Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[NH:21]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:25]1[N:20]=[N:21][C:22]([Cl:26])=[CH:23][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: ClC1=CC=CN(Cl)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cccc(C(C)(C)C)c1Oc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
17.5 g (107 mmol) of 2-tert-butyl-6-methylphenol, 11.9 g (106 mmol) of potassium tert-butoxide and 1,4-dioxane (250 mL) were mixed, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 15.0 g (101 mmol) of 2,6-dichloropyridazine and the resulting mixture was stirred at 100° C. for 3 hours and 15 minutes. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized form isopropyl ether to obtain 15.3 g (55.2 mmol, Yield: 54.6%) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=O)[CH:7]=[CH:6]2.Cl.[NH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21].C([O-])(=O)C.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH:14]1[NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21]1)[CH3:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C3N[C@H](C(=O)O)CS3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of (2S)-2-(6-methoxy-2-napthyl)-propanal (8.2 g; 38.3 mmoles) in acetone (50 ml) is added dropwise to a solution of (R)-cysteine hydrochloride (5.94 g; 37.6 mmoles) and of potassium acetate (3.69 g; 37.6 mmoles) in 100 ml of water and acetone (1:1 v/v) kept under stirring at room temperature.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]=[O:17])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:26])[C:5]=2[CH:4]=[C:3]([CH:16]=[O:17])[CH:2]=1
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)S(=O)c1ccccc1CC2
Reaction time: 2 h

Procedure:
Mix 2.84 g (11.83 mmole) of 10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde with 90 ml methylene chloride at 0° C. Add 2.3 g (11.33 mmoles) of 85% m-chloroperbenzoic acid, followed by the addition of 100 ml methylene chloride. Stir for 2 hours, and then add 4.6 g calcium hydroxide to the resulting clear solution at room temperature. After stirring the suspension for 15 minutes, filter to remove the inorganic solid, and evaporate the filtrate containing the dissolved product to dryness, producing as a residue a dry solid comprising the title product. Purify by recrystallization from acetonitrile, m.p. 158.5°-160° C.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[CH:25]=[O:26])=[CH:15][N:14]=1.Cl([O-])=[O:35].[Na+]>O.CC(C)=O.O>[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[C:25]([OH:35])=[O:26])=[CH:15][N:14]=1
Reactant: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
2-methyl-2-butene (11.7 ml) and sodium dihydrogen phosphate (3.98 g) were added to an acetone-water (80 ml-20 ml) solution of the compound 323-2 (7.1 g). The reaction solution was cooled on ice. Sodium chlorite (4 g) was added to the reaction solution, and the obtained mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 3:7), so as to obtain the title compound (5.77 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:16]=[N+]=[N-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([OH:11])[CH:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Temperature: 60 °C
Yield: 32.6 %

Procedure:
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60° C. overnight. After dilution with ether (500 mL), the reaction mixturewas washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellowish solid.
Reaction SMILES: [CH3:1][CH:2]([OH:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][CH:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A solution of alpha-methyl-4-fluorobenzyl alcohol (0.7 ml; 5.5 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (220 mg; 5.5 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (765 mg, 5.5 mmol) in dimethylformamide was chilled to 0° C., and activiated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.1 g of 2-fluoro-6-[1-(4-fluorophenyl)-ethoxy]-benzonitrile (78% yield).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].O[CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][N:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[C:6]([F:16])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[F:10])=[N:15]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)c(F)c1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2F)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.835 mmol, 0.2 g) was dissolved in THF under nitrogen atmosphere. (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (0.835 mmol, 0.146 g) and triphenylphosphine (1.252 mmol, 0.328 g) were dissolved in THF and added to the previous mixture. The resulting mixture was cooled to 0° C. Di-tert-butyl azodicarboxylate (1.252 mmol, 0.288 g) was added in small portions and stirred under cold conditions for 10 min. The flask was warmed to RT and stirred overnight. The solvent was evaporated. The residue was dissolved in ethanol and 10% HCl(g)/EtOH solution (15 ml) was slowly added. The resulting mixture was stirred overnight. The mixture was diluted with water and extracted twice with DCM. The combined organics were washed with water. The aqueous phases were combined and the pH was adjusted to 12 with 2 M NaOH. The aqueous phase was extracted three times with DCM. The combined organics were dried, filtered and evaporated. 0.167 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.17 (d, 3H), 1.31 (bs, 2H), 3.53 (bs, 1H), 3.88-4.04 (m, 1H), 4.09-4.26 (m, 1H), 6.82 (dd, 1H), 7.55 (d, 1H), 7.88 (dd, 1H).
