Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(C(O)=[O:26])C(C(OO)=O)=CC=1.[OH-].[K+]>C(OCC)(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:5])[C:2]2([CH3:4])[O:26][CH2:3]2)=[CH:8][C:9]=1[C:15]([F:16])([F:17])[F:18])#[N:14]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 77.3 %

Procedure:
N-Methacryloyl-4-cyano-3-trifluoromethylaniline (13.8 g, 54 mmol) and ethyl acetate (40 ml) were charged in a 300 ml four-neck flask, and the mixture was heated at 50° C.–55° C. A solution of mono-perphthalic acid in ethyl acetate (108.05 g, net 19.82 g, 110 mmol) was added dropwise at a temperature in the range of 50° C.–55° C. over 3.9 hr. After stirring at the above-mentioned temperature for 4.5 hr, a solution of mono-perphthalic acid in ethyl acetate (10.36 g, net 1.90 g, 10.4 mmol) was further added dropwise over 10 min. Then the mixture was stirred for 1 hr and left standing overnight at room temperature. The mixture was adjusted to pH=8 (universal test paper) with 20% aqueous KOH solution and partitioned. The organic layer was washed with deionized water (20 ml) in which Na2S2O5 (5.0 g) had been dissolved, dried over MgSO4, decolorized with activated carbon (carborafine 0.5 g), and concentrated under reduced pressure. Toluene (60 ml) was added to the residue and the mixture was heated to 80° C. After cooling to 25° C., the mixture was filtrated to give 4-cyano-N-(2,3-epoxy-2-methylpropionyl)-3-trifluoromethylaniline (11.37 g, yield 77.3%). Purity 98.7%.
Reaction SMILES: [CH:1]1(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:10](CC)CC)C.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH:1]1([C:17]23[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]2[C:15]([NH:10][C:18]3=[O:19])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: NC1CCCCC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(C3CCCCC3)C=CC=CC12
Temperature: 110 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Cyclohexylamine (50.20 ml, 0.44 mol) and triethylamine (51.76 ml, 0.37 mol) were added to a suspension of phthalic anhydride (50.00 g, 0.34 mol) in toluene (500 ml) at room temperature. The mixture was stirred at 110° C. overnight. The temperature of the system was then returned to room temperature, and a 0.1 N aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. The precipitated crystals were collected by suction filtration, washed with hexane, and then dried to give 55.28 g (71%) of 2-cyclohexylphthalimide as a white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>>[Cl:13][C:5]1[C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: Nc1c(Cl)ccc(C(F)(F)F)c1Cl

Procedure:
This material was prepared by chlorination of 2-chloro-5-trifluoromethyl aniline with N-chlorosuccinimide followed by chromatographic purification. The product was isolated as a yellow oil which was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH2:13][CH:14]([CH3:16])[CH3:15])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2.[OH:24]OS([O-])=O.[K+].[CH3:30][C:31](C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:24])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:30][CH3:31])=[O:22])=[CH:5]2
Reactant: CC(C)=O
Reactant: CC(C)CSc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(S(=O)CC(C)C)cc2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
The Ethyl 6-chloro-7-(isobutylthio)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7d) (0.47 g, 1.19 mmole) was dissolved in a mixture of acetone (10 mL) and water (10 mL) and cooled to 0° C. (ice bath). The reaction was treated with oxone (0.73 g, 1.19 mmole) and stirred at 0° C. for 10 minutes followed by warming to room temperature for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid which was subject to HPLC (reverse phase) and eluted with 50-95% ACN/water with 0.05% TFA to give a yellow solid (0.4 g, 82%): LCMS m/z 411.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.65 (s, 1H), 7.54 (s, 1H), 7.24 (s, 1H), 5.73 (q, 1H, J=7.0 Hz), 4.30 (m, 2H), 2.90 (m, 1H), 2.70 (m, 1H), 2.38 (m, 1H), 1.33 (m, 3H), 1.20 (m, 3H), 1.07 (m, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[C:9]([O:16][CH3:17])[CH:8]=1.C(=O)=O.CO.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>CCCCCC.C1COCC1>[Cl:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]([B:23]([OH:28])[OH:24])=[CH:8][C:9]=1[O:16][CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)cc(OC)c1Cl
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(B(O)O)cc(OC)c1Cl
Reaction time: 0.33 h

