Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(NC(C)C)(C)C.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1)=[O:23]>C1(C)C=CC=CC=1>[N+:31]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:30]=[CH:29][CH:28]=1)([O-:33])=[O:32]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 75.5 %

Procedure:
1-(2-pyridinyl)piperazine (0.65 mL, 4.3 mmol, Aldrich) and N,N-diisopropylamine (5.0 mL) in toluene (20 mL) were treated with 2-chloro-N-(3-nitrophenyl)acetamide (750 mg, 3.49 mmol, Lancaster) and heated to 60° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 25% ethyl acetate:hexanes) to provide 900 mg (76% yield) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H), 3.24 (s, 2H), 3.56 (m, 4H), 6.63 (ddd, 1H, J=7.1, 4.7, 0.7 Hz), 6.83 (d, 1H, J=8.8 Hz), 7.52 (ddd, 1H, J=8.5, 7.1, 2.0), 7.61 (dd, 1H, J=8.5, 8.5 Hz), 7.92 (ddd, 1H, J=8.1, 2.4, 1.0 Hz), 8.04 (ddd, 1H, J=8.5, 2.4, 1.0 Hz), 8.11 (ddd, 1H, J=4.8, 1.7, 0.7 Hz), 8.70 (dd, 1H, J=2.0, 2.0 Hz), 10.27 (br s, 1H); MS (DCI/NH3) m/e 342 (M+H)+; Anal. calcd for C17H19N5O3: C, 59.81; H, 5.61; N, 20.52. Found: C, 59.61; H, 5.55; N, 20.23.
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:11]=[CH:12][CH2:13][OH:14]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:11]2[O:5][C@H:12]2[CH2:13][OH:14])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OO
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a suspension of powdered 4 Å molecular sieves (3.2 g) in DCM (144 mL) was added Ti(O-iPr)4 (0.864 mL, 2.93 mmol), (+)-L-diisopropyl tartrate (0.924 mL, 4.39 mmol), and t-BuOOH (5.5 M in decane, 10.8 mL, 59.4 mmol). The mixture was cooled to −20° C. stirred for 1 h. A solution of 3,4-dichlorocinnamyl alcohol (6.0 g, 29.5 mmol) in DCM (30 mL) was added via cannula. After 18 h at −20° C., the reaction was quenched by addition of 10% aq. NaOH and brine (10%, 4 mL). The cooling bath was removed, and after stirring for 20 min, Et2O (30 mL) was added followed by MgSO4 (8 g) and diatomaceous earth (8 g). The mixture was stirred rapidly for 15 min then was filtered through a pad of diatomaceous earth, washing with excess Et2O. The filtrate was concentrated, and the desired epoxide was crystallized from the yellow residue with a warm DCM/hexanes mixture to afford 4.22 g (65%) of pale yellow crystals. The epoxide was determined to be >95% ee by 1H NMR analysis of both the R- and S-Mosher ester derivatives. 1H NMR (400 MHz, CDCl3): 7.42 (d, J=8.3, 1H), 7.37 (d, J=2.0, 1H), 7.13 (dd, J=8.3, 2.0, 1H), 4.04 (dd, J=12.9, 2.2, 1H), 3.91 (d, J=2.0, 1H), 3.82 (dd, J=12.9, 3.4, 1H), 3.18-3.11 (m, 1H), 1.80 (br s, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>O>[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reaction time: 24 h
Yield: 72.4 %

Procedure:
165 ml hydrochloric acid (32 wt. %) were diluted with 100 ml water, 60.0 g dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine were added to this approx. six molar hydrochloric acid and the mixture was stirred for 24 hours. The reaction mixture was washed three times with 50 ml diethyl ether each time, rendered alkaline (pH>10) with 100 ml sodium hydroxide solution (32 wt. %) and extracted three times with 100 ml methylene chloride each time. The extracts were combined, dried over sodium sulfate and filtered and the filtrate was concentrated. 36.1 g 4-dimethylamino-4-phenyl-cyclohexanone were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].[Cl:17]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[CH3:8][C:4]1[CH:5]=[C:6]([Cl:17])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(C)c1N[C@H](C(=O)O)C(C)C
Solvent: c1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Cl)cc(C)c1N[C@H](C(=O)O)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of the m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine, 0.21 g of N-chlorosuccinimide and 3 ml of benzene is heated at reflux for 2 hours. The reaction is diluted with hexane, washed with water (2×) and solvent stripped to give the crude product. To the crude product is added 0.1 g of N-chlorosuccinimide and 3 ml benzene. The mixture is heated at reflux for 30 min and then allowed to stand overnight at RT. The reaction is worked up by diluting with hexane, washing with water and stripping off solvent to yield the m-phenoxybenzyl ester of N-(2,6-dimethyl-4-chlorophenyl)valine, MS m/e 437.1 (M+, 15.3).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[F:22][C:2]1([F:1])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Temperature: 60 °C
Yield: 83.3 %