Reaction SMILES: [OH-:1].[Li+].C[O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:11][CH2:10]1>O1CCCC1>[C:5]([CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:29])=[O:1])[CH2:11][CH2:10]1)([OH:4])=[O:30]
Reactant: COC(=O)CCCN1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)CCCN1CCN(CCCCNC(=O)c2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous lithium hydroxide (5 mL of a 4 M solution) was added to a solution of 11 (2.50 g, 6.50 mmol) stirring in tetrahydrofuran (40 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed under vacuum and the residue dissolved in water (25 mL) and extracted with dichloromethane (1×25 mL). The aqueous solution was acidified to pH 6 as indicated by pH paper and extracted with ethyl acetate (3×25 mL). The acidic aqueous solution was evaporated to dryness and dried under vacuum to give the carboxylic acid 12 (3.58 g, quantitative yield) as a yellow foam: 1H NMR (300 MHz, CD3OD) δ 1.61-1.89 (m, 6H), 2.27-2.38 (m, 2H), 2.75-3.09 (m, 10H), 3.33-3.35 (m, 6H), 3.41 (t, J=6.3 Hz, 2H), 7.38-7.47 (m, 3H), 7.62-7.65 (m, 1H); ESI MS m/z 392 [C20H29N3O5+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[N:10]([C:22](=[O:24])[CH3:23])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)SCC(C(=O)O)N1C(C)=O

Procedure:
L-Cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved in water (200 ml), and the pH of the solution was adjusted to 5.07 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (76 ml, 684 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 3.5 hours to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (159 ml, 1141 mmol) under argon, and acetyl chloride (61 ml, 858 mmol) was slowly added dropwise thereto. The reaction mixture was heated under reflux for 4 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 95:5). After completion of the reaction, water (100 ml) was added thereto, and the pH of the mixture was adjusted to 2.5 with HCl. The aqueous layer was separated, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated until a weight of 900 g, to the residue was added heptane to allow recrystallization of the residue, and the crystals were washed with heptane/ethyl acetate=2/1, and dried at 50° C. under reduced pressure to give a crystal of a trans form of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 99%) (84 g, yield 57%). The melting point of the obtained crystal was measured using digital melting point measuring apparatus IA9100 manufactured by Electrothermal to be 138° C. to 141° C.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([NH2:12])=[N:7][NH:8][C:9]=1[O:10][CH3:11].O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:9]([O:10][CH3:11])=[N:8][N:7]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:12][C:6]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: COc1[nH]nc(N)c1Cc1cccc(Cl)c1Cl
Solvent: CC(=O)O
Product: COc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Yield: 12.9 %

Procedure:
A solution of 4-(2,3-dichlorobenzyl)-5-methoxy-1H-pyrazol-3-amine (301 mg, 1.1 mmol) and ethyl 3-oxo-3-(pyridin-4-yl)propanoate (223 mg, 1.15 mmol) in acetic acid (15 mL) was stirred at 100° C. for 4 h. Then the reaction mixture was concentrated under vacuo and the residue was purified by silica gel chromatography eluted with EA to EA/MeOH=4/1, and further recrystallized with DMSO/H2O to give the titled compound (57 mg, 13%) as a yellowish solid. LC/MS: MS (ES+) m/e 402 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.89 (s, 3H), 4.00 (s, 2H), 6.07 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.79 (d, J=5.1 Hz, 2H), 8.71 (d, J=5.1 Hz, 2H), 12.15 (s, 1H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][N:5]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12
