Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)([O:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:13][CH2:12][CH2:11][O:10][C@:8]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN2C(=O)c3ccccc3C2=O)c2cccc(Cl)c2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN)c2cccc(Cl)c2)C1
Temperature: 100 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)piperidine-1-carboxylate (0.6792 g, 1.32 mmol) and hydrazine monohydrate (2.350 g) in ethanol (20 mL) was heated at 100° C. for 19 h and then cooled to rt. The precipitates were filtered off and washed with CH2Cl2. After the filtrate was evaporated under reduced pressure, the crude (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate (0.410 g, 81%) was used in the next step without further purification. MS ESI +ve m/z 385 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13]1([CH:19]2[CH2:23][CH2:22][CH:21](O)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OC(=O)C)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:22]2[CH2:21][CH2:20][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: OC1CCC(c2ccccc2)C1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(=O)n(C2CCC(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.6 g, 6.8 mmol), 3-phenylcyclopentanol (1.32 g, 8.15 mmol) and triphenylphosphine (2.7 g, 10.2 mmol) in dry THF (15 mL) was slowly added diethyl azodicarboxylate (1.8 g, 10.2 mmol) at RT. The resulting yellow solution was stirred at room temperature for 17 h. The mixture was diluted in ethylacetate, washed with water, brine, dried over MgSO4, and chromatographed on silica gel using hexanes to 3:1 hexanes:ethylacetate, to afford the title compound. MS m/z: 376 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(C(C)C)C(C)C.Cl[C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCN
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(C)CCNc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Temperature: 100 °C
Yield: 33.7 %

Procedure:
N,N-dimethylethylenediamine (0.10 ml, 0.95 mmol) and DIPEA (0.11 ml, 0.63 mmol) were added to a solution of N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (100 mg, 0.32 mmol) in n-butanol (1 ml) and the reaction was heated in a sealed tube at 100° C. for 16 h. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (97:3) as the eluent to give the title compound (40 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[Na+].[Na+].O>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:37][C:38]#[N:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: N#CCN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Yield: 53.2 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013 mol) in methylisobutyl keton (100 ml) was stirred and refluxed. The mixture was cooled and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5 and 99/1). The pure fractions were collected and the solvent was evaporated, yielding 3.64g (53%) of (±)-cis-1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(cyanomethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (intermediate 6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8](O)([CH2:28][O:29]S(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([O:29][CH2:28]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@@]1(c2ccccc2F)CO1
Temperature: 40 °C
Yield: 72.2 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (100 mg) was dissolved in dimethylformamide (4 ml), to which potassium carbonate (42 mg) was added, and the mixture was heated at 40° C. for 1 hour. The resultant was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and a saturated aqueous solution of sodium chloride (10 ) successively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1/4). The desired fraction was concentrated and the residue was recrystallized from diisopropyl ether to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (58 mg) as a colorless crystalline powder.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>BrCCBr.C1COCC1>[OH:13][CH:14]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCCCCC=O
Reactant: CCCCCCCCCCBr
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)CCCCCCC(=O)OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
Magnesium metal (0.209 g, 8.71 mmol) was added into dry THF (10 ml) in a 50 ml two-necked round bottom flask fitted with a condenser and nitrogen gas inlet. The flask was heated to 70° C., then a few drops of 1,2 dibromoethane were added to the mixture, followed by the slow addition of 1-bromodecane (1.3 g, 5.81 mmol) while at reflux temperature. Stirring was continued for 30 min. After cooling, the Grignard reagent was added dropwise to a stirred solution of methyl 8-oxooctanoate (1.0 g, 5.8 mmol) in THF (10 ml) at −20° C., and the reaction mixture was slowly warmed to room temperature, where stirring was continued for 2 h. The mixture was quenched with saturated ammonium chloride solution, extracted with (3×25 ml) of ethyl acetate, and the combined organic layers were washed with brine solution, dried on anhydrous MgSO4, concentrated and purified on silica gel (2:8 ethyl acetate and hexanes) to obtain an off-white solid (450 mg, 47%).
Reaction SMILES: [Cl-].[C:2]([C:4]1([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>ClCCl>[CH2:24]([S:26]([N:7]1[CH2:8][CH2:9][C:4]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: N#CC1(CC2CCOCC2)CC[NH2+]CC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CCOCC2)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyano-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidinium chloride (9, 1 g, 3.1 mmol), dichloromethane (50 ml) and triethylamine (2.162 ml, 15.51 mmol). To this was added dropwise ethanesulfonyl chloride (0.317 ml, 3.1 mmol). The reaction was stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions were dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidine-4-carbonitrile (10) as a white solid. MS 301 (M+1)
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]CC)=[O:18])[C:12]2=[C:11]([Br:22])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11]([Br:22])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCn2c(C(=O)c3ccccc3)cc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1cc(Br)c2n1CCC2C(=O)O

