Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (0.075 g, 0.486 mmol), DIEA (0.162 mL, 0.926 mmol), and 1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.127 g, 0.463 mmol) in n-butanol (2.315 mL). The solution was stirred at 120° C. for 4 h under microwave irradiation and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give 4-amino-6-((1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (d, J=6.85 Hz, 3H) 5.60 (qd, J=7.04, 6.85 Hz, 1H) 7.08 (dd, J=9.00, 2.35 Hz, 1H) 7.15 (td, J=9.78, 8.90, 2.45 Hz, 1H) 7.25 (br. s., 2H) 7.69-7.81 (m, 2H) 7.84 (s, 1H) 8.08 (d, J=9.00 Hz, 1H) 8.63 (s, 1H) 8.67 (d, J=2.54 Hz, 1H); LC-MS (ESI) m/z 393.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Cl[C@:11]1(CO)[O:16][C:14]([C:17](=[O:19])C)(O)[C@:13](C(=O)C)([OH:20])[C@:12]1(C(=O)C)[OH:24].CO.N>C(Cl)(Cl)Cl>[CH:9]1[C:8]2[N:7]=[CH:6][N:5]([C@@H:11]3[O:16][C@H:14]([CH2:17][OH:19])[C@@H:13]([OH:20])[C@H:12]3[OH:24])[C:4]=2[N:3]=[CH:2][N:1]=1
Reactant: CC(=O)C1(O)O[C@](Cl)(CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Reactant: c1ncc2[nH]cnc2n1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)[C@H](O)[C@@H]1O

Procedure:
Nebularine was prepared by the use of the thallous salt of purine in the procedure of Brown et al., J. Biol. Chem. 204, 1019 (1953), in place of the chloromercuri salt used therein. The thallous salt of purine is condensed with chlorotriacetylribofuranose and the resulting acetyl derivative hydrolyzed to the product with methanol-ammonia. Other experimental conditions were identical. Crystalline nebularine was obtained after chromatography of the crude product on silica-gel with chloroform.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:19][C:8]1[C:9]2[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCN(CCC)c1cccc2[nH]c(=O)n(C)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Yield: 27.7 %

Procedure:
A mixture of 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoylperoxide in carbon tetrachloride (20 ml) was refluxed for 60 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 30% ethyl acetate/n-hexane to afford 73 mg (28%) of the title compound.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[P:18](Cl)(Cl)[Cl:19].Cl>[Cl-].[Zn+2].[Cl-]>[Cl:19][P:18]1[C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Oc1ccccc1-c1cccc2ccccc12
Reactant: ClP(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2c1ccc1ccccc21
Yield: 66 %

Procedure:
60 g (0.273 mol) of o-naphthylphenol and 0.6 g of zinc chloride are heated to 200° C. while stirring. 46 g (0.335 mol) of phosphorus trichloride are then added dropwise over a period of 5 hours and the mixture is subsequently stirred further for 4 hours under reflux. The off-gas (HCl) eliminated is conducted away. The mixture is then cooled and the excess phosphorus trichloride is distilled off under reduced pressure. The residue is distilled at a bath temperature of from 200° to 225° C. and 0.2 mbar by means of a bulb tube. This gives 51 g of 6-chloro-6H-benzo[e]naphth[2,1-c][1,21]oxaphosphorin which solidify in crystalline form. This corresponds to a yield of 66% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.N1C=CC=CC=1.[CH3:39][C:40](OC1C(=O)OC(=O)C1OC(C)=O)=[O:41]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:40]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[CH3:39]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CC(=O)OC1C(=O)OC(=O)C1OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.6 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydro-3-isoxazolyl]-3-pyridinyl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 200 mg, 0.46 mmol) was suspended in 2 mL of anhydrous dimethylformamide. Anhydrous pyridine (2 mL, 24 mmol), 4-dimethylaminopyridine (DMAP) (20 mg, 0.17 mmol) and di-O-acetyl-L-tartaric anhydride (210 mg, 0.97 mmol) were added and the solution was stirred for 16 hours at room temperature during which the mixture turned black. The reaction was quenched with 1 mL of methanol, the solvents evaporated in vacuo and the product isolated by flash chromatography on silica using a gradient from 0 to 5% methanol in dichloromethane to yield 50 mg (25%) of the title compound as an off white solid.
Reaction SMILES: O.[Cl:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:4]=1[NH2:5].[C:14](Cl)(Cl)=[S:15].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:4]=1[N:5]=[C:14]=[S:15]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1