Reactant: C1CC2NCCOC2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCOC2CCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine) (300 mg, 1.83 mmol) dissolved in dichloromethane (2.4 mL) was added benzyl chloroformate (0.44 mL, 2.57 mmol). Triethylamine (0.72 mL, 5.13 mmol) was added slowly to the reaction mixture, and the reaction was stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient), and then purified by chiral supercritical fluid chromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO2) to afford the trans stereoisomers of benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate. (4aS,7aS)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (faster eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262; (4aR,7aR)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (slower eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.5 g) and triethylamine (1.0 ml), and 4-nitrobenzoyl chloride (0.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=4)[CH2:35][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichlorophenyl)piperazine. The crude product was partitioned between dichlorormethane and 2 M aqueous sodium carbonate. The organic layer was washed with water, dried and evaporated. The residue was triturated with ethyl acetate—heptane (1:4) and the precipitate was collected by filtration and dried to give the title compound as white crystals. Yield 28%; m.p. 115-116° C.; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.30-8.20 (dd-like, 1H), 7.48-7.40 (d-like, 1H), 7.31-7.16 (m, 6H), 7.04-6.94 (dd-like, 1H), 3.83-3.47 (br m, 4H), 3.36-3.24 (br s, 4H+water); HPLC-MS: m/z=512 (M+H); IR (KBr): ν 1724,1706 cm−1.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cccc(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A mixture of 6-phenyl pyridone (3 g, 17.5 mmol; prepared according to Example 5) and phosphoryl bromide (7.2 g, 25.0 mmol) is heated to 100° C. for 5 h. The cooled mixture is poured into water (40 mL) and the pH is adjusted to 9 by addition of saturated aqueous sodium carbonate. Then the layers are separated and the aqueous layer is extracted with ethyl acetate (50 mL). The combined organic layers are dried with anhydrous magnesium sulphate and the solvent is evaporated in vacuo. The crude product is crystallized from aqueous ethanol. Subsequent purification by flash chromatography (silica gel, hexane/ethyl acetate 9/1 v/v) gives 2-bromo-6-phenyl pyridine (3.1 g, 76% of th.) as light brown crystals with mp 50° C.
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:6]2[S:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:18][CH:19]([CH3:22])[CH2:20]Br>CN(C=O)C.O>[CH3:18][CH:19]([CH3:22])[CH2:20][N:2]1[N:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[S:7][C:6]=2[S:1]1(=[O:14])=[O:15]
Reactant: CC(C)CBr
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NN=C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1N=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The product from step C (0.05 g, 0.18 mmol) was dissolved in DMF (1 mL). Sodium hydride (0.016 g, 40 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methylbromopropane (0.024 mL, 0.40 mmol) was added. The mixture was warmed to 60° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (1 mL) and the mixture was extracted with ethyl acetate (3×1 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid, crystallization in ethyl acetate-hexane gave 0.032 g (52%). mp:130°-132° C. 1HNMR (CDCl3):δ:0.96 (6H, d, 2CH3); 2.18 (1H, m, CH); 3.78 (2H, d, CH2); 5.27 (2H, s, NH2 exchangeable); 7.67 (1H, 1s, CH); 7.91 (1H, s, CH=N). Analysis calculated for C9H13N3O4S3 : C, 33.42; H, 4.05; N, 12.99. Found: C, 33.51; H, 4.04; N, 12.91.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:26]5[CH:27]=[C:23]([CH3:22])[N:24]=[N:25]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 81.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg, 0.53 mmol) was reacted with 249 mg (1.33 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 201 mg (1.33 mmol) of DBU in 15 ml of dry pyridine under nitrogen at 120° C. for 3 days. Small amounts of the solid present were removed by filtration, and the supernatant was concentrated under reduced pressure. Water and small amounts of acetonitrile were added to the residue and the grey solid was collected and dried to afford 180 mg (82%) of the desired product, m.p. 219°-220° C. 1H NMR (CDCl3) δ: 8.73 (s, 1H), 7.85 (dd, J=13.7Hz, 1.9HZ, 1H), 7.42 (s, 1H), 5.4-5.3 (m, 1H), 4.4-3.7 (m, 5H), 2.7-2.5 (m, 2H), 2.37 (s, 3H), 1.4-1.05 (m, 4H). Anal. calcd. for C20H19F2N5O3 : C, 57.83; H, 4.57; N, 16.86. Found: C, 57.81; H, 4.60; N, 16.31.