Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8](=[O:9])[C:7](OC)=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:12]>CO>[NH2:12][C:7]1[C:8](=[O:9])[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: COc1ccccc(Br)c1=O
Solvent: CO
Product: Nc1ccccc(Br)c1=O
Temperature: 80 °C

Procedure:
A solution of 7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one [1.0 g, described by T. Nozol et al., Proc. Japan Acad., 27, 556-60 (1951), (CA 46, 7560c)] in methanol (30 ml) is cooled to -20° C and saturated with gaseous ammonia. The reaction mixture is heated in a pressure bottle at 80° C for 4 hours and cooled to -70° C. The bottle is opened and the solvent is removed under reduced pressure. The residue is boiled with ethyl acetate and the ethyl acetate extract is evaporated to give 2-amino-7-bromo-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[CH3:3].Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)c1cccc(O)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-N,N-dimethylamino phenol (69) (3.43 g, 25 mmol) and 2-chloro N,N-dimethylacetamide (3.66 g, 30 mmol) in DMSO (30 mL) was added K2CO3 (6.7 g, 50 mmol) and the resulting suspension was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane (125 mL), and washed with water (2×100 mL), and brine (100 mL), and dried, and filtered, and the solvent was removed under vacuum. The crude product, Compound 70, was obtained as purple, thick oil that was used in the next step without additional purification.
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)(=O)C>[S:13]([C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])([OH:3])(=[O:2])=[O:1]
Reactant: CCOC(=O)C1=C(S)CCC1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 156.4 %

Procedure:
Sodium peroxyborate tetrahydrate (10.6 g) was admixed with acetic acid (57 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cyclopentene-1-carboxylate (3.9 g, synthesized in accordance with Tetrahedron, Vol.30, p.3753 (1974)) in acetic acid (7 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 12 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (20 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 2-sulfo-1-cyclopentene-1-carboxylate as a white powder (7.8 g) containing inorganic substances. This (1.0 g) was dissolved in thionyl chloride (3 ml) and then stirred at 80 to 90° C. for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (50 ml). The resultant aqueous solution was washed successively with water (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/5) to yield ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (153.7 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[N:10]=2)[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2nc(-c3ccncc3)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(-c3ccncc3)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A mixture containing 2.63 g of ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate, 0.42 g of 50% sodium hydride (dispersed in mineral oil) and 30 ml of dimethylformamide was heated at 50°-60° C. for 10 minutes. To the stirred mixture was added 1.31 g of ethyl iodide, and heating was continued for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo and the residue was taken up in a mixture of chloroform and water. The chloroform layer was separated and the chloroform was evaporated in vacuo to give crystals which were recrystallized from ethyl acetate to yield ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate (2.1 g, m.p. 185°-186° C.). This compound was heated at 90°-100° C. with 25 ml of 2N sodium hydroxide for 5 minutes. The reaction mixture was treated with decolorizing charcoal and filtered. The filtrate was adjusted to pH 6-7 with acetic acid and chilled. The resulting solid was collected by filtration and recrystallized from ethanol to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid (Compound 1) (1.5 g, m.p. 286°-288° C.).
