Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][C:12]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])=[O:13]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of resorcinol (5 g, 45.5 mmol) and 3-chloropropionic acid (5.2 g, 48 mmol), is added trifluoromethanesulfonic acid (25 g, 166 mmol) in one portion. The mixture is stirred at room temperature for 10 min, then heated at 80° C. for 30 min. The reaction is cooled to room temperature and the mixture is diluted with DCM (200 mL). The solution is slowly poured into ice water (200 mL). The bi-layer is separated, and the aqueous phase is extracted with DCM (2×40 mL). The combined organic phase is washed with brine and dried over sodium sulfate. The crude 3-chloro-1-(2,4-dihydroxy-phenyl)-propan-1-one is obtained as orange solid (6.9 g) after evaporation of solvent and carried on as is.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[C:3]=1[CH3:13]>[NH4+].[OH-].O.CCOCC>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Br)c(C)c1N
Temperature: 25 °C

Procedure:
To a stirring mixture of 1-bromo-4-methoxy-2-methyl-3-nitrobenzene (2.0 g, 8.13 mmol, see Tet. Lett., 2002, 43, 1063) in NH4OH (40 ml) was added a solution of (NH4)2Fe(SO4)2 (19.1 g, 48.8 mmol) in H2O (40 ml). The reaction mixture was stirred at reflux for 4 hours, cooled to room temperature, diluted with Et2O (120 ml), and filtered through celite. The filter cake was washed with Et2O. The aqueous layer was extracted with Et2O (50 ml). The combined organic layers were concentrated, and the residue was dissolved in Et2O and extracted with HCl (1M, 30 ml). The aqueous layer was basified until about pH 4 by addition of (NaOH 50%, 10 ml) and extracted with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated affording 3-Bromo-6-methoxy-2-methyl-phenylamine CXCV as an off-white solid (0.98 g, 56% yield).
Reaction SMILES: [Na:1].C[C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9]CC1COC2(CCOCC2)OC1.SC1NC2C=CC=CC=2N=1.[CH2:44]1[C:46]2([CH2:51][O:50][CH:49]([CH2:52]OC3C=CN=C(CO)C=3)[O:48][CH2:47]2)[CH2:45]1>>[Na:1].[CH2:45]1[C:46]2([CH2:51][O:50][CH:49]([CH2:52][O:9][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]4[NH:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)=[O:24])[CH:3]=3)[O:48][CH2:47]2)[CH2:44]1
Reactant: OCc1cc(OCC2OCC3(CC3)CO2)ccn1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: Sc1nc2ccccc2[nH]1
Agent: [Na]
Product: O=S(Cc1cc(OCC2OCC3(CC3)CO2)ccn1)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (10d) to (10f) of Example 10 was repeated using 2-mercaptobenzimidazole (291 mg, 1.94 mmol) and (4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)pyridin-2-yl)methanol (443 mg, 1.76 mmol) to obtain the title compound (300 mg) as a white solid. Note that, in the same process as in the step (10d), 2-mercaptobenzimidazole was added to the reaction mixture and further 2 equivalents of triethylamine was added. The mixture was stirred at room temperature for 2 days.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C:5]=2[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[N:1]1[C:6]2[CH2:7][CH:8]([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:9][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1Cc2nccnc2C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1Cc2nccnc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 1.3 g (8.7 mmol) of (6,7-dihydro-5H-cyclopentapyrazin-6-yl)-methanol in 15 ml of anhydrous dichloromethane was added at −15° C. 1.33 ml (9.52 mmol) of triethylamine and 0.74 ml (9.52 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 1 h. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 1.73 g (88%) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)=[N:7][C:6]=2[CH:15]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Sn](Cl)Cl>C(O)C>[NH2:16][C:3]1[C:2]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][C:6]2[N:7]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[O:9][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])c1cc2oc(-c3nccs3)nc2cc1Cl
Reactant: Oc1ccc(S)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1cc2oc(-c3nccs3)nc2cc1Sc1ccc(O)cc1
Temperature: 70 °C

Procedure:
To a flask equipped with a magnetic stir bar and vigreux column was added the product from Example 349A, 4-mercaptophenol, potassium carbonate, and ethanol. The mixture was refluxed for 2 hours followed by addition of tin dichloride while the mixture was maintained at 70° C. After heating overnight the mixture was then cooled and filtered through silica, eluting with 10% CH3OH/CHCl3. The organic layer was then concentrated under vacuum and subjected to purification via Reverse phase (C-18) column chromatography (3% to 100% CH3CN/H2O with 0.1% TFA) to provide the title product.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34]1([O:39][CH2:38][CH2:37][O:36]1)[CH3:35])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19].C(=O)(O)[O-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:14][O:15][N:16]=[C:17]([C:34]1([O:39][CH2:38][CH2:37][O:36]1)[CH3:35])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C1(C)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
Trifluoroacetic anhydride (0.1 ml.) and triethylamine (0.2 ml.) were added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 50 mg.) in dry tetrahydrofuran (5 ml.) and stirred at room temperature for 10 minutes. A sodium bicarbonate aqueous solution (2 ml.) was added to the resultant solution and heated for two minutes. Ethyl acetate and water were added to the solution, acidified with 6 N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer and extract were combined together, washed with water and a sodium chloride aqueous solution in turn and dried over magnesium sulfate. The solution was evaporated in vacuo, and the residue was pulverized with diethyl ether to give 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-cephem-4-carboxylic acid (syn isomer, 30 mg.)
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)C1CCCC1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)C3CCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclopentancarbonyl chloride provided the title compound. ESMS [M+H]+: 400.4
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH-].[Na+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>C1OCCOCCOCCOCCOC1.C1(C)C=CC=CC=1.CN(C=O)C.[I-].[Na+]>[F:10][C:8]([F:9])([F:11])[C:4]1[N:3]=[C:2]([O:1][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(C(F)(F)F)n1
Reactant: COC(=O)Cc1ccccc1CCl
Agent: C1COCCOCCOCCOCCO1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1COc1cccc(C(F)(F)F)n1
Yield: 82.5 %