Procedure:
Ethyl 4,4-difluoro-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (470 mg, 1.5 mmol) is suspended in ethanol (17 mL) and 1M NaOH solution (4.8 mL, 4.8 mmol) is added. The reaction mixture is heated at 60° C. for 1 h 50 min. Acetic acid (15 mL) and water (100 mL) are added and the resulting white solid is filtered and rinsed with water to afford the title compound (350 mg, 82%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[OH:27])=[O:12])(=O)C.[OH-].[Na+].Cl>>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[OH:27])=[O:12]
Reactant: CC(=O)Oc1ccccc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C[C@H]1O)c1ccccc1O
Temperature: 60 °C
Yield: 27 %

Procedure:
A mixture of 5 parts of cis-2-[3-hydroxy-1-(phenylmethyl)-4-piperidinylaminocarbonyl]phenol acetate (ester) and 30 parts of sodium hydroxide solution 1N was stirred and heated for four hours at 60° C. The reaction mixture was cooled to room temperature and neutralized with a hydrochloric acid solution 1N. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.21 parts (27%) of cis-2-hydroxy-N-[3-hydroxy-1-(phenylmethyl)-4-piperidinyl]benzamide; mp. 127.1° C. (compound 235).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[CH:15]=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:15][C:14]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:13]=3[F:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(F)ccc1F
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(F)ccc1F

Procedure:
In a manner similar to the methods described in Examplea 1a and 1b, 6-chloro-1,3-dihydro-indol-2-one (Aldrich) reacted with 2,5-difluoro-benzaldehyde to give 6-chloro-3-[1-(2,5-difluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently reacted with (t-BuOCO)2O and DMAP.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:39]([C:41]1([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)#[N:40].C([C@H]1CC[C@H](O)CC1)#N.C(I)CCCCCC.C([N-]C(C)C)(C)C.[Li+]>ClCCl.CCOCC>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([O:38][CH:44]3[CH2:45][CH2:46][C:41]([C:39]#[N:40])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:42][CH2:43]3)=[O:37])=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCC1(C#N)CCC(O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: CCCCCCCI
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2ccc(C(=O)OC3CCC(C#N)(CCCCCCC)CC3)cc2)cc1
Reaction time: 25 h

Procedure:
While cooling with ice, 4.54 g of dicyclohexylcarbodiimide in 10 ml of dichloromethane are added dropwise to a mixture of 6.24 g of 4-heptyloxy-4'-biphenylcarboxylic acid, 4.46 g of 4-cyano-4-heptylcyclohexanol [obtainable from trans-4-cyanocyclohexanol by protecting the hydroxyl group as THP ether, reaction with heptyl iodide and lithium diisopropylamide and subsequent cleavage of the protective group] and 0.2 g of 4-N,N'-dimethylaminopyridine in 45 ml of dichloromethane. After 25 hours, the precipitated urea derivative is filtered off by suction, the filtrate is diluted with methylene chloride and washing was carried out several times in sequence with dilute hydrochloric acid and with water. After drying, the removal of the solvent and purification by chromatography and crystallization, 4-cyano-4-heptylcyclohexyl 4-heptyloxy-4'-biphenylcarboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.[Br:18]Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:18][C:17]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3n(c2Br)CCCC3)c(Cl)c1
Reaction time: 2 h