Procedure:
A 12-L, 3-neck, round bottom flask equipped with a mechanical stirrer, a thermometer and a condenser connected to a 6-L water trap was charged sequentially with 2,6-dichloro-4-nitroaniline (500 g, 2.42 mol), toluene (5 L), thiophosgene (500 g, 4.35 mol), and dimethylformamide (5 mL, 0.065 mol). The mixture was heated to reflux over 1 hour and maintained at reflux for 4 hours. The black solution obtained was cooled over 15 hours to 23° C. The solvent was removed by rotary evaporation and the residual black oil was triturated with hexane (2 L), causing crystallization. After chilling for an hour, the rust-colored solid was collected by filtration, washed with hexane (1 L), and dried in the air at ambient temperature to a constant weight of 437 g (73%) of (1). (This material was of adequate purity to be used in the subsequent reaction; however, (1) can also be recrystallized in high yield from hexane.) The hexane filtrate was evaporated and the residue was dried under high vacuum for 15 hours, causing partial crystallization. The material was triturated with hexane (1 L) and collected by filtration. Recrystallization from hexane provided a second crop of (1) weighing 88.5 g. The total yield was 525.5 g (87%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:3]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:3]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCOC(=O)c1sc(N2CC[C@H](N)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 89.3 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (237a) (150 mg, 0.59 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (103 mg, 0.59 mmol), WSC hydrochloride (338 mg, 1.76 mmol), 1-hydroxybenzotriazole (79 mg, 0.59 mmol) and N-methylmorpholine (0.13 mL, 1.17 mmol), to obtain 217 mg of the title compound as a white solid (90%).
Reaction SMILES: CC1NC(C(OCC)=O)=C(C)C=1.I.C=O.[CH3:16][C:17]1[NH:18][C:19]([C:24](OCC)=O)=[C:20]([CH3:23])[C:21]=1[CH3:22]>CCOCC.C(O)(=O)C>[CH3:16][C:17]1[NH:18][C:19]([CH3:24])=[C:20]([CH3:23])[C:21]=1[CH3:22]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1C
Agent: C=O
Agent: CCOC(=O)c1[nH]c(C)cc1C
Agent: I
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1[nH]c(C)c(C)c1C

Procedure:
2,4-Dimethyl-5-carbethoxy-pyrrole (1.64 g), acetic acid (25 ml), aqueous hydriodic acid (25 ml) and paraformaldehyde (0.589g), were heated at 95°-100° C. for three hours under nitrogen with stirring. The work up was the same as that of 2,3,4-trimethyl-5-carbethoxy-pyrrole in Example 4 except the 2 × 75 ml of ether was used and care was taken to avoid exposure of the product to air. It was purified by distillation (10 mm, 60° C.) to give 0.628 g (52%), m.p. 106°-108° C. (lit4 m.p. 111°-112° C.).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:12][C:6]=2[CH:5]=1>C(O)(=O)C>[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH2:12][C:6]=2[CH:5]=1
Reactant: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(C2Cc3cc(F)ccc3Oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.15 G. of sodium borohydride are added in small portions over a period of 15 minutes to a solution of 12.3 g. of 1-[2-fluoro-dibenzo[b,f]oxepin-10-yl]-4-methyl-piperazine in 185 ml. of glacial acetic acid with cooling in such a manner that the temperature does not exceed 25° C. The mixture is stirred for an additional 1 hour at room temperature and the acetic acid is then evaporated in vacuo. The residue is partitioned between 3-N sodium hydroxide solution and chloroform. The aqueous phase is separated and extracted again with chloroform. The chloroform extracts are washed three time with water, dried over sodium sulfate, evaporated in vacuo, and there is obtained 1-[2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine as a crystalline residue. The dihydrochloride, prepared in ethanol, melts at 240°-241° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][CH:15]([O:24][CH2:25][CH3:26])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13].N1CCCCC1.O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:17]([C:16]([CH:15]([O:14][CH2:12][CH3:13])[O:24][CH2:25][CH3:26])=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)C(OCC)OCC

