Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:29]=[CH:28][C:9]2[N:10]([CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C:8]=2[CH:7]=1.Cl.[NH2:32][OH:33].C[O-].[Na+].Cl>CO>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][N:10]1[C:9]2[CH:28]=[CH:29][C:6]([CH:5]=[CH:4][C:3]([NH:32][OH:33])=[O:30])=[CH:7][C:8]=2[N:12]=[C:11]1[CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:17])[CH3:18])[CH3:27]
Reactant: NO
Reactant: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)OC)ccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)NO)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
To a stirred solution of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-7, 73.8 mg, 0.18 mmol) and hydroxylamine hydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 mL) was added sodium methoxide (30% in methanol) (0.8 mL, 3.6 mmol) at −78° C. The reaction mixture was then allowed to warm up slowly to room temperature. The reaction was monitored by LC/MS and was completed in around 15 min. 1N HCl was then added slowly into the reaction mixture at 0° C. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 22.2 mg (24.3%) of 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide was obtained as powder. HPLC purity: 99.5%, tR=0.94 min. LCMS m/z: 416 ([M+H]+). 1H NMR (CD3OD) δ 7.89 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.55 (d, J=15.8 Hz, 1H), 6.53 (d, J=15.8 Hz, 1H), 4.98 (t, J=7.3 Hz, 2H), 4.73 (s, 2H), 3.75 (t, J=7.5 Hz, 2H), 3.42 (q, J=7.2 Hz, 4H), 1.37 (t, J=7.3 Hz, 6H), 1.22 (s, 9H); 13C NMR (CD3OD) δ 182.5, 168.9, 162.2, 161.9, 154.8, 140.8, 137.9, 135.0, 133.9, 126.0, 119.3, 117.1, 112.9, 50.9, 40.5, 39.7, 36.7, 27.6, 9.1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)=[O:16]
Reactant: Cc1cc(N)ccc1Cl
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(Cl)c(C)c1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-3-methylaniline and methyl chlorooxoacetate.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9]C([C@@H](O)[C@H](N)CC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])[CH3:3]>Cl>[NH2:9][C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)[C@H](N)Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
The hydrolysis of bestatin in 6N HCl at 100° C for 18 hours yields L-leucine and an unusual amino acid. The ratio of these amino acids is 1:1. Bestatin gives positive Rydon-Smith and ninhydrin reactions. The amino acid sequence of bestatin shown in the structure was elucidated by fragmentation pattern in mass spectrum of bestatin methyl ester hydrochloride. Thus, the structure of bestatin is (2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1)[CH2:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]=2[N:29]=1)([OH:3])=[O:2].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:38][O:37][C:34]1[N:35]=[CH:36][C:31]([C@@H:5]([CH2:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:29]=2)[CH2:4][C:1]([OH:3])=[O:2])=[CH:32][N:33]=1
Reactant: COc1ncc([C@H](CC(=O)O)CC(=O)CCCCc2ccc3c(n2)N(C(=O)OC(C)(C)C)CCCC3)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc([C@H](CC(=O)O)CC(=O)CCCCc2ccc3c(n2)NCCCC3)cn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
The BOC-protected product of Example 11 (15 g) was dissolved in dichloromethane (75 ml) and the solution cooled to 5° C. Trifluoroacetic acid (48.7 g) was added dropwise maintaining the internal temperature at <10° C. The reaction mixture was then heated to 30° C. and aged for ca. 2 hours. The reaction mixture was then cooled to 0° C. and a 2M solution of sodium hydroxide was added dropwise maintaining the temperature at or below ambient. The resulting solution was allowed to settle for ca. 1 hour and the layers separated. The aqueous layer was treated with Ecosorb™ C-941 (0.75 g) at ambient temperature for 1 hour. The resulting mixture was filtered through a bed of Hyflo™. The filter-bed was washed with water (10 ml). The combined filtrates were acidified to pH 6.0 by adding concentrated hydrochloric acid (ca. 8 ml) whilst maintaining the temperature at or below ambient temperature. The aqueous solution was extracted with dichloromethane (2×150 ml) and the organics washed with water (50 ml). The solution was solvent switched to isopropanol (65 ml) at atmospheric pressure and the solution warmed to 40° C., seeded with 0.6% w/w seed, and maintained at 40° C. for 12 hours. Heating was then removed and the slurry allowed to cool to 20° C. Isolation by filtration and washing with isopropanol (3×15 ml) afforded the title compound (9.0g, 74% yield).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[CH:12][CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH:17]2[CH2:4][O:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=3)=[CH:14][CH:15]=1
Reactant: Oc1ccccc1C=Nc1ccc(Br)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1ccc(NC2COc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.145 g, 0.00362 mol) was added to a solution of trimethylsulfoxonium iodide (0.8 g, 0.00362 mol) in anhydrous dimethylsulfoxide (10 mL) and the resulting mixture was stirred under an atmosphere of nitrogen for 10 min. A solution of 2-{[(4-bromophenyl)imino]methyl}phenol (0.4 g, 0.00145 mol) in anhydrous dimethylsulfoxide (5 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2.5 hours. It was poured into ice-cold water (100 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield N-(4-bromophenyl)-N-(2,3-dihydrobenzo[b]furan-3-yl)amine (0.321 g, 0.0011 mol) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Product: COC(=O)c1cccc(/N=C/c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
