Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:7]1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:27]2[CH:26]=[CH:25][S:24][C:23]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(O)(CCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCC1(CCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.61 mL) was added dropwise to 6-([2,2′-bithiophen]-3-yl)undecan-6-ol (IIu) (0.33 g, 0.98 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over magnesium sulfate, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Iu) (0.0937 g, 30.0%). 1H-NMR (CDCl3): δ=7.13 (d, J=4.8 Hz, 2H), 6.92 (d, J=4.9 Hz, 2H), 1.83-1.78 (m, 4H), 1.21-1.04 (m, 8H), 1.00-0.87 (m, 4H), 0.77 (t, J=6.3 Hz, 6H). 13C-NMR (CDCl3): δ=158.76, 137.09, 125.09, 122.29, 53.87, 38.34, 32.87, 24.82, 23.05, 14.69
Reaction SMILES: [CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:24]([N:21]1[CH2:22][CH2:23][C@@H:19]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CC[C@@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)C1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CC[C@@H](N(C(=O)Nc2ncc(SCCN3CCCC3)s2)C2CCCCC2)C1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3(R)-yl]-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: C(OP([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=O)OCC)C.[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH:25]=O>C1COCC1.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:25]=[C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:17]#[N:18])[CH:27]=1
Reactant: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid diethyl ester (5.4 g, 19.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Lithium (bistrimethylsilyl)amide (20 mL, 20 mmol, [1M]) was the added dropwise. The resulting mixture was stirred 20 min, and then 5-fluoro-2-nitro-benzaldehyde (3.31 g, 19.6 mmol) was added. The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic phase was separated and dried with MgSO4 and filtered. The solvent was removed to yield an oil which was purified by silica column chromatography (120 g column, 20% EtOAc/heptane) to yield a solid.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1.Cl>C1COCC1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.9 %

Procedure:
Cinnamoyl chloride (89.2 g, 535 mmol) was dissolved in THF (170 mL) and added dropwise to a 0° C. solution of 2-fluoroaniline (54.1 g, 486 mmol) and pyridine (39.35 mL, 486.5 mmol) dissolved in THF (170 mL). The mixture was allowed to warm to ambient temperature after the addition and stirred for 15 hours. A solution of 2M HCl was added (1250 mL) and the mixture was stirred at ambient temperature for 8 hours, during which the initial oil solidified to a light pink solid. This material was collected by filtration, washed with several portions of water, and air-dried to provide the desired product (119.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:30]=[C:29]([OH:31])[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[C:17]=3[CH2:25][CH:26]=[CH2:27])[O:15][C:10]=2[CH:9]=1)=[O:5])[CH3:2].[H][H]>CN(C)C=O.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:30]=[C:29]([OH:31])[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[C:17]=3[CH2:25][CH2:26][CH3:27])[O:15][C:10]=2[CH:9]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1c(-c2cc(=O)c3c(O)cc(OCC(=O)OCC)cc3o2)ccc(OC)c1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCc1c(-c2cc(=O)c3c(O)cc(OCC(=O)OCC)cc3o2)ccc(OC)c1O

Procedure:
21.3 g of 7-ethoxycarbonylmethoxy-5-hydroxy-2-(2-allyl-3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one are dissolved in 300 ml of dimethylformamide. The solution is poured into 2 g of 10% palladium on carbon. The whole is hydrogenated at 50° C. under a pressure of 63×104Pa until the theoretical amount of hydrogen has been absorbed. The mixture is then filtered over Millipore and the solvent is removed by distillation under reduced pressure. The crude residue (21 g) may be used as it is. An analytical sample, obtained by recrystallisation from isopropanol, melts at 138° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>CN(C)C=O.CC(C)([O-])C.[K+]>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[NH:10][C:7](=[O:9])[CH3:8])[CH3:16]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To 50 ml dimethylformamide is added 5.7 g (51 mmoles) of potassium tert-butoxide and 11.1 g (51 mmoles) of diethyl acetamidomalonate and the resulting mixture stirred at 25° for 15 minutes. The solution is then cooled to 10° and a solution of 10.0 g (51 mmoles) of 4-cyanobenzyl bromide, Case, J. Am. Chem. Soc., 47, 1143, (1925) in 40 ml of dimethylformamide is added dropwise over 20 minutes. The mixture is then stirred at 25° for 1 hour after which a further 0.285 g (2.5 mmoles) of potassium tert-butoxide and 0.5 (2.5 mmoles) of diethyl acetamidomalonate are added and stirring continued for 1 hour at 25°. The reaction mixture is then poured into 300 ml of ice water, causing the product to precipitate. Filtration, washing with water and drying yields 10.3 g (31 mmoles, 61%) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester, m.p. 160°-163°.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=[N:2]1.[I:10](O)(=O)=O.II>C(O)C>[I:10][C:4]1[CH:3]=[N:2][NH:1][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccn[nH]1
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]ncc1I
Temperature: 60 °C
Yield: 348.6 %

