Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O.C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(OC(C(=O)O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (16 mmol) Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-2-phenylacetate was dissolved in 50 ml water/ethanol (1:1) and treated with 0.9 g potassium hydroxide. After stirring for 16 hours at room temperature, the mixture was extracted with ethyl acetate. The aqueous phase was acidified with 10% hydrochloric acid until it was pH 2 and extracted with ethyl acetate. After drying over magnesium sulphate, the ethyl acetate phase was concentrated the solid residue recrystallised from diisopropyl ether/ethyl acetate mixture.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:5])C.COCCN(CC1N(C)C(C(O)=O)=CN=1)C>>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(CCN(C)C)c1
Agent: COCCN(C)Cc1ncc(C(=O)O)n1C
Product: CN(C)CCn1cc(C(=O)O)cn1
Yield: 98 %

Procedure:
Using 1-(2-dimethylamino-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester, the title compound was prepared in the same manner as described for 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-3-methyl-3H-imidazole-4-carboxylic acid. White solid (>98% yield by 1H-NMR). MS: m/e=184(M+H+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([NH:25][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])([CH2:23][CH3:24])([CH3:22])[CH3:21]
Reactant: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O
Reactant: CCC(C)(C)N
Solvent: ClCCl
Product: CCC(C)(C)Nc1c(Nc2c(O)cccc2C#N)c(=O)c1=O

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.250 g, 0.00097 mol) and tert-amylamine (1.13 ml, 0.0097 mol) was stirred in enough CH2Cl2 to form a solution at room temperature for two days. During this time a precipitate forms. The reaction solvent is evaporated on a rotary evaporator, the residue is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and gives 3-(tert-amylamino)-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.135 g (0.00045 mol, 46%).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH:3]12[O:25][CH:4]1[CH2:5][CH:1]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2]2
Reactant: O=C(NC1CC=CC1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NC1CC2OC2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 152 %

Procedure:
To a solution of benzyl cyclopent-3-en-1-ylcarbamate (920 mg, 4.23 mmol) in DCM (20 mL), was added m-CPBA (2.0 g, 7.6 mmol) in portions at 0° C. The mixture was warmed up to RT and stirred at RT for 2 hours. The reaction was quenched by addition of sat. aqueous solution of K2CO3, and the resulting mixture was extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, and then concentrated in vacuo to afford the crude benzyl 6-oxabicyclo[3.1.0]hex-3-ylcarbamate (1.5 g), which was used in the next step directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.CCC([O-])(C)C.[Na+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: C1CCNC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(c2ccc(N3CCCC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.1 mg, 1.0 mmol), pyrrolidine (100.0 μL, 1.2 mmol), sodium tert-pentoxide (154.2 mg, 1.40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (24.5 mg, 0.030 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 0.030 mmol) was deareated under vacuum and then charged with nitrogen. To the mixture was added toluene (2.0 mL). The resulting mixture was heated at 100° C. for overnight. After cooling, the mixture was poured into ice-water and the resulting mixture was extracted with ethyl acetate (4×10 mL) The combined organic phase was washed with water and brine, then dried over Na2SO4, then filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate/heaxane to afford tert-butyl 1-(4-pyrrolidin-1-ylphenyl)cyclopropanecarboxylate.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>O.ClCCl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:19][Cl:18])=[CH:13][CH:12]=1
Reactant: Oc1ccc(-c2ccc(F)cc2F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(OCCCl)cc2)c(F)c1