4-Methoxybenzaldehyde (2.72 g, 19.98 mmol, 1.00 equiv), methyl 3-aminobenzoate (3 g, 19.85 mmol, 1.00 equiv), and methanol (30 mL) were placed in a 50-mL round-bottom flask and allowed to react, with stirring, at room temperature overnight. The resulting solids were collected by filtration and dried in an oven under reduced pressure, yielding 3 g (56%) of (E)-methyl 3-(4-methoxybenzylideneamino)benzoate as a yellow solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:20])[C:18]#[N:19])[CH:11]=[CH:10]2.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:20])[C:18]#[N:19])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(C(C)C#N)ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C#N)c1ccc2cc(O)ccc2c1
Temperature: -10 °C
Reaction time: 7 h

Procedure:
15.6 g of boron tribromide, were dissolved in 100 ml of methylene chloride and cooled to -10° C. To this, 80 ml of methylene chloride solution of 6.0 g oa (6-methoxy-2-naphthyl)-propanonitrile were added dropwise over 2 hours, followed by stirring for 7 hours at room temperature. The resulting reaction mixture was poured into 500 ml of iced water and extracted with ether, followed by washing the ether phase twice with water and then distilling off the solvent. The resulting solid was recrystallized with chloroformhexane mixture to obtain 4.5 g of oa (6-hydroxy-2-naphthyl)-propanonitrile.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:20])=[CH:22][CH:23]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1nc2ccccc2s1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-1,3-benzthiazole (40 mg, 0.27 mmol) in methylene chloride (1 ml) and pyridine (100 μl) was treated with 4-n-butylbenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with NaOH (0.5 ml, 5.0 M) and the resulting mixture stirred overnight. The resulting precipitate was collected by filtration and recrystallized from water to give 2-(4-n-butylbenzamido)-1,3-benzthiazole as pale yellow needles. (47 mg, 53%)
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In accordance with Scheme III, the epoxidation of (3β,5α)cholesta-7,14-dien-3-ol benzoate (2) to (3β,5α, 15α)-14,15-epoxycholest-7-en-3-ol benzoate (3) is carried out as described in Scheme II. Also when the epoxyolefin (3) is treated with a catalytic amount of a protic acid (preferably 70% perchloric acid) in acetone at a controlled temperature of about 23°-26° C. for 3 hours, the precursor compound (3β,5α)-3-(benzoyloxy)cholest-8(14)en-15-one (6) is obtained. However, it has been discovered that when the preceding reaction is conducted at a temperature of from about 15°-22° C. for 3 hours, the novel intermediate compound (3β,5α)-3-(benzoyloxy)cholest-7-en-15-one (5) is produced Further treatment of (5) with a protic acid (preferably 70% perchloric acid) in acetone at about 23°-26° C. for 2 hours also gives the precursor compound (6) which is refluxed with potassium carbonate in a protic solvent, preferably methanol, as described hereinbefore in Scheme II to give the product (7). The alternate debenzoylation procedures described in Scheme II may also be used to give the product (7).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:6][C:7]2[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=2)[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)c1c(O)csc1CSC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)csc1CSC
Reaction time: 2 h
Yield: 50.1 %

Procedure:
50 ml of N,N-dimethylformamide was added to 3.5 g (15.1 mmol) of ethyl 4-hydroxy-2-methylthiomethylthiophene-3-carboxylate, 3.3 g (15.1 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 2.1 g (15.2 mmol) of potassium carbonate, and the mixture was heated and stirred at from 90° to 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2.8 g (yield: 50.0%) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CC(C)([O-])C.[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CN(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (4.0 g, 16.1 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.6 g, 19.3 mmol) and benzyl bromide (2.1 ml, 17.7 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate=3:1) to give phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidinyl)acetate (3.42 g).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH3:14][C:15]([CH3:21])([CH2:18][C:19]#[CH:20])[CH2:16][OH:17]>CN(C=O)C>[C:6]([Si:10]([O:17][CH2:16][C:15]([CH3:21])([CH3:14])[CH2:18][C:19]#[CH:20])([CH3:13])[CH3:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C#CCC(C)(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 20 h

Procedure:
Imidazole (58.3 g, 857 mmol) and t-butydimethylchlorosilane (64.6 g, 429 mmol) were added to a stirred solution of 2,2-dimethylpent-4-yn-1-ol (43.7 g, 390 mmol) in DMF (195 mL), then the solution was stirred at 22° C., under N2, for 20 hours. The reaction solution was extracted with ether (3×300 mL), washed with water (100 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (330 g), eluting with hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 3.29 (s, 2H); 2.10 (d, J=2.8 Hz, 2H); 1.91 (t, J=2.6 Hz, 1H); 0.90 (s, 6H); 0.86 (s, 9H); 0.00 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:12][CH:13]=O>C(O)C>[N:1]1[CH:12]=[CH:13][N:7]2[C:2]=1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6]2