Procedure:
To 0.8 g (3.0 mmol) of the above 2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine stirring in 50 ml of methylene chloride at room temperature, 0.5 g (3.1 mmol) of bromine in 5 ml of methylene chloride was added dropwise. The solution was stirred for 2 h. Another 20 ml of methylene chloride and excess saturated aqueous sodium bicarbonate were added. After sufficient mixing, the methylene chloride layer was separated, washed with water and brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo gave a yellow solid residue which was purified by silica gel column chromatography (5:1 followed by 3:1 followed in turn by 1:1 hexane/ethyl acetate) to yield a 0.55 g sample of the title compound (m.p. 112-113° C.).
Reaction SMILES: [O:1]([NH:8][C:9](=O)[CH:10]=[CH:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[O:1]([N:8]=[C:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[CH:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=CSc1ccccc1)NOc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C(=CC(=NOc1ccccc1)Sc1ccccc1)Sc1ccccc1
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
N-phenoxy-3-(phenylthio)acrylamide (0.50 g) was suspended to toluene (5 ml), then phosphorus pentachloride (0.42 g) was added thereto under ice-cooling and stirred at same temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved to ethanol (15 ml). Sodium salt of thiophenol (0.73 g) was added to the solution under ice-cooling and heat refluxing for 2.5 hours. t-Butyl methyl ether (100 ml) was added to the reaction mixture, washed successively with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off inorganic salt and concentrated under reduced pressure. The residue was purified by medium pressure preparative high performance liquid chromatography (hexane:ethyl acetate=30:1) to obtain phenyl N-(phenoxy)-3-(phenylthio)thioacrylimidate (0.14 g) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: ClCC1CC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
5.0 g (28.9 mmol) 4-bromophenol, 3.93 g (43.4 mmol) (chloromethyl)cyclopropane and 7.99 g (57.8 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:9]([C:13]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[OH:16])=[O:14])[CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1.[Bi]=O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:9]([C:13]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[O:16])=[O:14])[CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: COc1ccc(C(O)C(=O)c2cccc(-c3cc(C)cs3)c2-c2ccccc2)cc1OC
Agent: O=[Bi]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=O)c2cccc(-c3cc(C)cs3)c2-c2ccccc2)cc1OC
Temperature: 90 °C
Yield: 65.5 %

Procedure:
A mixture of the benzoin from Step 2 (2.2 g, 6.9 mmol) and bismuth oxide (4 g, 8.6 mmol) in acetic acid (25 ml) was heated at 90° C. for 45 minutes. The hot reaction mixture was filtered and the filtrate concentrated in vacuo to give 2.0 g (90%) of a solid suitable for use without further purification: mp 109-110° C. Anal. Calc'd. for C17H16O4S (MW 316.40): C, 64.54; H, 5.10; S, 10.13. Found: C, 64.59; H, 5.02; S, 10.29.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(O)ccc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1cc(OCc2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of 4-hydroxybiphenyl-2-carboxaldehyde (80 mg, 0.40 mmol), potassium carbonate (111 mg, 0.80 mmol), and tetrabutylammonium iodide (15 mg, 0.04 mmol) in 0.8 mL of dry N,N-dimethylformamide was added benzyl bromide (72 μL, 0.60 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a white crystal (112 mg, 77%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:2].[CH3:31][Li]>C1COCC1.C(OCC)C>[OH:2][CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)[CH3:31]
Reactant: [Li]C
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C=O)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a chilled (−78° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-formyl-pyridin-4-yl)-propyl]-amide (368 mg, 0.91 mmol) in anhydrous THF (8 mL) was added a solution of 1.6 N methyl lithium (2.28 mL, 3.65 mmol) in diethyl ether and the mixture was slowly warmed to room temperature. After 3.5 hours, the reaction mixture was cooled to −78° C., quenched with saturated aqueous ammonium chloride and extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid {(S)-1-[2-(1-hydroxy-ethyl)-pyridin-4-yl]-propyl}-amide as a light yellow foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1.[Mg].S(=O)(=O)(O)O>CCOCC>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:4]([OH:6])([CH3:5])[CH2:3][CH2:2][OH:1])=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)c(F)c1
Reactant: CC(=O)CCO
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
0.44 g. of 1 -hydroxy-3-butanone in 40 ml. of ether is added dropwise, at 20° to stirred Grignard solution obtained from 2.69 g. of 4-bromo-2',4'-difluorobiphenyl and 0.24 g. of magnesium in 100 ml. of ether. The mixture is stirred for two hours more and the resulting alcoholate is decomposed with dilute sulfuric acid. The ether phase is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [Na].[K].C(O)C=C.C(O)C1C=CC=CC=1.Cl[C:16]1[CH:17]=[C:18]([CH:22]=[C:23](Cl)[N:24]=1)[C:19]([OH:21])=[O:20]>O.CN(C)C=O.C1(C)C=CC=CC=1.O1CCCC1>[C:19]([OH:21])(=[O:20])[C:18]1[CH:22]=[CH:23][N:24]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: [K]
Agent: [Na]
Solvent: OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C=CCO
Product: O=C(O)c1ccncc1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
A sodium or potassium salt of allyl alcohol, benzyl alcohol, or substituted benzyl alcohol is dissolved in a solvent that does not affect the reaction, such as tetrahydrofuran, toluene, and dimethylformamide, and preferably dimethylformamide. A sodium salt of 2,6-dichloroisonicotinic acid is added to the resulting solution at room temperature. The resulting mixture is stirred at 60 to 100° C. for 2 to 24 hours. The mixture is allowed to react, preferably, at 80° C. for 4 hours. Here, 2 to 10 equivalent, and preferably 4 equivalent amount of alcoholate is used relative to a sodium salt of 2,6-dichloroisonicotinic acid. After the reaction has completed, water is added to the reaction product, and a water layer is separated using ethyl acetate or a like solvent. The pH of the water layer is adjusted to 5 to 6 using 1N-hydrochloric acid or acetic acid. The result is subjected to extraction using ethyl acetate, a mixed solvent of ethyl acetate and n-hexane, toluene, or the like. The extract is dried over sodium sulfate, magnesium sulfate, etc., and then concentrated to obtain an isonicotinic acid derivative of allyloxy, benzyloxy, or substituted benzyloxy (2)(in the present specification, the isonicotinic acid derivative of allyloxy, benzyloxy, or substituted benzyloxy (2) may be referred to as isonicotinic acid derivative (2)).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH:13][CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12].CO.[BH4-].[Na+]>O>[CH2:10]([N:13]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12]
Reactant: C=CCNCC=C
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCN(CC=C)Cc1ccccc1O
Temperature: 0 °C
Yield: 64 %

