Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:17]([S:19]Cl)=[O:18]>>[O:18]=[C:17]1[NH:1][C:2]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:19]1
Reactant: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)SCl
Product: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][N:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:7]=[CH:8][C:3]2=[O:2])=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc(OC)nc2)cc1
Reactant: OCc1ccc(CBr)cc1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(CO)cc3)c2)cc1
Yield: 80.4 %

Procedure:
According to Scheme 4 Step 1: The title compound was prepared according to Example 6 Step 2, from 2-methoxy-5-(4-methoxyphenyl)pyridine (1 eq, 4.60 mmol, 1.00 g) and (4-(bromomethyl)phenyl)methanol (1.1 eq, 5.10 mmol 1.00 g). Reaction conditions: 5 hours at 70° C. and room temperature overnight. The residue was triturated with pentane, yielding the title compound (3.70 mmol, 1.20 g, 80%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CC([O-])(C)C.[K+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][N:38]4[CH2:39][CH2:40][N:35]([C:30]5[N:29]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH2:36][CH2:37]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CC3CC(c4ccc(CN5CCCC5)cc4)C3)CC2)nc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a stirring solution of toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (159.9 mg, 0.40 mmol) prepared above (Example 4, General Procedure A, Step G) in 2 mL of THF was added 1-(2-pyrimidyl)piperizine (136.2 mg, 0.8 mmol) followed by a solution of KOtBu (136 uL, 0.8 mmol, 1M THF). The reaction was heated to 70 □C (oil bath). After 1 hour DMF (1 mL) was added along with K2CO3 (2 eq). The reaction was then heated to 100 □C. After 3 hours the reaction was cooled to rt and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2, quenched with a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was back extracted with 3:1 chloroform:isopropyl alcohol. The combined organic layers were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 10 g ISCO column, eluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (70.0 mg, 44%) as a colorless oil, and a mixture of cis:trans isomers. The bis-HCl salt was generated by dissolving the title compound in EtOAc and then a solution of HCl (2 eq, 1M HCl, THF) was added. The colorless solid was collected and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([OH:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40]([O:47][C:48](=[O:51])[CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([O:27][CH2:49][C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:51])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)c2ccccc2n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccccc2n1
Reaction time: 16 h

Procedure:
To a solution of 6.5 g of (S)-2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester 50 ml of DMF, 6.5 g of cesium carbonate and 4.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step. Yield: 8.9 g.
Reaction SMILES: ClCC(O)=[O:4].[CH3:6][C:7]1[NH:12][C:11](=S)[NH:10][C:9](=[O:14])[C:8]=1[CH2:15][C:16]([OH:18])=[O:17]>>[CH3:6][C:7]1[NH:12][C:11](=[O:4])[NH:10][C:9](=[O:14])[C:8]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCl
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1CC(=O)O
Product: Cc1[nH]c(=O)[nH]c(=O)c1CC(=O)O
Yield: 76.9 %