Procedure:
(4)-(1) A solution of 2-nitrobenzaldehyde (9.0672 g), ethyl 4,4-diethoxyacetoacetate (13.0944 g) and piperidine (1 ml) in benzene (45 ml) was refluxed under azeotropic dehydration for 3 hours. To the resultant solution was added water, and the solution was extracted with diethyl ether. The extract was washed three times with water, dried and then the solvent was removed under reduced pressure to give ethyl 2-(2-nitrobenzylidene)-4, 4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (7.7496 g) was heated in an oil bath (95° to 100° C.) for 8 hours. The resultant mixture was extracted with diethyl ether, and the extract was washed with water and dried. The solvent was removed from the extract. The residue was purified by column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give oily diethyl 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (19.3 g). The product was crystallized in n-hexane and the crystals were collected by filtration and then recrystallized from a mixture of n-hexane and diethyl ether to give the pure compound, m.p. 80° to 81.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.36 g, 0.74 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.32 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=474.3.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[OH:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([NH:15][CH2:16][C:17](=[O:19])[N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)=[O:14]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
DIPEA (0.239 mL, 1.39 mmol) was added drop wise to (2-hydroxy-benzoyl amino)-acetic acid (90 mg, 0.46 mmol) in DMF (7 mL). EDCI (221 mg, 1.15 mmol) and HOBT (74 mg, 0.55 mmol) were added consecutively and after 5 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone (162 mg, 0.55 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded 2-hydroxy-N-[2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl]-benzamide in 25% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 12.0 (s, 1H), 9.1 (t, 1H), 7.9 (m, 3H), 7.7 (d, 1H), 7.6 (m, 1H), 7.4 (t, 1H), 6.9 (t, 2H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:7](=[O:8])/[C:6](=[C:9](\[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)/[CH2:10][CH2:11][CH2:12][CH3:13])/[C:5]([CH2:22][C:23]([O:25]C)=O)=[N:4]1.Cl>CC(O)C>[CH2:10]([C:9]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:23](=[O:25])[CH:22]=[C:5]2[NH:4][N:3]([CH3:2])[C:7](=[O:8])[C:6]=12)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC/C(NCc1ccccn1)=C1/C(=O)N(C)N=C1CC(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: CCCCc1c2c(=O)n(C)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 80 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.082 g, 3.57 mmol, 1 equiv.) in i-PrOH (75 ml), was treated with methyl [(4Z)-1-methyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]pentylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (0.61 g, 3.57 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.59 ml of a 20% aqueous HCl solution. 50 ml of i -PrOH were removed in vacuo and 25 ml of H2O were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×5 ml), then with cyclohexane and dried in vacuo. 0.88 g of pure product 4-butyl-2-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 80%. 1HNMR ( DMSO-d6, 400 MHz): 0.80 (3H, t, J=7.2 Hz); 1.29-1.35 (2H, m); 1.38-1.43 (2H, m); 3.19 (3H, s); 3.22-3.24 (2H, m); 5.49 (2H, s); 5.72 (1H, s); 7.42 (1H, d, J=8 Hz); 7.62 (1H, t, J=6.6 Hz); 8.12 (1H, t, J=8 Hz); 8.65 (1H, d, J=5.2 Hz). MS (ESI+): 313.4; MS (ESI−): 311.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Titanium tetrachloride (1.70 mL, 15.5 mmol) was added dropwise to a suspension of zinc powder (2.12 g, 32.4 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 82 (1.18 g, 4.00 mmol) and cyclohexanone (1.18 g, 12.0 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.15 g (80%) of compound 83 as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.58 (br s, 6H), 2.20 (m, 4H), 5.10 (br s, 1H), 6.77 (m, 2H), 6.89 (t, J=8.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O>[CH2:21]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 4 h

Procedure:
50 parts of p-acetylaminophenylsulfinic acid and 25 parts of sodium hydrogen carbonate are suspended in 300 parts of water. While stirring intensely 36 parts of allyl bromide is dripped in within three hours at 50° to 60° C. Stirring is continued for another four hours at 60° C. 45 parts of p-allylsulfonylacetanilide is obtained with a melting point of 116° to 118° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15]Cl)[CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[I-].[Na+].[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.CN(C)C=O.CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCl)cc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCC(Cc4ccccc4)CC3)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
2.5 Grams of 4-methyl-6-(3-chloropropoxy)carbostyril, 1.8 g of sodium iodide were mixed with 50 ml of acetone and the mixture was stirred at 50° C. for 1 hour, then 50 ml of dimethylformamide was added and acetone was removed by distillation under a reduced pressure. To the residue thus obtained was added 1.5 g of triethylamine and 1.6 g of 4-benzylpiperidine and the mixture was heated at 70°-80° C. for 7 hours under stirring condition. The reaction mixture was then concentrated under a reduced pressure to dryness and to the residue thus obtained was added 60 ml of a 5%-sodium hydrogencarbonate aqueous solution and stirred to obtain the insoluble matters. The insoluble matters were collected by filtration, washed with water and then recrystallized from methanol to obtain 3.2 g (yield: 82%) of 4-methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]-carbostyril as in the form of yellowish prism-like crystals. Melting point: 177°-178° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>CN(C)C=O>[C:20]1([C:17]2[S:18][CH:19]=[C:15]([CH2:14][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1csc(-c2ccccc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1csc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Prepare a solution of potassium phthalimide (457 mg, 2.47 mmol) in dimethylformamide (6 mL). Add a solution of 4-bromomethyl-2-phenyl-thiophene (523 mg, 2.06 mmol) in dimethylformamide (6 mL), dropwise. Stir the reaction mixture overnight at room temperature under nitrogen. Concentrate the solution, redissolve in ethyl acetate, wash with saturated aqueous sodium hydrogencarbonate (20 mL), then brine (20 mL). Dry (magnesium sulfate), filter aid concentrate. Preform flash chromatography of the resulting residue on silica gel eluting with 5:1 hexane/ethyl acetate to afford 565 mg of 2-(5-phenylthiophen-3-ylmethyl)isoindole-1,3-dione as a yellow solid. 1H NMR (CDCl3) δ 7.84-7.88 (m, 2H), 7.70-7.72 (m, 2H0, 7.54-7.57 (m, 2H), 7.25-7.34 (m, 5H), 4.83 (s, 2H).