Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:13])[C:9]#[C:10][CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O1CCOCC1>[OH:12][CH2:11][C:10]#[C:9][CH2:8][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: OCC#CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC#CCO)cc1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At 10° C., a solution of triethylamine (17.5 ml, 128.0 mmol) in absolute dioxane (60 ml) is added dropwise to a solution of but-2-yne-1,4-diol (10 g, 116.1 mmol) and 4-toluenesulfonyl chloride (24.4 g, 128.0 mmol) in absolute dioxane (230 ml), and the mixture is stirred for 2 h. The mixture is then stirred at RT overnight. The reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8.5:1.5)] on a silica gel column. This gives the title compound (7.5 g) as a light yellow oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(I)C=C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:14]=[CH2:13])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: C=CCI
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
3,4-Dichlorophenylacetonitrile (5 g, 26.87 mmol, 1 eq) in THF (50 mL) was cooled to −78° C. under Ar. LDA (2 M in THF, 16.1 mL, 32.2 mmol, 1.2 eq) was added and the reaction was warmed to 0° C. over 1 h. The reaction was re-cooled to −78° C. and allyl iodide (2.67 mL, 26.87 mmol, 1 eq) was added then the reaction was stirred at −78° C. for a further 2 h. The reaction was diluted with EtOAc (150 mL) and washed with aqueous HCl (1 M, 100 mL), saturated aqueous Na2S2O3 (100 mL) and saturated aqueous NaCl (100 mL). The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 2-(3,4-dichlorophenyl)-pent-4-ene-nitrile (6.3 g, ˜28 mmol) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[C:29]3[CH:30]=[CH:31][C:32](O)=[CH:33][C:28]=3[O:27][CH:26]=2)[CH2:20]1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([N:21]3[CH2:20][C@H:19]([CH2:18][O:17][CH3:16])[O:23][C:22]3=[O:24])=[CH:26][O:27][C:28]=2[CH:33]=1)(=[O:5])=[O:4]
Reactant: COC[C@H]1CN(c2coc3cc(O)ccc23)C(=O)O1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: COC[C@H]1CN(c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C(=O)O1

Procedure:
5.8 ml (0.035 mol) of trifluoromethanesulphonic anhydride are added slowly to a solution, maintained at -20° C., of 7.6 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one in 60 ml of pyridine. After returning to room temperature, the mixture is poured into ice and is brought to a pH of 6 by means of 2N hydrochloric acid. The product is then extracted with ethyl acetate, the solvent is evaporated under reduced pressure and the product is purified by chromatography on silica gel with a 10/90 mixture of cyclohexane and dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=O)[NH:6]2.[OH-:17].[Na+]>C(O)C>[C:12]([C:5]1[NH:6][C:7]2[C:3]([C:4]=1[CH2:5][C:12]([OH:14])=[O:17])=[C:2]([Cl:1])[C:10]([Cl:11])=[CH:9][CH:8]=2)(=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2ccc(Cl)c(Cl)c12
Temperature: 25 °C
Yield: 94 %

Procedure:
To a suspension of ethyl 4,5-dichloroindole-2-carboxylate (Ishii et al., Chem. Pharm. Bull., 1974, 22, 1981., 1.8 g, 7.0 mmol) in ethanol (40 ml) was added 2N aqueous NaOH (10 ml) and the mixture was heated at reflux temperature for 2 h. The mixture was cooled to room temperature and concentrated. The residual solid was acidified with 2N aqueous HCl (30 ml) and extracted with diethyl ether (80 ml×2). The organic extracts were dried (MgSO4) and concentrated to give 1.5 g (94%) of the title compound as yellow solids.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCCCO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCCO)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-aminobutan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.53 (m, 2H) 1.53-1.64 (m, 2H) 2.44 (s, 3H) 3.27-3.33 (m, 2H) 3.44 (br. s., 2H) 4.43 (br. s., 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.07-8.27 (m, 1H) 8.41 (d, J=6.57 Hz, 2H) 8.70 (t, J=5.43 Hz, 1H) 8.85-8.97 (m, 1H) 12.82-13.57 (m, 1H). MS m/z [M+H]+ 392.2
Reaction SMILES: [C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.CO>O1CCOCC1>[C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(O)C(C=C1CCCCC1)n1cncn1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)C(OCc1ccccc1Cl)C(C=C1CCCCC1)n1cncn1
Temperature: 65 °C
Yield: 61 %