Procedure:
A 10% aq chloroacetic acid solution (150 mL; 159 mmol) was added to 2-(6-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetic acid (7.3 g; 36.5 mmol). The mixture was stirred under reflux for 24 h and cooled in an ice-bath. The formed solid was collected by filtration, washed with water and dried under reduced pressure to give 5.17 g (77%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][CH2:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CSCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 4 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example No. 126 (0.07 g) and Pd/C (10%, 0.120 g) in 3:1 CH2Cl2 /MeOH (20 mL) was placed on a Parr hydrogenator under 45 psi of H2 and shaken for 4 h. Another 0.08 g of Pd/C was added, and the resulting mixture is shaken for 2 h. The reaction mixture is then filtered through Celite, 0.120 g of fresh catalyst was added, and the resulting mixture was shaken under H2 for 6 h. The reaction mixture is then filtered through Celite and concentrated in vacuo. Crystallization from EtOH gave 0.015 g of the title compound as a solid.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].C(#N)C.N(OC(C)(C)C)=O.C(Br)(Br)[Br:39]>>[Br:39][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]
Reactant: BrC(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (43.8 g) was stirred in a mixture of bromoform (141 ml) and dry acetonitrile (63 ml ). Tert-butyl nitrite (29.9 g) was added dropwise during 5 minutes, and the mixture heated at 60°-70° C. for 2.75 hours. After cooling to 25° C. a further addition of tert-butyl nitrite (29.9 g) was made, and the heating resumed for 2 hours. Evaporation in vacuo gave a yellow oily solid which was triturated with hexane and filtered off. Two recrystallisations from toluene/hexane gave 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) 4-trifluoromethanesulphonylpyrazole as a yellow solid (34.0 g), m.p. 136°-137° C.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([NH2:15])[CH:10]=[C:9]([NH2:16])[N:8]=1.[N+:17](OS(=O)(=O)O)([O-:19])=[O:18].[OH-].[Na+]>>[Br:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([NH2:15])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([NH2:16])[N:8]=1
Reactant: O=[N+]([O-])OS(=O)(=O)O
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(Br)nc(N)c([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
460 Parts of concentrated H2SO4 are charged into a reaction vessel and 106.5 parts of 2-bromo-3-cyano-4,6-diamino-pyridine are added by small amounts whilst the temperature is kept at 15°-20° C by cooling with ice. After the starting material has dissolved completely, the solution is cooled to 10° to 15° C and at this temperature 69.1 g of nitrosulphuric acid (50%) are added dropwise in the course of 45 minutes. When the addition is complete, the reaction solution is stirred for 11/2 hours at room temperature, then poured onto 500 parts of ice so that the temperature does not exceed 20°-25° C (ice bath). The suspension is neutralised with 1000 parts of concentrated NaOH while cooling, whereupon the product precipitates completely. The brown product is filtered off, washed free of salt with 1500 parts of water and dried in vacuo at 70° C.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:16]2[N:24]=[C:4]([OH:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1

Procedure:
The title compound was prepared from 3-oxo-3-phenyl-propionic acid ethyl ester and benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 6.92 (s, 1H), 7.50-7.65 (m, 6H), 8.15-8.20 (m, 2H), 8.26 (d, J=7.2 Hz, 2H), 12.80 (br s, 1H); MS: m/z (ESI) 247 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH:8]([C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](C(=O)O)C(C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@@H](C(=O)O)C(CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of (E)-2(R)-[1-(RS)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-3-methylbutyric acid in ethanol was shaken in a hydrogen atmosphere in the presence of 10% palladium on charcoal catalyst until the uptake of hydrogen had stopped. The catalyst was filtered off and the solvent was evaporated to give 2(R)-[1(RS)-(tert.-butoxycarbonyl)-4-phenylbutyl]-3-methylbutyric acid in the form of a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:23][C:22]([CH3:24])=[C:21]3[C:17]=2[CH2:18][C@H:19]2[C:25]([CH3:27])([CH3:26])[C@H:20]23)=[O:15])=[CH:7][C:6]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:28][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:15])[C:16]2[S:23][C:22]([CH3:24])=[C:21]3[C:17]=2[CH2:18][C@H:19]2[C:25]([CH3:26])([CH3:27])[C@H:20]23)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.55 g, 3.89 mmol) in DCM (60 mL) and DIPEA (1.07 mL, 6.22 mmol) is added methane sulfonylchloride (0.362 mL, 4.67 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.362 mL, 4.67 mmol) is added and stirring is continued for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-ethyl ester (1.57 g) as an orange resin; LC-MS: tR=1.14 min, [M+1]+=477.35; 1H NMR (CDCl3): δ 6.86 (s, 2H), 4.57-4.50 (m, 2H), 4.05-4.00 (m, 2H), 3.10 8s, 3H), 3.03-2.85 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.37 8s, 3H), 2.25 (s, 6H), 1.92-1.85 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:39]([F:42])([F:41])[F:40])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:38])(=[N:31]C(=O)C(F)(F)F)=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:39]([F:40])([F:42])[F:41])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:38])(=[NH:31])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=N)(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12