Procedure:
A solution of 250 mg. of ethyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 8 ml. of methanol is treated under an atmosphere of nitrogen, with a solution of 200 mg. of sodium hydroxide in 1 ml. of water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with 5 ml. of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18]>C(O)C.O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:1])=[C:8]([NH2:18])[C:10]([F:13])([F:12])[F:11])[CH3:7]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)=C(N)C(F)(F)F
Temperature: 25 °C
Yield: 104.3 %

Procedure:
Ethyl α-methyl-4,4,4-trifluoroacetoacetate (24.5 g, 124 mmol) and ammonium acetate (28.6 g, 372 mmol) were dissolved in ethanol (50 ml) and water (2.5 ml). The solution was heated under reflux for 16 hours, allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to give the product as a pale brown liquid (25.5 g, 100% yield) which was used without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([OH:35])[CH2:22][N:23]([CH3:34])[C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21](=[O:35])[CH2:22][N:23]([CH3:34])[C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxybutyl]-N-methylcarbamate (12.84 g) in chloroform (150 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin reagent) (15.50 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium sulfite solution and saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to give benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2-oxobutyl]-N-methylcarbamate (10.92 g). To a solution of the obtained compound (7.95 g) in methanol (70 ml) were added methyl orthoformate (70 ml) and pyridinium p-toluenesulfonate (4.08 g) and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was concentrated, and ethyl acetate was added to the residue and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2,2-dimethoxybutyl]-N-methylcarbamate (2.25 g).
Reaction SMILES: [OH:1][CH:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].C([Sn](=O)CCCC)CCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[OH:1][CH:2]([CH2:6][O:7][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH2:3][C:4]#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCC(O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(O)CC#N)cc1
Reaction time: 2 h

Procedure:
tosylating 3,4-dihydroxybutanenitrile by reacting 3,4-dihydroxybutanenitrile with dibutyltinoxide, p-toluene sulphonyl chloride and a base in the presence of an organic solvent, at a temperature ranging between 25-30° C. under nitrogen atmosphere, for a period of 1-3 hrs., adding water to the above said reaction mixture and separating the organic layer, followed by concentration and purification by known method to obtain the racemic 3-hydroxy-4-tosyloxybutanenitrile, ii) resoluting racemic 3-hydroxy-4-tosyloxybutanenitrile with an acetylating agent in the presence of lipase in an organic solvent, at a temperature of 25-30° C. followed by filtration and washing to obtain (R)-3-hydroxy-4-tosyloxybutanenitrile, iii) converting (R)-3-hydroxy-4-tosyloxybutanenitrile (R)-GABOB and (R)-carnitine by reacting it with a base in an organic solvent under reflux for an overnight period followed by evaporation, adding concentrated HCl to the resultant residue and heating to a temperature in the range of 60-90° C., for a period of about 6 hr followed by evaporation and purification by known method to obtain the desired product.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][C@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13]1>>[CH3:11][C@@H:12]1[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][N:17]1[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH2:8]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@@H]1CN(C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 23 starting with 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (R)-tert-butyl 3-methyl-piperazine-1-carboxylate gave (R)-5-(2,4-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-amine as a brown solid (94 mg, 62% over four steps). 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 3.66 (s, 3H), 3.59-3.44 (m, 2H), 2.99-2.86 (m, 3H), 2.46-2.31 (m, 4H), 2.03 (t, J=10.7 Hz, 1H), 0.87 (d, J=6.3 Hz, 3H). Exchangeable NH2 not observed.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[C:6]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:1]2=[O:3])=[CH:12][CH:13]=1
Reactant: Fc1ccc(C2=CCCC2)cc1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccc(F)cc1
Temperature: 40 °C
Yield: 69.8 %