Reaction SMILES: Cl[C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: COCOc1cc(C#N)cnc1Cl
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)cnc1Oc1ccc2c(c1)COB2O
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To a mixture of 6-chloro-5-methoxymethoxy-nicotinonitrile (0.68 g, 3.42 mmol) and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.56 g, 3.76 mmol) in DMF (10 mL) was added cesium carbonate (2.45 g, 7.52 mmol). The resulting suspension was heated at 80° C. for overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by flash chromatography on silica gel using 1-100% MeOH/EtOAc gradient elution to yield the title compound (0.40 g, 40%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 7.14 (d, J=7.4 Hz, 1H), 5.40 (s, 2H), 4.98 (s, 2H), 3.45 (s, 3H); MS (ES) m/z: 313 (M+1)+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=5)=[CH:27][C:26]=4[NH:43][C:44]4[C:45]5[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=5[N:47]=[CH:48][N:49]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[S:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=3)=[O:42])=[CH:27][C:26]=2[NH:43][C:44]2[C:45]3[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=3[N:47]=[CH:48][N:49]=2)=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(F)(F)F)s4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(F)(F)F)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A solution of the product of Example 154C (114 mg, 0.1416 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (11.9 mg, 0.2833 mmol) in water (2 mL) at ambient temperature, then heated at 65° for 30 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), adjusted the aqueous pH to 5-6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Trituration of the residue with 3% methanol/methylene chloride afforded the title compound as a light yellow solid (57 mg, 69%). 1H NMR (300 MHz, DMSO-d6/TFA) δ ppm: 1.35 (d, J=6.62 Hz, 6 H) 3.08-3.51 (m, 1 H) 7.25 (d, J=8.46 Hz, 1 H) 7.39 (d, J=8.46 Hz, 2 H) 7.55 (d, J=8.82 Hz, 2 H) 7.94 (d, J=8.82 Hz, 1 H) 8.18 (dd, J=8.46, 2.21 Hz, 1 H) 8.27 (d, J=1.84 Hz, 1 H) 8.99 (s, 1 H) 9.10 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 583 (M+H)+, (ESI−) m/z 581 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][NH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:21][CH:20]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(CN=C=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Solvent: C1CCOC1
Product: COC(CNC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
A solution containing 1.5 g of the compound prepared in stage A in 10 ml ofbenzene is added to a solution containing 1.4 g of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione in 5 ml of tetrahydrofuran.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7](O[Si](C)(C)C)=[C:6](O[Si](C)(C)C)[CH2:5][CH2:4]1)[CH3:2].[ClH:20].Cl.[C:22]([CH:25]([NH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[NH:24])[NH2:23]>>[ClH:20].[ClH:20].[NH2:24][C:22]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:31][C:7]2[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=2[N:23]=1
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Agent: Cl
Product: CCOC(=O)c1nc2c(nc1N)CCN(CC)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)azepine and ethyl 2-amidino-2-aminoacetate dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[OH:14][CH2:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([O:14][CH2:15][C:16]([CH2:21][O:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])([CH2:19][O:20][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])[CH2:17][O:18][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: OCC(CO)(CO)CO
Product: COc1ccc(C(=O)OCC(COC(=O)c2ccc(OC)cc2OC)(COC(=O)c2ccc(OC)cc2OC)COC(=O)c2ccc(OC)cc2OC)c(OC)c1
Yield: 78 %

