Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]([NH:14][NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]3[N:14]=[N:15][CH:37]=[C:38]([CH3:39])[C:11]=3[C:10](=[O:26])[CH2:9]2)[CH:7]=1
Reactant: CC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)ccc3F)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a mixture of 5-(5-chloro-2-fluorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), anhydrous potassium carbonate (1.68 g), methanol (20 ml) and 1,2-dimethoxyethane (10 ml) was added under ice-cooling 1-bromopropan-2-one (0.87 g), and the mixture was stirred for 2 hours at room temperature, and then for 6 hours at 80° C. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.338 g) as yellowish brown crystals.
Reaction SMILES: Cl.Br[C:3]1[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[Cl:9][C:7]1[CH:8]=[C:3]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
In a 2 dram reaction vial was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloric acid salt (0.5 g, 1.9 mmol) from Example I(1), step 1b, 4-nitroaniline (0.27 g, 1.9 mmol), 1.0 M potassium tert-butoxide in THF (7.6 ml, 7.6 mmol) and DMF (1.4 ml). Under N2, the reaction was stirred for 16 hr at 50° C. and the concentrated in vacuo. The resulting material was taken up in ethyl acetate and washed with H2O (2×50 ml) and then brine (1×20 ml). the organic layers were combined and dried over Na2SO4 and filtered. Following solvent evaporation, 0.42 g of crude 6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:17])[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.[CH:18](O)=O>C(OCC)C>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9](=[O:17])[C:10]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:18]1
Reactant: O=CO
Reactant: CNc1ccccc1C(=O)Cc1nnnn1C
Solvent: CCOCC
Product: Cn1nnnc1-c1cn(C)c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone (0.2 g) and formic acid (5 ml) was heated on a steam bath for 16 hours. The mixture was cooled to ambient temperature and diluted with diethyl ether (80 ml). The resulting precipitate was collected and crystallised from industrial methylated spirit to give the novel compound 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 219°-221°, identical to the product of Example 1(a).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[N:42]1[CH:47]=[C:46](B(O)O)[CH:45]=[N:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:46]3[CH:47]=[N:42][CH:43]=[N:44][CH:45]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cncnc1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 73.4 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (207 mg, 0.3 mmol) and pyrimidin-5-ylboronic acid (124 mg, 1.0 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-pyrimidin-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (142 mg, 73%) as a light yellow viscous oil: ES(+)-HRMS m/e calculated for C37H44N2O6S (M+H)+ 645.2993, found 645.2987.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCN(CC)CC.[CH2:27]=[C:28]=[O:29]>C(Cl)Cl>[C:28]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:29])[CH3:27]
Reactant: C=C=O
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mmol) in anhydrous CH2Cl2 (1 ml) is cooled in an ice-bath and treated withtriethylamine (Et3N) (7 μl, 0.05 mmol). Ketene is passed through the resulting solution for 10 mins. The solvent and excess ketene are removed in vacuo to leave crude benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17]O)[CH2:6]1)(=[O:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:20])[CH3:21].[C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:7]([CH2:17][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[S:27](=[O:28])(=[O:29])[NH2:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)NS(N)(=O)=O
Product: CC(=O)S[C@@H]1C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1

Procedure:
N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) in Step A-6 in Preparative Example 7-A. (2S,4R)-4-Acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with N-t-butoxycarbonylsulfamide in the similar manner as in the paragraph (b) in Step A-6 in Production Example 7-A under a condition for Step C-8 shown in Table 2 to give (2S,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino) methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.9 to 2.0 (m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH2:30].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(CNc3ccc4ccccc4c3)c2)cnc1N
Yield: 26.2 %