Procedure:
A solution of 13.1 g (0.15 mol) of 1-cyclohexylidene-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-ol (Example 2) in 50 ml of dioxane was added dropwise to a suspension of 2.0 g of 80% strength sodium hydride in 50 ml of dioxane and the mixture was then warmed to 65° C. for 45 minutes. After cooling, 10.0 g (0.06 mol) of 2-chlorobenzyl chloride were added dropwise and the mixture was heated under reflux overnight. 5 ml of methanol were then added and the reaction was concentrated. The residue was taken up in methylene chloride and the methylene chloride mixture was washed several times with water. The organic phase was dried over sodium sulphate, concentrated and finally degassed under a high vacuum. 14.2 g (72% of theory) of 1-cyclohexylidene-3-(2-chlorobenzyloxy)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentane were obtained as a yellowish oil with a refractive index of nD20 =1.5349.
Reaction SMILES: CO[C:3]1C(O)=C[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]1[O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23]CCOCCOC1.BrCC1OCCO1.C([O-])(O)=O.[Na+]>CCOCC.CN(C=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=[C:31]([O:32][CH3:15])[C:30]=1[O:29][CH2:28][CH:27]1[O:23][CH2:24][CH2:25][O:26]1
Reactant: COc1cc(O)c(OC)c([N+](=O)[O-])c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: BrCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCC1OCCO1
Temperature: 140 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a mixture of 2,5-dimethoxy-3-hydroxynitrobenzene (2.0 g, 8.43 mmol), 18-crown-6 (2.97 g, 8.43 mmol) and bromomethyl dioxolane (4.22 g, 25.3 mmol) was added DMF (60 ml). The solution was then heated for a total of 1.5 h in the CEM microwave at 140° C., initial voltage=300 W. The solution was poured on to a mixture of sat. NaHCO3 and Et2O, the layers separated and the aqueous extracted with Et2O. The combined organic layers were washed with water (4×50 ml), 1M HCl (50 ml) and brine (2×50 ml), dried over MgSO4 filtered and evaporated. Hexanes were added to the solid residue and the resulting suspension stirred for 1 h. The product was isolated by filtration and dried in a vacuum oven to afford the title compound (1.45 g, 57%). m/z 286 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](Cl)=[O:24])([CH3:19])([CH3:18])[CH3:17]>>[C:30]([C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:28]=1[OH:29])[C:23]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(C(C)(C)C)c1O

Procedure:
Acylation of 2-phenylbenzofuran with 3,5-di-t-butyl-4-hydroxybenzoyl chloride as described above gives 3-(3,5-di-t-butyl-4-hydroxybenzoyl)-2-phenylbenzofuran which, upon reaction with 3-diethylaminopropyl chloride and potassium hydroxide in ethanol according to procedures described above, gives the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1c(O)cccc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(O)cccc1C(F)(F)F
Yield: 87 %

Procedure:
A mixture of 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-3-trifluoromethyl-phenol (53 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([O:17][Si](C)(C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCO
Solvent: CC#N
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5 g, 16.4 mmol) in acetonitrile at 0° C. was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (6.4 g, 18 mmol). The solution was stirred overnight at room temperature, concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-60% EtOAc in hexanes to give 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (3.1 g) To a stirred solution of 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (500 mg, 2 mmol) in ethanol (6 mL) was added sodium borohydride (100 mg, 2.6 mmol). After 0.5 hr, the mixture was concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-70% EtOAc in hexanes to give (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (120 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[CH3:9].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)cc1Br
Temperature: 0 °C
Yield: 48.3 %

