bromide and 1.38 g (10.0 mmol) of potassium carbonate were refluxed in a solvent mixture of 20 ml of dioxane and 0.3 ml of water with heating for 5 hours. After cooling down to room temperature, the insolubles were filtered off, and the dioxane was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.23 g of [2-ethenyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (yield 43.8%) as a pale yellow liquid (nD20 1.5328).
Reaction SMILES: CS[C:3](=[NH:17])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH3:18][NH:19][CH3:20]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:20])[C:3]([NH2:17])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNC
Solvent: c1ccncc1
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 80° C. for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-144° C.) which was recrystallised from hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH2:13]1[O:26][C:25]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20](O)=O)=[CH:16][C:15]=2[O:14]1>>[CH2:13]1[O:26][C:25]2[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]3[NH:1][C:2]4[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=4[N:8]=3)=[CH:16][C:15]=2[O:14]1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Product: Cn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(C)c1=O
Yield: 12.5 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 5.0 g (29.4 retool) of 5,6-diamino-1,3-dimethyluracil and 6.78 g (35.3 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 1.20 g (yield 13%) of Compound 95 as a pale yellow powder.
Reaction SMILES: [CH3:1][S:2]([CH:5]([S:7]([O-:10])(=O)=[O:8])[CH3:6])(=[O:4])=[O:3].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:13].Cl>ClCCl>[CH3:1][S:2]([CH:5]([S:7]([Cl:13])(=[O:10])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: CC(S(C)(=O)=O)S(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(S(C)(=O)=O)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 g of sodium 1-(methylsulfonyl)ethanesulfonate (Formula II, X=R=CH3, Y=Na) and 5.34 g of phosphorus pentachloride was stirred under an inert atmosphere at room temperature. After about 20 minutes, the evolution of hydrogen chloride and the generation of heat were observed, and shortly thereafter the mixture became liquid. The mixture was maintained at 80°-100° C. overnight, cooled, and diluted with dichloromethane. The mixture was filtered, the residue was washed with dichloromethane, and the solvent was evaporated from the dichloromethane solution (combined portions) with a stream of nitrogen. The residual oil was concentrated further with a vacuum pump: weight of oil, 3.8 g. The mass spectrum and the proton NMR showed that this material was principally 1-(methylsulfonyl)ethanesulfonyl chloride (Formula III, R=X=CH3 and Z=Cl): MS (electron-impact, direct-probe temperature 20° C.), m/e 207 (M+1), 171 (M - Cl); 1H NMR (300.6 MHz, CDCl3), δ 2.07 (d, CH3CH), 3.32 (s, CH3SO2), 4.84 (q, CHCH3). The infrared spectrum (KBr) included strong bands at 1375, 1325, 1170, 1150, 960, 760, 715, 595, 535, 505, 490 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:20][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:6]([Cl:19])[CH:5]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Cl)c(Oc3nc4ccc(Cl)cc4s3)c(Cl)c2)cc1

Procedure:
4-Acetyl-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide was synthesized (36%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-acetyl-benzenesulfonyl chloride (Fluka) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (br s, 1H), 8.18 (dd, J=7.8, 1.7 Hz, 2H), 8.15 (d, J=2.2 Hz, 1H), 8.01 (d, J 7.8, 1.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.32 (s, 2H), 2.63 (s, 3H). MS (EI): m/z 525 (M−H).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:10]=[C:11]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:25]=3[S:36]([NH2:39])(=[O:38])=[O:37])[CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])C1C=CC=CC=1.Cl>CCO.[OH-].[OH-].[Pd+2]>[CH3:15][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([F:34])([F:35])[F:33])[C:25]=3[S:36]([NH2:39])(=[O:38])=[O:37])[CH:20]=[CH:19][N:18]=2)=[CH:10][C:9]=1[NH:8][CH3:1]
Reactant: Cc1ccc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)cc1N(C)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)ccc1C
Reaction time: 0.5 h

Procedure:
A suspension of 44 mg 20% Pd(OH)2 on charcoal in EtOH (10 mL) is treated with H2 under vigorous stirring. To this 2-{2-[3-(benzyl-methyl-amino)-4-methyl-phenylamino]-pyrimidine-4-ylamino}-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (28 mg, 0.049 mmol) and 0.1 mL of 1 M HCl are added (final volume ca. 20 mL). After stirring for 30 min under H2 the catalyst is removed by filtration and the residue of the filtrate, neutralized with ammonia, is purified by chromatography (silica gel, CH2Cl2/CH3OH 95:5), yielding the title compound. 1H-NMR (400 MHz, DMSO-d6): 1.95 (s, CH3—C(4″)); 2.59 (d, J=5, NHCH3); 4.83 (q, J=5, NHCH3); 4.90 (q, J=9.4, OCH2CF3); 6.15 (d, J=6, H—C(5′)); 6.72(d, J=2, H—C(2″)); 6.75 (d, J=8.5, H—C(5″)); 6.9 (dd, J=8.5 and 2, H—C(6″)); 6.93 (d, J=8.5, H—C(5)); 6.8-7.5 (b, SO2NH2); 7.4 (t, J=8.5 H—C(4)); 8.03 (d, J=6, H—C(6′)); 8.23 (d, J=8.5, H—C(3)); 8.95 (s, NH); 9.0-10.1 (b, NH).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:36])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH:38]=[O:39].O>C1C=CC=CC=1>[OH:39][CH:38]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:36])[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: O=C1NC(SCC#Cc2ccc(F)cc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1

Procedure:
3-(Triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (1.02g) and t-butyl glyoxalate (2.76g) were refluxed in dry benzene (50ml) with provision for the removal of water. After 1 hour the benzene solution was washed 5 times with water, dried and evaporated. The residue was chromatographed on silica to give 1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (.969g).