Procedure:
A suspension of N-(1H-pyrazol-5-yl)acetamide (60 g, 0.48 mol), iodic acid (21.1 g, 0.12 mol) and iodine (61 g, 0.24 mol) in ethanol (1.6 L) was heated at 60° C. for 1.5 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and 2 M Na2S2O3 aq. solution. The layers were separated and the aqueous extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to provide the title compound as a solid (105 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH:26]=[O:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
To a solution of 3.43 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-4-methyl-2-propylimidazole-5-carboxaldehyde (from Example 320, Part D) in 22 mL of methanol and 22 mL of tetrahydrofuran at 25° C. was added in several portions, 3.09 g of sodium borohydride. The reaction mixture was stirred at 25° C. for 1.5 hours and then was poured into dilute aqueous sodium hydroxide solution. After stirring for 0.2 hour at 25° C. this solution was extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: ethyl acetate/benzene) furnished 3.32 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(=O)(=O)(O)O.[CH3:16]O>ClCCl>[C:1]([O:10][CH3:16])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: CO
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccccc1O
Reaction time: 18 h

Procedure:
Combine salicylic acid (19.4 g, 140.5 mmol), sulfuric acid (20 mL), and methanol (100 mL). Heat to reflux. After 18 hours, pour the reaction mixture into dichloromethane. Separate the layers and extract the aqueous layer twice with dichloromethane. Combine the organic layers and extract three times with 5%.aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter and evaporate invacuo to give methyl salicylate: Rf=0.60 (silica gel, 1/10 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1C=CC=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+].C(CC(O)=O)#N>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])/[CH:16]=[CH:22]/[C:21]#[N:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: N#CCC(=O)O
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(/C=C/C#N)c1cccc(OCc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of benzyloxy aldehyde III (320 g, 1.26 mol) in toluene (1.2 L) was added pyridine (600 mL), ammonium acetate (15 g, 0.19 mol) and cyanoacetic acid (200 g, 2.35 mol) and the mixture was refluxed for 72 hours. The reaction was diluted with ethyl acetate (3.5 L), washed with water (2 L) and washed with 1N HCl (until pH of the water layer becomes acidic), washed with brine (1 L) and the organic layer was dried and concentrated under reduced pressure to yield 317 g (91 %) cyanide XXXIV. M+1=278
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][NH:33]N)=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CNN)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(Cn2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (675 mg, 2 mmol), (4-methoxybenzyl)hydrazine hydrochloride (755 mg, 4 mmol), and Et3N (0.558 mL, 4 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (367 mg, 43% yield) as an off-white solid: mp 159-161° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.73 (3H, s), 5.67 (2H, s), 6.69-6.75 (3H, m), 6.81-6.86 (2H, m), 7.41 (1H, d, J=1.9 Hz), 7.45-7.51 (1H, m), 7.54-7.59 (1H, m), 7.65-7.71 (3H, m), 8.17 (1H, d, J=7.9 Hz). LC-MS (ESI) m/z 427 [M+H]+. Anal. Calcd for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.95; H, 4.14; N, 13.08.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH3:33]>C(OCCO)C>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:29]=[CH:28][C:27]=1[CH3:33]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(Cl)c3)c2cc1OC
Yield: 99.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 170.0 mg (1.2 mmol) of 2-chloro-4-amino-toluene to give 350.9 mg (99.4%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 353.9,355.8.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:27]([OH:28])=[C:26]([N:24]3[CH:25]=[C:21]([C:19]#[N:20])[CH:22]=[N:23]3)[CH:32]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c1
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (103 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1.4 mL) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred for 2.5 h and then Hunig's base (297 μl, 1.708 mmol) was added and the resulting red solution was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜50 mL). The solid was filtered and dried in vacuum to give the title compound (65.4 mg, 39.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.81 Hz, 2H) 7.27 (dq, J=8.46, 4.17 Hz, 1H) 7.31-7.44 (m, 4H) 8.29 (s, 1H) 8.33-8.58 (m, 3H) 8.93 (s, 1H) 8.98 (s, 1H) 9.30 (t, J=5.81 Hz, 1H) 12.33-14.49 (br s, 1H). MS m/z [M+H]+ 386.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C(=O)([O-])[OH:36].[Na+]>CC(C)=O.Cl>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C@H:25]2[CH2:26][C@@:4]3([CH3:5])[C@@H:6]([CH2:7][CH2:8][C:3]3=[O:2])[C@H:15]3[C@H:24]2[C@@H:23]2[C:18]([CH2:17][CH2:16]3)=[CH:19][C:20](=[O:36])[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: O=C([O-])O
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-oestrene are dissolved in 500 ml of acetone and, under an inert gas, 12.5 ml of 4N aqueous hydrochloric acid are added. The reaction mixture is stirred for 2 hours at 40° C. and then poured onto cold saturated sodium hydrogen carbonate solution, and the aqueous phase is extracted repeatedly with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 12.94 g of 11β-(4-methoxyphenyl)-4-oestrene-3,17-dione are obtained in the form of a white foam.
Reaction SMILES: C([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)C.Cl[CH2:28][C:29]1N(CC)C2C=NC(C(F)(F)F)=CC=2N=1.N1C=CN=C1C1SC=CN=1>>[CH2:28]([N:5]1[C:6]2[CH:7]=[N:8][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:10][C:11]=2[N:3]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:29]
Reactant: CCn1c(CCl)nc2cc(C(F)(F)F)ncc21
Reactant: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Agent: c1c[nH]c(-c2nccs2)n1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(F)(F)F)ncc21

