Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]([CH3:25])([CH3:24])[O:15][C:14]2=[O:26])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:16]1([CH3:25])[O:15][C:14](=[O:26])[N:13]([C@H:10]2[CH2:11][CH2:12][C:7]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:8][CH2:9]2)[C@H:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(OS(=O)(=O)C(F)(F)F)CC2)[C@H]1c1ccccc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N([C@@H]2CC=C(c3cccnc3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
A microwave tube was charged with (S)-4-((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (0.205 g, 0.489 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.120 g, 0.587 mmol), tetrakis(triphenylphosphine)palladium(0) (0.085 g, 0.073 mmol) and sodium carbonate (0.155 g, 1.466 mmol). Dioxane (1.70 mL) and water (0.25 mL) were added and the vial was charged with argon. The reaction mixture was heated to 100° C. with microwave for 1 h. The reaction mixture was purified via column chromatography on silica gel (RediSep 12 g column, gradient elution with 0% to 50% (90:10 CH2Cl2—MeOH—CH2Cl2) to afford (S)-5,5-dimethyl-4-phenyl-3-((S)-4-(pyridin-3-yl)cyclohex-3-en-1-yl)oxazolidin-2-one (0.128 g, 0.367 mmol, 75% yield) as a yellow oil.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:19])=[O:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+]>CO.ClCCl>[C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:19])=[O:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)Nc1cc(C(=O)O)c(C)cc1C(N)=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of (R)-methyl 5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoate (300 mg, 1.13 mmol) in methanol (2.0 mL) and dichloromethane (1.0 mL) was added 2.0M aqueous sodium hydroxide solution (2.0 mL, 4.0 mmol). The reaction mixture was heated to 45° C. and stirred for 2 h, at which time it was cooled to room temperature and all volatiles were removed by rotary evaporation. To the residual solution was slowly added 1.0M aqueous hydrochloric acid until pH<2. The yellow precipitate was collected by filtration and washed with water to afford (R)-5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoic acid (210 mg, 65%). MS (EI) for C13H18N2O3: 251 (MH+).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([OH:24])[CH:23]=1.O[CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([CH:23]=1)[O:24][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
Di-tert-butyl azodicarboxylate (5.27 g, 23.0 mmol) in DCM (10 mL) was added into a solution of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (4.22 g, 21.0 mmol) and triphenyl phosphine (6.0 g, 23.0 mmol) in anhydrous DCM (40 mL) at 0° C. The solution was allowed to warm to ambient temperature overnight, concentrated in vacuo and the crude product triturated with n-pentane/diethyl ether (×2) to remove the triphenyl phosphine oxide by-product. The sample was purified by dry flash chromatography (1:10→1:1 EtOAc/iso-hexane) to yield yellow oil (2.6 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)Cl>[CH2:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: O=C1CCCc2cccc(Cl)c21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC=CCC1CCc2cccc(Cl)c2C1=O
Yield: 35 %

Procedure:
8.85 g of 8-chloro-1-tetralone were dissolved in 90 ml of tetrachloromethane under argon and added to 21.0 ml of 3-buten-2-ol and 190 mg of p-toluenesulfonic acid. The reaction solution was heated to reflux on a water separator for 9 days. The solvent was removed in a vacuum and the residue was chromatographed on 200 g of silica gel firstly with hexane/ethyl acetate 9:1 and then with hexane/ethyl acetate 4:1. In addition to large amounts of unreacted educt (8.3 g), there were obtained 4.1 g (35%) of 2-(2-buten-1-yl)-8-chloro-1-tetralone as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)cs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Clc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (24.6 mmol) and hydrazine hydrate (49.2 mmol) in 25 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 4.5 g (99% yield) 3-(4-chloro-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=2)=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.S(=O)(=O)(O)O.[Pd]>[C:27]([C:21]1[CH:20]=[C:19]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:24]=[C:23]([CH3:25])[C:22]=1[OH:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)CCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 12 h
Yield: 68.1 %

Procedure:
8.17 g (19 mmol) of 1,5-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,5-pentanedione in 80 ml of ethyl acetate and 3-5 drops of concentrated sulfuric acid are hydrogenated over 1.6 g of Pd/C (5%) at room temperature under atmospheric pressure. After 12 hours, the uptake of hydrogen has ended. The catalyst is filtered over Celite and the resulting colourless solution is concentrated on a rotary evaporator. Chromatography of the liquid residue (SiO2, hexane/ethyl acetate 19:1) gives 5.13 g (67% of theory) of 1,5-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)pentane as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:32])([F:33])[F:34]
Reactant: COc1ccc(N)cc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Yield: 46 %