Procedure:
Under an argon atomsphere, to dry THF (2 mL) stirred in a dry ice-methanol bath was gradually added a 1.57 M solution of n-butyllithium in hexane (0.8 mL), followed by the dropwise addition of a solution of 1-bromo-4-chloro-3,5-dimethoxybenzene (160 mg) in dry THF (2 mL). After the mixture was stirred for 20 minutes in the dry ice-methanol bath, triisopropyl borate (0.18 mL) was added and the mixture was additionally stirred for 20 minutes. The reaction mixture was then stirred at room temperature for 1 hour and pH of the mixture was adjusted at 3 using 4 M hydrochloric acid. The mixture was stirred at 0° C. for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate-hexane giving the title compound as white powder.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)(=[NH:3])[NH2:2].[CH3:14][CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17].C[O-].[Na+]>C(O)C>[O:9]1[C:8]2[CH:12]=[CH:13][C:5]([CH2:4][C:1]3[N:2]=[C:16]([OH:17])[C:15]([CH3:14])=[C:21]([OH:22])[N:3]=3)=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: N=C(N)Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(Cc2ccc3c(c2)OCO3)nc1O

Procedure:
To ethanol (350 mL) was added 5-(amidino)methyl-1,3-benzodioxolane (50 g, 0.23 mol), diethyl methylmalonate (50 mL), and sodium methoxide (120 mL of 25 wt % in methanol). After refluxing for 5 hours, the solvent was removed in vacuo. The residue was dissolved in water, washed with ethyl acetate, treated with charcoal, and acidified with 6 N HCl. The resulting solid was collected by filtration, washed with water, CH3CN and ethyl ether to give 54 g of 2-[(1,3-benzodioxol-5-yl)methyl]-4,6-dihydroxy-5-methylpyrimidine.
Reaction SMILES: [OH:1][C@H:2]([C@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)[C:19]1=[O:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].CC([Si](C)(C)[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O)(C)C.S1C=CC=C1B(O)O>>[OH:1][C@H:2]([C@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][CH2:38][OH:37])=[CH:26][CH:25]=2)[C:19]1=[O:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1B(O)O
Reactant: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(I)cc2)C1=O
Agent: OB(O)c1cccs1
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(-c3ccccc3CCO)cc2)C1=O
Yield: 33.7 %

Procedure:
According to the Step 22-1 in synthetic method for EXAMPLE 22, compound 106-2 (30 mg) and [2-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]phenyl]boronic acid (31.4 mg) were used instead of 14-4 and 2-thiopheneboronic acid to obtain compound 106-3 (10 mg) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:3]1=2.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][C:34]([NH:1][CH:2]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[CH2:6][S:5][C:4]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:3]3=4)=[O:35])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: Cc1ccc2c(c1)C(N)c1ccccc1CS2
Reactant: O=C(O)CCCN1CCN(c2ccc(F)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(NC(=O)CCCN1CCN(c3ccc(F)cc3)CC1)c1ccccc1CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
A mixture of 2.4 g of 11-amino-2-methyl-6,11-dihydrodibenzo[b,e]thiepin, 2.9 g of 4-[4-(4-fluorophenyl)-1-piperazinyl]butyric acid, 2.3 g of dicyclohexylcarbodiimide and 50 ml of methylene chloride is stirred at room temperature for 15 hours. After removal of the precipitated crystals by filtration, the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give 2.0 g of the title compound, m.p. 205°-207° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[N:9]1[C:17]([NH2:18])=[C:16]2[C:12]([N:13]=[CH:14][NH:15]2)=[N:11][CH:10]=1>N1C=CC=CC=1>[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([NH:18][C:17]1[N:9]=[CH:10][N:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[N:13]2)=[O:7]
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2nc[nH]c12)c1ccsc1
Yield: 60 %

Procedure:
62.6 g (0.439 mole) of thiophene-3-carbonyl chloride are added to a suspension of 19.7 g (0.146 mole) of adenine in 100 ml of dry pyridine. The mixture is refluxed for 10 hours, the pyridine is distilled off, the residue is taken up in chloroform, the solution is washed with dilute sodium bicarbonate solution and dried over sodium sulfate, and the solvent is then stripped off in a rotary evaporator. The solid residue is stirred repeatedly with cyclohexane and then recrystallized from ethanol and dried at about 40° C. under reduced pressure. 6-(3-Thenoylamino)-purine is obtained in a yield of 60%.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12.Cl.[NH2:42][O:43][CH2:44][CH3:45].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:44]([O:43]/[N:42]=[C:3](\[C:2]([CH3:39])([CH3:40])[CH3:1])/[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12)[CH3:45]
Reactant: CCON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N/OCC)C(C)(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 7.4 %