Procedure:
25 g (134 mmol) of 2-bromo-4-aminotoluene are placed in 400 ml of 1M sulfuric acid in a round-bottomed flask, and the mixture is then cooled to 0° C. 13 g (190 mmol) of sodium nitrite dissolved in 30 ml of water are added, followed by addition of 21 ml of concentrated sulfuric acid. The mixture is refluxed for 4 hours. It is then extracted with ethyl ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10) to give 12.1 g (48%) of the expected product in the form of a brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:37][CH3:38])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](/[CH:33]=[N:34]/OC)[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH2:39].CC#N>CO.[OH-].[Na+].O>[C:33]([C:20]1[C:21]2[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:14]=[N:13][C:12]([N:9]3[CH2:8][CH2:7][C:6]([CH2:37][CH3:38])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]3)=[N:17][CH:16]=2)[CH:19]=1)(=[O:39])[NH2:34]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(/C=N/OC)c2s1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C(N)=O)c2s1
Temperature: 65 °C
Yield: 5 %

Procedure:
Ethyl-4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-[(E)-methoxyiminomethyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (619 mg, 1.147 mmol) 100 was suspended in MeOH (9 mL) and NaOH(aq) (1M, 9 mL), sealed in a microwave vessel, irradiated at 85° C. for 1 h, followed by conventionally heating overnight at 65° C. The reaction was diluted with water (40 mL) and washed with EtOAc (1×50 mL). Acidification of the aqueous phase with HCl(aq) (1M, pH 2) and back extracting with EtOAc (3×60 mL) yielded a waxy solid which was subjected directly to reverse phase chromatography (5-100% H2O/MeCN) yielding 25 mg (5% yield) of the Compound 193 as a by-product to the aldoxime. 1H NMR (DMSO-d6) δ 8.84 (s, 2H), 8.33 (s, 1H), 8.11 (d, J=1.4 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.71 (s, 1H), 6.87 (t, J=5.4 Hz, 1H), 4.46 (dd, J=9.9, 3.6 Hz, 2H), 3.18 (qd, J=13.2, 4.8 Hz, 4H), 2.06 (d, J=13.4 Hz, 2H), 1.54 (q, J=7.4 Hz, 2H), 1.35 (td, J=13.6, 4.0 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H). MS: 498.2 [M+H]+.
Reaction SMILES: C[O:2][CH:3]1[CH:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:12](=[O:13])[CH:7]2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1.C(O[CH:22]=[CH:23][CH:24]=[CH2:25])(=O)C>C1C=CC=CC=1>[OH:2][CH:3]1[C:8]2[C:9](=[O:14])[C:10]3[C:11]([C:12](=[O:13])[C:7]=2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: C=CC=COC(C)=O
Reactant: COC1OC(C(C)=O)CC2C(=O)C=CC(=O)C12
Solvent: c1ccccc1
Product: CC(=O)C1CC2=C(C(=O)c3ccccc3C2=O)C(O)O1
Temperature: 60 °C
Yield: 30.2 %