Procedure:
To a stirred solution of p-anisidine (74 mg, 0.6 mmol), pyridine (0.14 ml, 1.0 mmol) and 4-dimethylaminopyridine (10 mg) in EtOAc (10 ml) was added a solution of (R)-N-[2,3-dichloro-4-(chlorosulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg, 0.5 mmol) (Method 1) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature overnight, washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on a Bond Elut column (using 10% EtOAc in DCM as eluent) to give the title compound as a foam (114 mg, 0.23 mmol); NMR: 1.6 (s, 3H), 3.6 (s, 3H), 6.8 (d, 2H), 7.0 (d, 2H), 7.95 (d, 1H), 8.1 (d, 1H); m/z 485.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:42]=[CH:41][C:34]2[O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38][C:33]=2[CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:22]1([S:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:28][C@@H:29]([C:31]3[CH:42]=[CH:41][C:34]4[O:35][C:36]([CH3:39])([CH3:40])[O:37][CH2:38][C:33]=4[CH:32]=3)[OH:30])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(c1ccc(C#CCCOCCCCCCBr)cc1)C1CCCC1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3ccc(S(=O)(=O)C4CCCC4)cc3)ccc2O1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a stirred solution of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-4-(cyclopentylsulfonyl) benzene (280 mg) in DMF (10 ml) were added (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (WO 0266422 A1) (170 mg) and diisopropylethylamine (165 μl). The mixture was heated at 50° for 22 h before being allowed to cool to room temperature. The mixture was dissolved in EtOAC, washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (10 g), gradient 0% to 30% [MeOH-aqueous ammonia (10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (127 mg) LCMS RT=2.87 min
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:14]2[O:16][CH2:15]2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-4-hydroxy benzaldehyde (3.0 gm 0.0167 m) in 1.5 N sodium hydroxide (25 m) at 50° is added epichlorohydrin (4.4 gm, 0.048 m). After stirring at 50° for 3 hours, the solution is cooled and extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(2,3-epoxypropoxy)-benzaldehyde (3 g) which is used without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2].[C-:31]#[N:32].[K+]>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C#N)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 89.7 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (9.55 g, 20.0 mmol) in anhydrous dimethylsulfoxide was added potassium cyanide (1.43 g, 22.0 mmol). After stirring at 70-80° C. for 4.5 hours, the mixture was cooled to room temperature, quenched with water (500 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (45 ml), dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (7.60 g, 90% yield) as a beige powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])[CH3:3].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][C:20](=[O:22])[C:19]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH:7][C:20]([C:19]1([NH:18][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22])[CH3:3]
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(C)C
Reaction time: 72 h

Procedure:
30 ml of dimethylformamide was added to a flask in which 5 g (27 mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one were placed. Then, 3.53 g (27.4 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred for 3 days. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 8.3 g (quantitative) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6](=O)[NH:7][CH:8]=1.[OH-:10].[Na+]>C(NCC)C>[CH2:6]([N:7]([CH2:2][C:3]1[C:8](=[O:10])[NH:7][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH3:3])[CH3:5]
Reactant: O=c1ccc(CBr)c[nH]1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCNCC
Product: CCN(CC)Cc1ccc[nH]c1=O
Yield: 34 %

Procedure:
The 5-bromomethyl-2-pyridone was taken up in diethyl amine and the solution refluxed for 1 hour. The solution was then treated with 10% sodium hydroxide at 0° C. and washed with chloroform. The aqueous phase was treated with hydrochloric acid to a pH of 6.0 and extracted with chloroform/methanol (5:1). The solution was dried over Na2SO4 and the solvent was then evaporated. The product, (N,N-diethylaminomethyl)-2-pyridone, was obtained in 34% yield. HRMS: m/e, M+ found; 180.1251, 20.8%. Calc. for C10H16N2O; 180.1263, −6.3 ppm. 1H NMR (ppm): 13.1 (broad, 1H, NH), 7.49 (dd, J3-4=9.2 Hz, J4-6=2.4 Hz, 1H, C(4)H), 7.25 (d, J4-6=2.4 Hz, 1H, C(6)H), 6.55 (d, J3-4=9.2 Hz, 1H, C(3)H), 3.30 (s, 2H, CH2O), 2.45 (q, J=7.1 Hz, 4H, N(CH2CH3)2), 1.00 (t, J=7.1 Hz, 6H, N(CH2CH3)2). IR (cm−1) : 1660(vs), ν(C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:24][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:10]2=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[C:11]2=[CH:12]1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c2ccccc21
Temperature: 25 °C