Procedure:
The compound 2',4'-difluoro-4(2-chloroethoxy)biphenyl is prepared by a process wherein to a solution of 15 g of sodium hydroxide in 30 ml of water there is added 68.2 g of 4-(2',4'-difluorophenyl)phenol and 106 g of 2-chloroethyl-p-toluene-sulfonate. The mixture is heated to about 95°-100° C. while stirring (at 96°-98° C. an exothermic reaction occurs) and maintained at this temperature for 5 hours. The resulting material is diluted with dichloromethane, washed with water, and evacuated until dry. The crude product is crystallized using isopropyl alcohol to yield 62 g (69% of theory) of the final product. If a further crop (9 g) of pure product can be obtained from the mother liquor, the total yield of the product is 80% of theory.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1B(O)O.[F-].[Cs+]>COCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:6]1[CH:7]=[C:2]([C:37]2[NH:36][CH:40]=[CH:39][N:38]=2)[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reactant: OB(O)c1ncc[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ncc[nH]5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7.1 (0.78 g, 1.42 mmol), 1H-imidazol-2-ylboronic acid (0.024 g, 2.13 mmol, 1.5 equiv.), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride CDM complex (0.12 g, 0.14 mmol, 0.1 equiv.) and cesium fluoride (0.65 g, 4.25 mmol, 3.0 equiv.) in dimethoxymethane (12 mL) was bubbled with Ar, then placed under an argon atmosphere in a sealed vial, and was heated at 100° C. for 3 days. The reaction mixture was then added to ice water (50 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (4×50 mL). The combined organics were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 50% hexane/20% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.5 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min) to give tert-butyl (1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.28 g, 37%):
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32](N)=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].OS(O)(=O)=O>C([O-])([O-])=O.[Na+].[Na+]>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([OH:38])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(-c2cnc(N)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cnc(-c2cnc(O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (15 mg) and NaNO2 (10 mg) was added into a H2SO4 solution (0.1 ml of concentrated H2SO4 diluted with 0.3 ml of water). The reaction was stirred at room temperature for one hour. Then, the reaction mixture was neutralized with a saturated Na2CO3 solution (10 ml). The solvents were concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 4.2 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. 1H NMR (500 MHz, CD3OD) δ8.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.64 (m, 8H). MS m/z: (M+H)+ Calc'd for C25H23N6O5: 487.17; found 487.22. HPLC retention time: 1.13 minutes (column A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20](C(O)=O)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C.O>[Br:36][C:20]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12
Reactant: O=C(O)c1c(-c2cccc(F)c2)nn2cc(C(F)(F)F)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (403 mg, 1.24 mmol) and NaHCO3 (355 mg, 3.4 eq) in DMF (10 ml) was added NBS (1.1 eq, 244 mg) and the resulting solution stirred at rt for 1.5 h. The mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic phases were washed with water (3×10 ml), dried and concentrated in vacuo to give the title compound as a brown solid (390 mg, 85%). MH+ 358/359
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].CNCCNC>CS(C)=O>[C:9]1([S:15]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Fc1cccc(I)c1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)c1cccc(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 1-fluoro-3-iodobenzene (2.22 g, 10 mmol), sodium phenylsulfinate (2.16 g, 13 mmol), copper (1) trifluoromethylsulfonate-benzene complex (0.15 g, 0.3 mmol), N,N′-dimethylethylenediamine (0.95 g, 1.09 mmol) and dimethyl sulfoxide (20 mL) was heated at 90° C. under nitrogen with stirring for 2 h then at 115° C. for 18 h. Mixture was cooled then partitioned between water (150 mL) and 1:1 Et2O− EtOAc (100 mL) and the organic phase was washed with water (3×100 mL), dried (Na2SO4) and evaporated in vacuo to give a beige solid. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (1.725 g, 73%) as a colourless solid. 1H NMR (CDCl3): 8.02-7.93 (2H, m), 7.81-7.71 (1H, m), 7.71-7.46 (5H, m), 7.28 (1H, m).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([NH:32][C:8](=[O:10])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:34]([C:41]([F:42])([F:43])[F:44])[CH:35]=1)#[N:38]
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)Nc2ccc(C#N)cc2C(F)(F)F)C2CCCCC2)c(OC)n1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The crude product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile and water (containing 0.5% formic acid). Light brown foam (19%). MS (TS) (M+H+)+: 600.3.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N+:11]([C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(I)c2c(c1)CCO2
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cc2c(c(-c3cccnc3)c1)OCC2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
2,3-Dihydro-7-iodo-5-nitrobenzofuran (0.76 g, 0.0026 mole) and 3-pyridylboronic acid (0.32 g, 0.0026 mole) in 50% aqueous 1,2-dimethoxyethane (50 ml) were treated under argon with sodium carbonate (1.17 g, 0.011 mole) and tetrakis triphenylphosphine palladium (0) (0.06 g, 0.06 g, 0.000052 mole) and heated under reflux for 18 hours. The mixture was allowed to cool to ambient temperature, diluted with deionised water, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate/60-80° petroleum ether to afford the title compound (0.19 g, 30%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:39]([C:40]34[CH2:45][CH:44]3[CH2:43][NH:42][CH2:41]4)=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28]C(OC(C)(C)C)=O)[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.Cl>O1CCOCC1.CC(O)C>[F:47][C:2]([F:1])([F:46])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:12]2[C:39]([C:40]34[CH2:45][CH:44]3[CH2:43][NH:42][CH2:41]4)=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH2:28])[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(C34CNCC3C4)cc21
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(C34CNCC3C4)cc21
Reaction time: 8 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-3-[(tert.-butoxycarbonylamino)-methyl]-phenylamino}-6-[3-aza-bicyclo[3.1.0]hex-1-yl]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (compound 185, 3.3 g, 4.7 mmol), 6 mL 4M HCl in dioxane, 10 mL dioxane and 5 mL 2-propanol is stirred overnight. The resulting precipitate is collected by filtration, diluted with EtOAc and washed with 1N aq NaOH. The organic phase is dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:34]2([CH3:35])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([CH3:29])[CH2:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9][C@@H:8]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:7]1)=[O:4].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH:55](=[O:60])[CH2:56][CH:57]([CH3:59])[CH3:58].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(NC(C)C)(C)C.C(OCC)C>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:34]2([CH3:35])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:29])[CH:19]([S:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:55]([OH:60])[CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:9][C@@H:8]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:7]1)=[O:4]
Reactant: CC(C)CC=O
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)C(C(O)CC(C)C)S(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
In 2 ml of tetrahydrofuran was dissolved 50 mg of 1α,3β-bis(methoxycarbonyloxy)-20-methyl-21-phenylsulfonylpregna-5,7-diene and the solution was cooled in a dry ice-acetone bath in an argon atmosphere. To the solution was added 0.4 ml of a solution of lithium diisopropylamide prepared from 2 ml of a 1.5N solution of butyllithium in hexane and 0.5 ml of diisopropylamine in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at -30° C. for 30 minutes and then again cooled in a dry ice-acetone bath. A solution of 150 mg of isovaleraldehyde in 1 ml of tetrahydrofuran was added and the mixture was stirred for 4 hours while the mixture was gradually warmed to -30° C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was allowed to warm to ambient temperature. Diethyl ether was added to the reaction mixture and the organic layer was separated, the aqueous layer was extracted with diethyl ether. The organic layer was combined, washed in sequence with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 28 mg of 1α,3β-bis(methoxycarbonyloxy)-22-phenylsulfonylcholesta-5,7-dien-23-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][C:50](=[O:54])[CH2:51][CH2:52][CH3:53])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][C:50](=[O:54])[CH2:51][CH2:52][CH3:53])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(=O)OC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)OC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 100.2 %