Procedure:
A solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (0.075 g, 0.29 mmol), naphthalen-2-amine (0.21 g, 1.5 mmol), glacial AcOH (0.033 mL, 0.56 mmol) and NaBH(OAc)3 (0.093 g, 0.44 mmol) in THF (1.1 mL) was heated to 80° C. for 12 h. Upon cooling, saturated NaHCO3 (aq) was added (25 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 29.1 mg (26% yield) of 3-amino-N-methyl-6-{3-[(naphthalen-2-ylamino)methyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz, 4-DMSO): 8.84 (s, 1H), 8.77 (d, 1H), 8.22 (s, 1H), 8.05 (dt, 1H), 7.62 (t, 2H), 7.51 (d, 1H), 7.41 (d, 2H), 7.27 (dt, 1H), 7.10 (dt, 2H), 6.77 (d, 1H), 6.57 (t, 1H), 4.46 (d, 2H), 2.85 (d, 3H); MS (EI) for C23H21N5O: 384 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O1CCCC1.C([BH3-])#N.[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[CH:13][CH:14]=1)#[N:2]
Reactant: COC(=O)CN
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 2.0 g of 2'-cyano-4-formyl-biphenyl, 1.22 g of 2-aminoethanoic acid methyl ester hydrochloride, 9.6 g of molecular sieve 5 A and 26 ml of tetrahydrofuran is stirred at room temperature for 36 hours and then cooled to 0° to 5°. 680 mg of sodium cyanoborohydride (90%) dissolved in 4.8 ml of methanol are added. The mixture is stirred at room temperature for 24 hours and then concentrated in vacuo. The crude product is purified by means of flash chromatography (180 g of silica gel; ethyl acetate/petroleum ether=1:1). 1H-NMR (DMSO-d6): 3.63 ppm (s, 3 H); 3.79 ppm (s, 2H); 7.4 to 8.0 ppm (m, 10H); 2.6 ppm (1H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29](Br)[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37](C)C=O.C(N)CN>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29]([C:36]#[N:37])[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCC(OC(=O)c1ccccc1)C(Br)CC
Agent: CCCCCCc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: NCCN
Product: CCCC(OC(=O)c1ccccc1)C(C#N)CC
Yield: 66 %

Procedure:
2.65 g (5.10-3 moles) of p-hexyl biphenyl-3-bromo-4-heptyl benzoate and 0.6 g (6.7×10-3 moles) of cuprous cyanide are introduced into 10 ml of dimethyl formamide. After the solution has been heated under reflux for 7.5 hours, it is cooled and poured into a mixture of 60 ml of deionized water and 5.5 ml of ethylene diamine. After stirring, the solution is extracted with ether. 2.2 g of crude product are obtained, being purified by chromatography on a column of silica, followed by recrystallization from ethanol. 1.6 g of pure product are obtained, corresponding to a yield of 66%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)[CH:2]=[CH2:3].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCOCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 123 %

Procedure:
A reaction mixture containing 14 g of allyl(4-chlorobutyl) ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 mL of dimethylformamide was stirred at 90° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with toluene. The toluene layer was well washed with water, and then toluene was distilled off. 20 g of sodium hydroxide, 50 mL of water and 200 mL of ethanol were added to the resulting residue, followed by refluxing for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to make the reaction mixture acidic. The mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. A residue obtained by distilling the solvent was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 20 was prepared from diphenyl acetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][S:45]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46]>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:51]3[CH2:52][CH2:53][CH:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CCC(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and 4-(methylsulfonyl)piperidine (PharmaBlock, Carrboro, N.C.) (0.085 g, 0.519 mmol). 1H NMR (400 MHz, CDCl3) δ 11.67 (s, 1H); 8.71 (d, J=2.15 Hz, 1H); 8.36 (d, J=2.54 Hz, 1H); 8.18 (d, J=2.35 Hz, 1H); 8.11 (dd, J=9.00, 2.74 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.76 (s, 2H); 3.94 (s, 3H); 3.49 (s, 2H); 3.10 (d, J=11.35 Hz, 2H); 2.80-2.86 (m, 4H); 2.55 (s, 3H); 2.00-2.18 (m, 4H); 1.84-2.00 (m, 3H). m/z (ESI, +ve ion) 484.9 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[S:16]([CH2:22][C:23]#[N:24])([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>C(O)C.N1CCCCC1>[C:20]([CH2:19][S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])#[N:21]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)C)c1O