Procedure:
12 g of 2-hydroxybenzaldehyde was placed in a 500 ml round bottom flask with 100 ml of diallyl amine and 100 ml of methanol. The reaction mixture was then cooled to 0° C. 4 g of NaBH4 (powder) was slowly added within 2.5 hrs and the temperature was kept at 0-6° C. Water was then added to the reaction mixture to terminate the reaction. The reaction mixture was then concentrated, and extracted with ethyl acetate and water. The organic phase was collected and concentrated to obtain crude product. The obtained crude product was eluted and purified with mobile phase eluant of n-hexane:ethylacetate (EA)=4: 1 and solid phase of silica gel. 12.8 g of the product of formula (IX) was obtained and recovery yield was 64%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][O:16][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3COCC3C2)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of (1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl)-methanol (7.89 g, 31.2 mmol) and p-toluenesulfonic acid monohydrate (7.12 g, 37.4 mmol) in toluene (150 mL) was heated under a Dean Stark trap (120° C., 20 h). The reaction mixture was cooled (rt) and treated with 1 N NaOH (50 mL). The aqueous phase was extracted with methyl tert-butyl ether (3×50 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using MeOH (0.2 M NH3):DCM (0-5%) to afford the title compound as a yellow oil (5.08 g, 80%). 1H NMR (500 MHz, CDCl3): 7.37-7.29 (m, 4H), 7.29-7.24 (m, 1H), 3.87-3.79 (m, 2H), 3.65-3.56 (m, 4H), 2.86-2.75 (m, 2H), 2.75-2.66 (m, 2H), 2.34 (dt, J=12.2, 6.1, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[OH-].[K+].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.Cl>CS(C)=O>[N:19]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1[nH]c2cc(-n3cnc4ccccc43)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 130 °C
Yield: 12.2 %

Procedure:
A dry DMSO solution containing 1.2 g of 6-fluoro-7-nitroquinoxaline-2,3-(1H,4H)-dione, 740 mg of potassium hydroxide powder and 1.3 g of benzimidazole was stirred with heating at 130° C. for 5.5 hours. The reaction mixture was then poured in ice-water, followed by addition of hydrochloric acid, and the mixture was filtered at pH about 9 to separate insolubles. The filtrate was then adjusted to pH about 7 with hydrochloric acid, whereupon crystals separated out again. These crystals were collected by filtration to provide 210 mg of 6-(benzimidazol-1-yl)-7-nitroquinoxaline-2,3-(1H,4H)-dione.