Reactant: O=CCCl
Reactant: Nc1ccc(C(=O)O)nn1
Solvent: CCO
Product: O=C(O)c1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 6-aminopyridazine-3-carboxylic acid (1-1) (1.39 g, 10 mmol) in ethanol in a sealed flask was added 2-chloroacetaldehyde (4 mL, 40% aqueous). The reaction mixture was stirred at room temperature for 5 min, then heated at 100° C. overnight. After cooled to room temperature, the mixture was concentrated to afford the title compound (1.63 g). MS (m/z): 164 (M+1)+
Reaction SMILES: [OH:1][C@@:2]12[CH2:19][C@@H:18]([O:20]C(=O)C(C)(C)C)[CH2:17][CH2:16][C@:15]1([CH3:27])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9](=[O:28])[C@H:8]1[CH2:29][C@@H:7]31)[CH:4]=[CH:3]2.[OH-].[K+]>C(O)(=O)C.O1CCCC1.[Zn]>[OH:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:27])[C@:2]([OH:1])([CH:3]=[CH:4][C@@H:5]3[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[C@@H:7]3[CH2:29][C@@H:8]3[C:9]2=[O:28])[CH2:19]1
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
The starting material of the process is 3β-hydroxy-15β,16β-methyleneandrost-5-en-17-one. The hydroxy in 7β position is introduced in a fermentation process using Botryodiplodia malorum, the resultant compound is acetylated in a regioselective manner with pivalic anhydride in the presence of 4-dimethylaminopyridine yielding the corresponding 3β-pivaloyloxy derivative. Said pivaloyloxy derivative was reacted with tert-butyl hydroperoxide in the presence of VO (acetonylacetonate)2 catalyst to give the 5β,6β-epoxy derivative which, in turn, was reacted with triphenylphosphine and carbon tetrachloride in dichloromethane to yield the 7α-chloro derivative. Said 7α-chloro derivative was reacted with zinc in a mixture of acetic acid and tetrahydrofuran yielding the 5β-hydroxy-15β,16β-methylene-3β-pivaloyloxyandrost-6-en-17-one which then was hydrolyzed with potassium hydroxide to give 3β,5β-dihydroxy-15β,16β-methyleneandrost-6-en-17-one.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:36]=[CH:35][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=3)=[C:17]([Cl:18])[C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:18][C:17]1[C:13]2[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH:36]=[CH:35][C:14]=2[S:15][C:16]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:21]([C:31]([F:33])([F:32])[F:34])[CH:20]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
3-{[3-Chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester (43 mg, 0.079 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 23 mg of 3-{[3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.10 (s, 1H), 7.96-8.02 (m, 3H), 7.54 (d, 1H), 7.46 (d, 1H), 7.35-7.37 (m, 3H), 7.28-7.29 (m, 2H), 4.37 (s, 2H), 3.26 (m, 2H), 2.71 (m, 2H), MS (ES+) 490.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.Cl[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].CC(C)=O.[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([N:3]1[C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=[C:2]1[NH2:1])=[O:13])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)Cl
Reactant: N#Cc1nc(N)[nH]c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)n1c(N)nc(C#N)c1C#N
Temperature: 0 °C

Procedure:
2 g of 2-amino-4,5-dicyanoimidazole and 2 g of allyl chloroformate were added to 20 ml of acetone and further 3 ml of water solution containing 20% of sodium hydroxide was added dropwise to it under stirring at a temperature of 15° to 20°C. After the resulting solution was stirred during an hour at a room temperature, it was poured into ice-water and thereby white crystal was separated out.
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:48]([NH2:50])[CH3:49].C1COCC1>ClCCl.C1COCC1>[CH2:48]([NH:50][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1)[CH3:49]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Reactant: CCN
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
(S)-9-Methylthio-5-(1-tert-butoxycarbonylpiperidin-4-yl)methyl-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.51 g, 5.61 mmol) obtained in Step 1 was dissolved in dichloromethane (40 mL), and the mixture was stirred at room temperature for 20 minutes after adding 3-chloroperbenzoic acid (65%; 1.94 g, 7.29 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was dissolved in THF (10 mL), and the mixture was stirred overnight after adding a 2.0 mol/L ethylamine/THF solution (14.0 mL, 28.1 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 23) (2.09 g, 84%) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH2:15])[N:7]=1.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15]
Reactant: COCCOc1nc(N)c2nc[nH]c2n1
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1nc(N)c2ncn(Cc3cccc(CBr)c3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
2-(2-Methoxy-ethoxy)-9H-purin-6-ylamine (1 g, 4.78 mmol) (1), α,α′-dibromo-m-xylene (2.52 g, 9.56 mmol) and anhydrous potassium carbonate (1.32 g, 9.56 mmol) were combined in DMF (10 mL) and stirred at ambient temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (2×), brine, dried with Na2SO4, and evaporated under vacuum. The crude product was purified by chromatography on silica gel with 0-10% methanol in ethyl acetate as eluent. Evaporation of the appropriate fractions gave 9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine (2) (1.1 g, 2.80 mmol, 59%). MS: 392/394 (MH+).