Procedure:
Using the procedure of Eample I, 2,4-dimethoxybenzoyl chloride was allowed to react with pentaerythritol in the molar ratio of 4:1. The reaction gave a 78% yield of white crystalline product having a melting point of 125°-126.5° C. and the infrared spectrum was a consistent with the expected tetraester with no hydroxyl band and an ester carbonyl band at 5.85μ (s).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.Cl.[NH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[CH3:21]>[Pd].[Pt].C(N(CC)CC)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=1
Reactant: C[C@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Yield: 70 %

Procedure:
A mixture of 5 g of 4-(2-fluorobenzyloxy)benzaldehyde, prepared according to the Ex. 1 and the corresponding amount L-alaninamide hydrochloride and triethylamine is hydrogenated according to the same procedure of Example 2, but using wet (50% H2O) Pd/C 10% instead of wet (50% H2O) Pt/C 5% to obtain (S)-2-[4-(2-fluorobenzyloxy) benzylamino]propanamide (Ib) in a 70% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C([N-:14]C(C)C)(C)C.[Li+].O.O.O.C([O-])(=O)C.[Na+].N[O:28][S:29]([OH:32])(=O)=O>O1CCCC1.CCCCCC>[S:29]([C:9]1[O:10][C:3]2[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=1)(=[O:32])(=[O:28])[NH2:14]
Reactant: NOS(=O)(=O)O
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cncc2ccoc12
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cncc2cc(S(N)(=O)=O)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 7-methylfuro[3,2-c]pyridine (1.33 g, 10 mmol) in distilled tetrahydrofuran (20 ml), under a nitrogen atmosphere and cooled to -70° C., was added dropwise 0.7M lithium diisopropylamide in tetrahydrofuran (15.5 ml, 11 mmol) to give a gummy precipitate. After stirring for 0.5 hour, sulfur dioxide gas was bubbled over the reaction surface to give a white precipitate. After slowly warming this mixture to room temperature, hexane was added and the precipitate collected by filtration. This precipitate was washed with diethyl ether and air dried. The resultant lithium sulfinate salt (3.5 g) was dissolved in water (25 ml) and sodium acetate trihydrate (8.2 g, 60 mmol) and hydroxylamine-O-sulfonic acid (2.33 g, 20 mmol) were added. After stirring for 20 hours, the precipitated product was collected by filtration, then dissolved in ethyl acetate/methanol, dried over anhydrous sodium sulfate and filtered through a charcoal pad. The resultant solution was evaporated and the residue triturated with diethyl ether to give solid product (1.24 g, 58% yield). Recrystallization from ethyl acetate gave 1.1 g, m.p. 179.5°-181.5° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[C:14]1([CH2:20][O:21][C:22]2[C:23]([CH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.CCOCC>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:38]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][CH2:28][C:23]2[C:22]([O:21][CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Reactant: c1ccc(CNCCCCCCOCCCc2ncccc2OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN(CCCCCCOCCCc1ncccc1OCc1ccccc1)Cc1ccccc1)c1ccc(O)c(CO)c1
Yield: 56.2 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (460 mg), N-[6-[3-[3-(phenylmethoxy)-2-pyridinyl]propoxy]hexyl]benzenemethanamine (800 mg) and DEA (485 mg) in THF (15 ml) was left at room temperature overnight. Water (30 ml) and ether (30 ml) were added, the phases were separated and the organic layer was re-extracted with ether (50 ml). The combined extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with ethyl acetate/triethylamine (99:1) followed by ethyl acetate/methanol/triethylamine (90:10:1) to give the title compound as an orange oil (620 mg), t.l.c. (ethyl acetate/methanol/triethylamine 80:20:1) Rf 0.66.
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13](F)[CH:12]=2)[CH2:6][C:7]=1[OH:8].BrC1C=CC(OC(C)C)=C(F)C=1.[Cl:40]C1C(=O)OC(CCC2C=CC(OC)=C(Cl)C=2)(C2CCCC2)CC=1O.ClC1C2NC(S)=NC=2C=C(C(F)(F)F)C=1.[Cl:80][C:81]1[CH:93]=[CH:92][C:84]2[N:85]([CH:89](C)C)[C:86]([SH:88])=[N:87][C:83]=2[CH:82]=1>>[Cl:40][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:5]2([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[O:4][C:3](=[O:27])[C:2]([S:88][C:86]3[N:85]([CH3:89])[C:84]4[CH:92]=[CH:93][C:81]([Cl:80])=[CH:82][C:83]=4[N:87]=3)=[C:7]([OH:8])[CH2:6]2)[CH:16]=[CH:15][C:14]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1F
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: CC(C)Oc1ccc(Br)cc1F
Agent: FC(F)(F)c1cc(Cl)c2[nH]c(S)nc2c1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(40), where 3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one, where 4-bromo-2-fluoro-1-isopropoxybenzene was) was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:21])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[NH:16][C:11]2=[CH:10][CH:9]=1>C(O)C>[F:21][C:7]([F:6])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.[CH3:14][CH2:15][C:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc2nc(C(F)(F)F)ccc2[nH]1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCC(=O)[O-]
Product: FC(F)(F)c1ccc2[nH]ccc2n1
Yield: 168.5 %