Procedure:
A mixture of 4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.3 g), (aminooxy)ethane hydrochloride (1.1 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.024 g, 7%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.Br[C:24]1[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=1[CH3:29]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:24]3[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=3[CH3:29])[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Reactant: Cc1nn(C)c(C)c1Br
Product: Cc1nn(C)c(C)c1-c1cccc(-n2c(N)nc3ccccc32)c1

Procedure:
2-Amino-1-[3-(1,3,5-trimethyl-4-pyrazolyl)phenyl]benzimidazole was prepared from 3-(2-amino-1-benzimidazolyl)-phenyl-1,3,2-dioxaborinane and 4-bromo- 1,3,5-trimethylpyrazole by method A. mp 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]1[CH2:31][C@@H:30]([NH2:32])[C@H:29]([NH2:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:30]1[CH2:31][CH2:26][CH2:27][CH2:28][CH:29]1[NH2:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (-)-R,R-1,2-diaminocyclohexane (0.314 g, 2.75 mmol), triethylamine (0.306 g, 3.06 mmol) and benzene (30 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.110 g, 8.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]([C:17]([OH:19])=O)=[CH:10]2)=[O:5].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH2:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@@H:57]([NH:58][C:17]([C:11]1[N:12]([CH3:16])[C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[OH:1])=[CH:15][CH:14]=2)=[O:19])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1cc2cc(NC(=O)c3ccccc3O)ccc2n1C)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The product of step (b) (1.36 g, 4.38 mM), PyBrOP (2.45 g, 5.26 mM), and (S)-N-benzyl-N-methyl-2-phenylglycinamide (1.91 g, 6.57 mM) were placed in a 50 mL round bottom flask. DMF (20 mL) was added and the mixture was cooled to 0° C. and treated with diisopropyl ethylamine (3 mL, 17.52 mM). After the addition was complete the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (120 mL) and the mixture was washed with 1N HCl (20 mL), water (20 mL) and brine (20 mL). The ethyl acetate was dried with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% diethyl ether in CH2Cl2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=O.C([O:23][C:24](=O)[C:25](=[O:30])[CH2:26][CH2:27][S:28][CH3:29])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:17]([C:16]4[CH:19]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=4[OH:20])[C:26]([CH2:27][S:28][CH3:29])=[C:25]([OH:30])[C:24]3=[O:23])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CCSC
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: CSCC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(Cl)ccc1O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 5-Chloro2-Hydroxybenzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Methylsulfanyl-2-oxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41][C:42]1([O:45]C1)[CH3:43].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C:42]([OH:45])([CH3:43])[CH3:41])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (83.0 mg, 0.143 mmol), isobutylene oxide (113 mg, 1.56 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=1:1, developed once) to give the title compound as a colorless oil (62.3 mg, 82%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1.[Cl-].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[Zn+]>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>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1
Reactant: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Reactant: Fc1ccc([Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: Cc1cc(-n2cc(-c3ccc(F)cc3F)nc2C)cc2ccc(=O)[nH]c12

Procedure:
This compound, m.p. 262°-5°, was prepared similarly to Example 11 using 6-(4-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, 2,4-difluorophenyl zinc chloride and tetrakis(triphenylphosphine)palladium (O) as the starting materials:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:26][CH:25]([S:22]([NH:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH3:36])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(-c2ccc([C@@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(+,−) Trans propane-2-sulfonic acid {2-[4′-(2-amino-ethyl)-biphenyl-4-yl]-cyclopentyl}-amide (prepared in example 9) was dissolved in 20 mL of dry methylene chloride and triethylamine added (0.275 mL, 1.98 mmol). To this stirred mixture was added acetyl chloride (0.084 mL, 1.19 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated in vacuo and chromatographed on a Chromatotron® eluting with 98:2 methylene chloride:methanol which afforded 150 mg (64% 2 steps) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6]2)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCCCC1CN(Cc2ccccc2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a mixture of 2-(3-aminopropyl)-4-benzylmorpholine (2.0 g), 4-amino-5-chloro-2-methoxybenzoic acid (1.7 g) and dichloromethane (40 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.8 g) is added, and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. The eluate with chloroform is discarded, and the subsequent eluates with methanol-chloroform (1:9) are pooled and evaporated to give the title compound (2.5 g) as an oil.