Procedure:
A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% hydrogen peroxide (23 mL, 149 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol) while stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the contents of the separatory funnel were vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol, 69.9% yield) as a colorless oil. LC-MS (M+H)+=177.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.12-7.18 (2H, m), 6.98-7.04 (2H, m), 3.29 (1H, dd, J=11.6, 8.5 Hz), 2.42-2.54 (2H, m), 2.27 (1H, ddd, J=19.1, 10.5, 8.9 Hz), 2.12-2.20 (1H, m), 2.01-2.12 (1H, m), 1.87-1.99 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[CH2:9][C:4]2(OCC[O:5]2)[CH2:3]1.Cl>C1COCC1>[CH3:13][C:10]1([CH3:14])[CH2:9][C:4](=[O:5])[CH2:3][C:2]([CH3:15])([CH3:1])[C:11]1=[O:12]
Reactant: CC1(C)CC2(CC(C)(C)C1=O)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CC(=O)CC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a solution of 7,7,9,9-tetramethyl-1,4-dioxa-spiro[4.5]decan-8-one (4.15 g, 0.019 mol, 1.0 eq.) in THF (60 mL) was added 1 N HCl (30 mL) and the resulting mixture was stirred at room temperature overnight, concentrated to remove most of the THF, extracted with 3×EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated to give 2,2,6,6-tetramethyl-cyclohexane-1,4-dione as a white solid (3.43 g, >100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:12]=[C:13]([C@@:18]2([O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]2[OH:22])[O:19][CH3:20])[CH:14]=[CH:15][C:16]=1[F:17].C(O[C:35](=[O:37])[CH3:36])(=O)C.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([O:22][C@@H:21]1[C@@H:23]([O:24][C:21](=[O:22])[CH3:23])[C@H:25]([O:26][C:25](=[O:26])[CH3:27])[C@@H:27]([CH2:29][O:30][C:35](=[O:37])[CH3:36])[O:28][C@:18]1([C:13]1[CH:14]=[CH:15][C:16]([F:17])=[C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:12]=1)[O:19][CH3:20])(=[O:19])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@]1(c2ccc(F)c(Cc3cc4ccccc4s3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(F)c(Cc3cc4ccccc4s3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the above-obtained toluene solution of methyl 1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-α-glucopyranoside were added pyridine (7.39 g) and 4-dimethylaminopyridine (19 mg). Thereto was added acetic anhydride (7.94 g) at 1.7 to 3.3° C., followed by stirring at room temperature for 12 hours. To the reaction mixture was added hydrochloric acid (2 M, 50 ml), followed by extraction. The organic layer was washed with a 5% aqueous sodium hydrogencarbonate solution (75 ml) and successively with an aqueous sodium chloride solution (25%, 50 ml), and subjected to vacuum distillation to distil off the solvent until the residue became 15 ml, to obtain, as a toluene solution, methyl 2,3,4,6-tetra-O-acetyl-1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-α-glucopyranoside.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH3:15][N:16]([CH:18]=[C:4]([C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Yield: 64.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.5 g, 77.34 mmol) and N,N-Dimethylformamide dimethyl acetal (9.21 g, 77.34 mmol) were dissolved in benzene (10 mL). The mixture was heated under reflux for 1 h. The solvent was evaporated and distilled with a Kugelrohr apparatus to give 12 g of ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (yield 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:47][CH2:46][C:45]5[CH:44]=[CH:43][C:42]([N:39]6[CH2:40][CH2:41][O:36][CH2:37][CH2:38]6)=[CH:49][CH:48]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCOCC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C

Procedure:
The product is prepared by following the procedure described in example 34, stage (j) starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.196 cm3 of 4-morpholinobenzylamine instead of the cyclopropylamine used in example 34, stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/2 by volume as eluents), 0.031 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-yl-benzyl)amine is obtained with the following characteristics:
Reaction SMILES: C(O[C:6]([NH:8][C:9]([CH2:17]O)([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])(C)(C)C.[NH2:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:20][N:19]3[CH2:17][C:9]([CH2:10][OH:12])([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:8][C:6]3=[O:7])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)CC(CO)(NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)CC1(CO)CN(CC23CC4CC(CC(C4)C2)C3)C(=O)N1

Procedure:
The title compound was prepared following procedures analogous to those described in Example 27 using (±)-2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-4-methylpentanoic acid and 1-(aminomethyl)adamantane. MS m/z=321.