Procedure:
As described previously for the preparation of 1-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine, nucleophilic displacement of the 2-chloromethyl-3-ethyl-6-trifluoromethyl-3H-imidazo[4,5-c]pyridine with the same 2-(1H-imidazol-2-yl)-thiazole followed by usual work provides 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (CD3OD) δ 9.02 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=3 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 6.29 (s, 2H), 4.56 (q, J=7.5 Hz, 2H), 1.52 (t, J=7.5 Hz, 3H) m/z 379 [M+1]
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Br.[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>CN(C=O)C>[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the mesylate from Example 28G (methanesulfonic acid, 2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester) and potassium carbonate in DMF was added (R)-2-methylpyrrolidine hydrobromide [CAS 117607-13-3]. The mixture was stirred at 50° C. overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel eluted with 7.5/20/70 MeOH/EtOAc/CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3, free base): δ 0.88-1.0 (m, 2H), 1.18 (d, J=6 Hz, 3H), 1.4-2.4 (m, 11H), 2.9 (m, 1H), 3.15-3.23 (m, 1H), 7.15 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.66 (q, J=9 Hz, 4H). MS (DCl—NH3) m/z 331.2 (M+H)+. Anal. Calc. for C23H26N2C4H6O6 1.25H2O (L-tartaric acid salt): C, 64.46; H, 6.91; N, 5.57. Found: C, 64.46; H, 6.91; N, 5.57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[CH:4]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:4]1[C:5]2[C:6]3[CH:17]=[CH:16][S:15][C:7]=3[C:8](=[O:14])[NH:9][C:10]=2[C:11]([CH3:13])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 83 %

Procedure:
Following Step 4 from General Procedure A, 8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (6.4 g, 26 mmol) was reacted with N-bromosuccinimide (5.0 g, 26 mmol) to afford the desired product (7.0 g, 82%) as a brown solid: ESI MS m/z 329 [C12H7BrFNO2S+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([C:9](=C(C)C)[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[O:29]=[O+][O-].O=O>CO.C(Cl)Cl>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[O:29])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O

Procedure:
Into a solution of 970 mg (2.5 mmol) methyl 2-((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidin-2-on-1-yl)-3-methylbut-2-enoate in 40 ml of methanol, at -10° C., for 120 minutes a mixture of ozone and oxygen is introduced at a rate of 0.1 mmol per minute. The clear solution is diluted with 60 ml of methylene chloride and the mixture subsequently washed with 50 ml of aqueous sodium bisulfite solution (10%) and 100 ml of saturated sodium chloride solution. After drying of the organic layer over sodium sulfate, filtration and evaporation of the filtrate in vacuo 780 mg of a noncrystalline solid is obtained (86%) (title compound). IR spectrum in methylene chloride: 3400, 1835, 1755, 1720 and 1510 cm-1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[CH2:10]Br.[C:12]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[I:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][N:31]([C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(I)cc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of the product of Step B (0.34 g; 0.87 mmol) hydrochloride salt of tritylamine (0.22 g; 0.87 mmol) and N,N-diisopropylethylamine (DIPEA) (0.49 ml; 2.8 mmol) in anhydrous DMF (3 ml) was stirred for 2 h at 60° C. under N2. After removing the solvent in vacuo, the residue was diluted to 15 ml with ethyl acetate (EtOAc) and washed with, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc, 8:2) to give pure title compound (0.2 g; 48%) as colourless heavy syrup. 1H-NMR (CDCl3) 3.86 (s, 2H); 3.87 (s, 2H); 6.81-7.57 (m, 18H).