Procedure:
A mixture of methyl (1-methoxy-5,8 dioxo-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.450 mmol) and acetoxy butadiene (80 μg, 0.675 mmol) in dry benzene (5 mL) was heated for 3 hours at 60° C. under argon atmosphere. The solvent was then removed in vacuo and the resultting adduct was dissolved in 10 mL of toluene and then aromatized on silica gel by flash chromatography (toluene:ethyl acetate; 90%:10% followed by 70%:30%). Evaporation of the solvents gave 37 mg (31% yield) of pure titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH2:8])[CH:7]=1.C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[C:32]([F:41])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH:8][C:29](=[O:28])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[C:32]([F:41])[CH:31]=2)[CH:7]=1
Reactant: Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)c(F)c1
Product: O=C(Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1)c1ccc(-c2nnn[nH]2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 84, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenylamine (Example 84, intermediate a) and 3-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid methyl ester. Off-white powder (35%). MS (Turbo Spray): m/z=566.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([OH:29])=[O:28].CCCCCCC>CC(C)=O>[CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Agent: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 251 mg of prasugrel base form I in 3.75 ml acetone at room temperature (20-25° C.), a solution of 50.6 l (1.1 eq) 65% aqueous nitric acid in 1.25 ml acetone was added in portions and the resulting mixture was stirred at room temperature for about 15 minutes. After addition of 5 ml heptane at 0-5° C. (ice bath), the clear reaction mixture turned to an emulsion (clear oil drops on the bottom of the flask). A white precipitate was obtained after storage for 17 hours at about −25° C. The mixture containing the precipitate was stirred for 1 hour at 0-5° C. (ice bath), filtered off, washed with 1 ml cold acetone/heptane (1:1) and dried at 40° C./10 mbar for about 2.5 hours. White crystals (269 mg) of prasugrel nitrate were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([P:6]([C:13](=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:5].[CH2:30](O)[C:31]#C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[CH3:22][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]([P:6]([CH2:8][C:9]([O:11][CH2:12][C:30]#[CH:31])=[O:10])([C:4](=[O:5])[C:3]1[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:2]=1[CH3:1])=[O:7])=[O:23]
Reactant: C#CCO
Reactant: COC(=O)CP(=O)(C(=O)c1c(C)cc(C)cc1C)C(=O)c1c(C)cc(C)cc1C
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C#CCOC(=O)CP(=O)(C(=O)c1c(C)cc(C)cc1C)C(=O)c1c(C)cc(C)cc1C
Yield: 55 %

Procedure:
2.9 g (7 mmol) methyl 2-(bis(2,4,6-trimethylbenzoyl)-phosphinyl)acetate (example 22) is dissolved in a tenfold excess of 2-propyn-1-ol and heated to 90° C. during 12 hours in the presence of 10 mol % dibutyltin dilaurate. Excess 2-propyn-1-ol is distilled off under vacuum and the residual oil purified by preparative column chromatography (silica gel, eluent toluene/ethyl acetate 9:1). 1.7 g (55%) propyn-3-yl 2-[bis(2,4,6-trimethylbenzoyl)-phosphoryl]acetate are obtained as yellowish oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH:32]1([NH:37][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC5CCCC5)c4)cc23)CC1
Yield: 72.1 %

Procedure:
Following the general procedure of example 5, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45 mg, 0.101 mmol), cyclopentylamine (90 uL, 0.090 mmol) and NaBH(OAc)3 (197 mg, 0.93 mmol) were reacted to give the title compound (33.0 mg, 64%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[S:16]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])(=[O:17])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCCBr)c2c3ccccc3nc3ccccc23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 450 mg (1.20 mmol) of N-(9-acridyl)-mesitylenesulfonamide in 20 mL of DMF was placed under an atmosphere of argon and cooled to 0° C. To the cooled solution was added 36 mg (1.42 mmol) of NaH (95%). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 1 hr. Then the reaction mixture was cooled to 0° C., and 1.65 mL (12.1 mmol) of 1,5-dibromopentane were added. The reaction mixture was stirred at 70-80° C. for 23 hr. The reaction mixture was cooled, and quenched with 20 mL of water. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was washed with CH2Cl2 (2×20 mL). The CH2Cl2 washes were combined with the organic phase, dried with MgSO4, and evaporated to dryness. The material was purified by column chromatography on silica gel with CH2Cl2 to afford 382.2 mg (60%) of bromide 42 as an orange oil: 1H NMR (300 MHz, CDCl3, TMS) δ 8.25 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.76 (t, J=8 Hz, 2H), 7.45 (t, J=8 Hz, 2H), 6.87 (s, 2H), 4.0-3.9 (m, 2H), 3.27 (t, J=6.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 6H), 1.8-1.6 (m, 4H), 1.4-1.3 (m, 2H).