Procedure:
The mixture of 5.0 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 0.81 g of 50% sodium hydride in mineral oil and 100 ml of anhydrous tetrahydrofuran is refluxed for 2 hours. It is cooled to room temperature, combined with 3.0 g of methyl iodide while stirring and another 1.0 g thereof is added after one hour. The mixture is stirred overnight at room temperature, filtered and the residue recrystallized from tetrahydrofuran-heptane, to yield the 5-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 322°-323°.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: OCc1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)ccc2nn1C1CC1
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a suspension of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (67 mg) and triphenylphosphine (140 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (125 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (34 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.C(Cl)(Cl)Cl.Cl>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2nccs2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 126 %

Procedure:
4-Bromoacetophenone (500 mg, 2.51 mmol) and 2-(tributylstannyl)thiazole (0.948 ml, 3.014 mmol) were dissolved in 1,4-dioxane (8 ml), and bis(triphenylphosphine)palladium dichloride (176 mg), was added to the solution under an argon gas atmosphere. The mixture was stirred at 90° C. for 8 hours. After the reaction solution was cooled to room temperature, chloroform and 1 N—HCl were added to the solution, and the extraction/separation step was carried out. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to yield the title compound (643 mg) as an opaque white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH3:51][C:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:58][S:55]([C:52]5([CH3:51])[CH2:54][CH2:53]5)(=[O:57])=[O:56])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
A solution of the acid 13e (250 mg, 0.46 mmol) and EDAC (150 mg, 0.6 mmol) in dry DCM (4 ml) was stirred overnight at room temperature. Methylcyclopropane sulphonamide (78 mg, 0.58 mmol) and DBU (182 mg, 1.2 mmol) were added and the mixture was stirred for additional 6 hours at room temperature. 5% Citric acid was added and the mixture was extracted with ethyl acetate. The organic phase was washed two times with 5% citric acid and water, dried with sodium sulphate and evaporated under reduced pressure. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the pure title compound, (130 mg, 44%), (M+H)+652.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N+:13]2([CH2:19][C:20](=[O:27])[NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)[CH3:18])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:35](O)(=O)C(C1C=CC=CC=1)(C1C=CC=CC=1)O>>[Br-:1].[OH:34][C:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH2:12][C@@H:17]1[CH2:16][CH2:15][CH2:14][N+:13]([CH2:19][C:20](=[O:27])[NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)([CH3:35])[CH2:18]1)=[O:10]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](COC(=O)C(O)(c2ccccc2)c2ccccc2)C1

Procedure:
This compound is prepared by an analogous method (1R/S,2R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide: (Example 2) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with benzilic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[CH2:35]Br.C([O-])([O-])=O.[K+].[K+].N#N>CC#N>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[CH2:35][N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(C1CCCc2cccnc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 51.9 %

Procedure:
To a solution of 2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide (3.72 g, 11.0 mmol) dissolved in CH3CN (120 mL) was added 2-bromomethyl-5-cyano-benzoic acid methyl ester (2.79 g, 11.0 mmol) and K2CO3 (4.56 g, 33.0 mmol). The mixture was stirred for 18 hours at 80° C. under a positive pressure of N2. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (150 mL). Brine (150 mL) was added and the mixture was extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a black oil. Purification via column chromatography on silica gel (hexanes:EtOAc, 2:1, v/v) afforded 5-cyano-2-{[(2-nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-methyl}-benzoic acid methyl ester as a yellow solid (2.89 g, 52%). 1H NMR (CDCl3) δ 1.55 (m, 1H), 1.89 (m, 2H), 2.34 (m, 1H), 2.66 (m, 2H), 4.44 (d, 1H, J=18.9 Hz), 5.18 (d, 1H, J=18.9 Hz), 5.38 (m, 1H), 6.98 (dd, 1H, J=7.5, 4.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.75 (m, 4H), 7.91 (d, 1H, J=4.4 Hz), 8.12 (m, 3H).