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-butyryloxymethyl-morpholine-4-carboxylic acid tert-butyl ester (295 mg, 0.397 mmol) in ethanol (29 mL). Add 20% palladium hydroxide on carbon (330 mg) and stir under 1 atmosphere of hydrogen gas for 48 hours. Filter through a filtering agent and wash with ethanol. Concentrate the filtrate to give the desired compound as a white foam (188 mg, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:19]=[CH:18][C:11]([O:12][C:13]2[CH:14]=[CH:15][CH2:16][CH:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:20].[BH4-].[Na+]>O1CCCC1.[OH-].[Na+].C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[OH:20])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CC(Oc2ccc(Oc3ccccc3)cc2)=CC1
Reactant: O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Hg+2]
Solvent: C1CCOC1
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 12.6 g of 3-(4-phenoxyphenoxy)-cyclopenten-1-ene in 25 ml of tetrahydrofurane is added dropwise in the course of 1 hour to a mixture of 15.9 g of mercury(II) acetate, 35 ml of water and 50 ml of tetrahydrofurane. The mixture is stirred for about 15 hours at room temperature, then 50 ml of 3 N sodium hydroxide solution are added dropwise in the course of 11/2 hours, followed by the dropwise addition in the course of 1 hour of 50 ml of a 0.5 N solution of sodium borohydride in 3 N sodium hydroxide solution. The reaction mixture is stirred for 2 hours at room temperature and precipitated mercury is removed by filtration. The filtrate is poured into ice-water and, after extraction with ether, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Fractional distillation of the residue yields 2-(4-phenoxyphenoxy)cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:2]1.C(O)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>[Pd].C(OCC)(=O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:18][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:17][C:16]3=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:33])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc2c(cc1C=Cc1ccccn1)OCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2cc3c(cc2CCc2ccccn2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) is hydrogenated on a Parr apparatus in 200 ml. of ethanol with 2.0 g. of 10% palladium on carbon as catalyst. After the reduction is complete, the mixture is filtered and the solvent evaporated. The residue consisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine is immediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5 g., 0.044 mole) added. The solution is stirred for 30 min. A basic workup according to the procedure of Example 25 affords 10 g. of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide obtained analytically pure by crystallization from ethyl acetate.