Procedure:
A mixture of 500 mg of 3,5-diisopropyl-4-hydroxybenzaldehyde and 700 mg of sulfonyl diacetonitrile in 6 ml of ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide 50 mg of M27 along with 30 mg of M29.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][NH:20]C(=O)C(F)(F)F)[C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:20][CH2:19][CH2:18][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: Cc1nc(C(=O)N(C)CCNC(=O)C(F)(F)F)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)N(C)CCN)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl-[2-(2,2,2-trifluoro-ethanoylamino)-ethyl]-amide, D4 (443 mg, 1.14 mmol) im methanol/water (30 ml/10 ml) was treated with solid K2CO3 (787 mg, 5.70 mmol) and stirred at room temperature, under argon for 16 h. The methanol was removed in vacuo. The residue was diluted with water and extracted with ethyl acetate (3×). The combined organics were dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a yellow gum (240 mg, 72%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[F:23][C:24]([F:36])([F:35])[CH2:25][CH2:26][S:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:17][C:14]([CH3:15])([CH3:16])[CH:13]([C:18]([F:19])([F:20])[F:21])[CH2:12][CH2:11][CH:30]([S:27]([CH2:26][CH2:25][C:24]([F:35])([F:36])[F:23])(=[O:29])=[O:28])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCCC(C(C)(C)C)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(C(C)(C)C)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a solution of 2.9 g of 4,4-dimethyl-3-(trifluoromethyl)pentyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 1.2 g of potassium carbonate at room temperature. The reaction mixture was heated to 90° C., stirred at the same temperature for 6 hours, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 2.00 g of methyl 6,6-dimethyl-5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)heptanoate (hereinafter referred to as the present compound (7)).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:28]O)[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[S:40][CH2:28][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[N:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](CO)C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)[C@H]1CSC(c2ccccc2OCc2ccccc2)=N1

Procedure:
N-[2-(Benzyloxy)benzoyl]-L-serine benzyl ester (20 mg, 0.05 mmol) and Lawesson's reagent [2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide] (20 mg, 0.05 mmol, 1 equiv.) were dissolved in toluene (15 mL). After being refluxed overnight under nitrogen, the reaction mixture was diluted with EtOAc (20 mL), washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel eluting with hexanes/EtOAc (6/1) to yield thiazoline (7) as a clear oil. Rf=0.3 (hexanes/EtOAc, 6:1); 1H NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, ArH), 7.51-7.49 (m, 2H, ArH), 7.42-7.25 (m, 9H, ArH), 7.02-6.95 (m, 2H, ArH), 5.28 (d, 1H, PhCHH), 5.20 (d, 1H, PhCHH), 5.18 (s, 2H, CH2Ph), 5.12 (dd, 1H, CHCH2), 3.60-3.47 (m, 2H, CHCH2); MS (FAB) m/z 404 MH+, measured exact mass: 404.1313, calculated exact mass: 404.1320.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13]1)[N:8]1[CH:24]([CH3:26])[S:25][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32].II.[Cl:35]S(O)(=O)=O>>[Cl:35][C:10]1[C:11]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH2:13]2)=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]1[CH:24]([CH3:26])[S:25][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32]
Reactant: CCOC(=O)c1c2n(c3cc(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Reactant: O=S(=O)(O)Cl
Agent: II
Product: CCOC(=O)c1c2n(c3c(Cl)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2

Procedure:
To a solution of 1.50 g of ethyl 6-fluoro-1-methyl-4-oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate in 4.0 ml of chlorosulfonic acid, a trace of iodine was added, and the mixture was bubbled with chlorine gas for 1 hour under ice cooling with stirring. The reaction mixture was poured into ice water and was extracted with chloroform. The extract was washed with aqueous potassium carbonate and water, dried and evaporated. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as an eluent to give 1.61 g of the desired compound, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether. The obtained crystals were consistent with that of Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Br
Yield: 61.3 %

Procedure:
1.79 g (0.0093 mol) of 1-benzyl-4-hydroxypiperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 70 ml of toluene and treated with 1.63 g (0.00745 mol) of 2-bromo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.71 g (61%) of 1-benzyl-piperidin-4-yl 2-bromo-benzoate were obtained as yellowish crystals; m.p. 69°-70°.