Procedure:
1 mL (18.71 mmol) of concentrated sulfuric acid is added to a solution of 0.2 g (0.87 mmol) of 5-trifluoromethyl-pyrrolo[3,2-b]pyridine-2-carboxylic acid, obtained in Stage 10.2, in 10 mL of ethanol. It is stirred under reflux for 20 hours then the solution is cooled, and concentrated at reduced pressure. The resultant residue is then taken up in 50 mL of dichloromethane then washed successively with 20 mL of a saturated aqueous solution of sodium bicarbonate, 40 mL of water and 20 mL of saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated at reduced pressure. We obtain 0.19 g of product, which is used as it is in the next stage.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[ClH:19].Cl[O-].[Na+]>CC(O)C>[Cl:19][I:16]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:3]([C:4]([F:7])([F:6])[F:5])([C:2]([F:1])([F:17])[F:18])[O:8]1
Reactant: Cl
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)O
Product: Cc1ccc2c(c1)C(C(F)(F)F)(C(F)(F)F)OI2Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Compound 2 (60 mg, 156 μmol) was dissolved in 2 mL propan-2-ol, 10 μL hydrochloric acid (37%) and 50 μL sodium hypochlorite solution (10-15% in water) were added. A white precipitate appeared instantaneously. The reaction mixture was stirred 5 min at room temperature. The solvent was removed under vacuum and the residue was purified over silica gel column using dichloromethane as eluant to give 50 mg (119 μmol, 76% yield) of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][NH2:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36].O.C(Cl)[Cl:41]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][NH:14][S:35]([C:30]2[CH:31]=[CH:32][C:33]([Cl:41])=[CH:34][CH:29]=2)(=[O:37])=[O:36])=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: COCOc1ccc(CC(CN)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1ccc(CC(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 4.98 g of 3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propylamine and 100 ml of the solution of 2.22 g of triethylamine in methylene chloride was added 4.63 g of chlorobenzenesulfonyl chloride, and stirred at room temperature for four hours. The reaction mixture was poured into water, and the organic phase was separated which was then extracted with methylene chloride from aqueous phase. The combined organic phases were washed in saturated aqueous sodium chloride, and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 3.79 g of N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])N(C)[C:29](=[O:30])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[OH-:35].[K+]>>[CH3:34][N:2]([CH3:1])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])[O:30][C:29](=[O:35])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)N(C)C3=O
Reactant: [OH-]
Agent: [K+]
Product: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)OC3=O

Procedure:
The starting material is prepared in the following manner: 950 mg (2.1 mmol) (±)-12-(3-dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6,13-dimethyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are heated under reflux for 16 hours in 150 ml 15% methanolic potassium hydroxide solution. The solution is evaporated to one half, mixed with 100 ml of water and weakly acidified with semi-concentrated hydrochloric acid. The precipitate obtained is filtered off, stirred with 50 ml 5% sodium hydrogen carbonate solution, again filtered and dried. (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained in the form of a yellow amorphous powder.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]1[C:13]([S:14][C:15]([F:18])([F:17])[F:16])=[C:12]([CH3:19])[N:11]([C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][C:21]=2[Cl:31])[N:10]=1)#[N:8].C(#N)C.[OH2:35]>C(OCC)(=O)C.[Ru](Cl)(Cl)Cl>[C:7]([C:9]1[C:13]([S:14]([C:15]([F:17])([F:16])[F:18])(=[O:2])=[O:35])=[C:12]([CH3:19])[N:11]([C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:29])([F:30])[F:28])=[CH:22][C:21]=2[Cl:31])[N:10]=1)#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 68 %

Procedure:
Sodium periodate (20 mg) and ruthenium chloride (3 mg) were added to a solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole (100 mg), that is described in Example 1, in a mixture of acetonitrile-water (4:1). The reaction mixture was stirred overnight whereupon the mixture was diluted with ethyl acetate and filtered over silica gel. The organic filtrate was washed with water, dried over anhydrous magnesium sulfate, filtered over Celite and concentrated under reduced pressure to give the title compound as a white solid (73 mg, 68%). MS (ES): M/Z [M+H]=452. 1H NMR: (400 MHz, DMSO-d6): 2.46 (s, 3H) and 7.87 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −63.77 (s, 3F) and −79.83 (s, 3F).