Procedure:
To a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[S-methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl]ethyl]-1-naphthalenecarboxamide (i.e. the title compound of Example 3) (60 mg) in methanol (4 mL) was added potassium carbonate (230 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was filtered through a short pad of silical gel and rinsed with ethyl acetate. After concentration, the residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 92:8) as eluent to provide the title product, a compound of the present invention, as a white solid (39 mg, 76% yield).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2>CCCCCC.C(OCC)(=O)C>[N:24]1[C:25]2[C:20](=[C:19]([NH:18][CH2:6][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:3][C:2]([CH3:11])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:1])[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Reactant: Nc1cccc2ncccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(CNc1cccc2ncccc12)C(F)(F)F)c1ccccc1
Yield: 17.9 %

Procedure:
Analogously to Example 1, 300 mg (1.22 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 882 mg (6.12 mmol) of 5-aminoquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-75%), 85 mg of product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and cyclopropanecarboxylic acid chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 0.82-0.88 (m, 4H) 1.27-1.37 (m, J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2H) 1.83 (dq, J=6.32, 6.15 Hz, 1H) 2.23 (t, J=7.33 Hz, 2H) 6.75 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.88 (td, J=13.64, 7.83 Hz, 4H) 8.14 (d, J=8.08 Hz, 1H) 10.58 (s, 1H); ESI-MS: m/z calc'd for C25H24N4O2S 444.55. found 445.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][O:32][CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC/C=C/C(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: COC/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 29.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (11 mg, 29.9%). Data: UPLC (C) Rt: 1.58 min; m/z 498.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[CH:27]=[C:14]2[C:15]3[C:20]([CH2:21][CH2:22][N:13]2[C:12](=[O:28])[N:11]=1)=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3>CC(O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[C:14]1=[CH:27][C:10](=[N:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[CH3:1])[NH:11][C:12](=[O:28])[N:13]1[CH2:22][CH2:21]2
Reactant: Cc1ccccc1N
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)[nH]c(=O)n1CC2
Temperature: 25 °C
Yield: 100.4 %

Procedure:
2-Methylaniline (5.44 ml, 51 mmol) and 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (5 g, 17 mmol) were suspended in propan-2-ol (400 ml) and heated at reflux, under nitrogen, for 24 h After cooling to room temperature, the solution was concentrated in vacuo and the residue purified by flash column chromatography [dichloromethane/methanol (98:2–96:4)] to afford the title compound (6.2 g, quantitative yield) as a yellow/orange solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:22]2[NH:27][C:26](=[O:28])[C:25]([Cl:29])=[CH:24][CH:23]=2)=[CH:16]\[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>>[Cl:29][C:25]1[C:26](=[O:28])[NH:27][C:22](/[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=2)=[CH:16]/[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
Acetic anhydride (5 mL) was added to 6-[(E)-1-(4-aminophenyl)-2-cyclopentylethenyl]-3-chloropyridin-2(1H)-one (173 mg), and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). This was powdered with ethyl acetate, and filtration operation gave the title compound as a light yellow powder (75 mg, 38%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([N:15]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]2[C:17]([N:18]([CH3:33])[C:19](=[O:32])[N:20]([CH3:31])[C:21]2=[O:30])=[CH:16]1)[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[N+]1([O-])CC[O:40]CC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]([N:10]([N:15]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22]2[C:17]([N:18]([CH3:33])[C:19](=[O:32])[N:20]([CH3:31])[C:21]2=[O:30])=[CH:16]1)[CH2:11][CH2:12][C:13]([OH:40])=[O:14])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(N(CCCO)C(=O)OCc3ccccc3)cc2n(C)c1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n(N(CCC(=O)O)C(=O)OCc3ccccc3)cc2n(C)c1=O
Reaction time: 0.5 h

Procedure:
Tetrapropylammonium perruthenate (0.152 g, 0.432 mmol) was added to a solution of (1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-(3-hydroxy-propyl)-carbamic acid benzyl ester (step 2) (2 g, 4.32 mmol) and N-methylmorpholine oxide monohydrate (commercial) (2.92 g, 21.62 mmol) in Acetonitrile (40 ml). The mixture was stirred at room temp. for 30 mins. The reaction mixture was quenched with isopropanol (50 mL) and stirred for 20 mins. The mixture was then evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with EtOAc followed by 1% acetic acid/EtOAc afforded the title compound as a white solid.