Procedure:
A mixture of 2-hydroxy-6-trifluoromethylpyridine (2.0 g, 12.3 mmol), sodium hydroxide (0.52 g, 12.9 mmol) and 15-crown-5 (1 drop) in dry toluene (25 ml) were stirred at reflux for 2 hours. The toluene was removed under reduced pressure and the white salt residue was dissolved in dry DMF (15 ml). Methyl 2-chloromethylphenylacetate (2.44 g, 12.3 mmol) in dry DMF (15 ml) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at 75° C. for 2 hours, poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed in vacuo leaving an oil which was purified by column chromatography (silica eluted with 10% ethyl acetate in hexane) to give methyl 2-(6-tri-fluoromethylpyrid-2-yloxymethyl)phenylacetate (3.3 g, 83%) (Compound No.5 in Table 1) as a yellow oil; 1H NMR (270 MHz)δ: 3.68(3H,s), 3.84(2H,s), 5.46(2H,s), 6.89(1H,d), 7,20-7.70(6H,m) ppm.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].O.[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[OH:28])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22][C:21]2=[O:31]>>[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH:12]([CH3:14])[CH3:13])[O:24][C:23]([CH3:29])([CH3:30])[CH2:22][C:21]2=[O:31]
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc2c(cc1O)C(=O)CC(C)(C)O2
Temperature: 130 °C
Yield: 90 %

Procedure:
In 80 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 130° C. for 6 hours, poured into 200 ml of water and extracted with 100 ml of carbon tetrachloride. To the aqueous layer 50 ml of an 5% sodium hydroxide solution are added and the mixture is cooled below 5° C. The mixture is acidified with concentrated hydrochloric acid, the precipitated crystalline substance is filtered off and crystallized from methanol. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 138°-139° C.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].[NH4+].CN(C)C=O.C(=S)=[S:31]>C(N(CC)CC)C>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:31])[N:13]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
In the same manner as described in Example 11, 9.6 g of adenosine 1-oxide monohydrate was treated with a 5N sodium hydroxide aqueous solution and Diaion SK-1B (ammonium-type). 60 ml of N,N-dimethylformamide and 60 ml of triethylamine were added to the resulting residue to form a solution, and 30 ml of carbon disulfide was then added to the solution. The resulting mixture was allowed to react in an autoclave at 130° C for 4 hours under autogenous pressure (about 10 kg/cm2). The reaction mixture was concentrated to dryness followed by working up in the same manner as described in Example 11 to obtain 9.35 g of 2-thioadenosine as crystals having a melting point of 198° C (with decomposition) in a 98% yield.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20].C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[C:19]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Piperazin-1-yl-benzoic acid hydrochlorid (10.5 mmol) is dissolved in 15 ml Dioxan and 11.6 ml NaOH (2N) and cooled to 0° C. Simultaneously, FMOC-chloride (11.6 mmol) in dioxan (5 ml) and diisopropyl-ethylamine (11.6 mmol) in dioxan (5 ml) are added dropwise over 20 minutes at 0° C. and the mixture is stirred for 15 minutes and is then allowed to warm up to rt and is stirred over night. The mixture is diluted with water (50 ml) and extracted 2 times with diethylether. The water phase is acidified with aqueous HCl (4N) at 0-4° C. and the solid material formed is filtered off, washed with water and dried (vacuum). A white powder with Rf=0.2 (CH2Cl2/MeOH =95:5) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 519.26 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19](=O)[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@@:3]1([OH:23])[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:19]2/[C:2]([CH3:1])([CH3:24])[C@@:3]3([OH:23])[C@:16]([CH3:21])([CH2:17][CH2:18]/2)[C@@H:15]2[C@H:6]([C@H:7]4[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:22])[CH2:9][CH2:8]4)[CH2:5][CH2:4]3)[CH2:28]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@]12O
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@]12O

Procedure:
The title compound was obtained in 51% yield following the procedure described in Example 2 and starting from 4,4-dimethyl-5α,17β-dihydroxyandrostan-3-one (Preparation 28, 33 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 69 mg). The crude product was triturated with Et2O and the resulting precipitate was filtered to give the title compound I-by.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:21][CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:22])=[O:36])=[CH:27][CH:26]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: CN(C)c1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CN(C)c1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 4-dimethylaminonaphthalenecarboxylic acid (89 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (149 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cc(Br)c(Br)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
10 g (0.034 mol) of 4,5-dibromo-thiophene-2-carbonyl chloride in 100 ml of toluene are treated dropwise at room temperature with 5.0 g (0.068 mol) of tert-butyl-amine in 20 ml of toluene. The reaction mixture is then stirred at 50° C. for one hour, cooled to room temperature and treated with water. The organic phase is separated off, rewashed with water and concentrated under reduced pressure. After treating the residue with hexane, the crystalline residue which is deposited is filtered off and dried at 50° C. under reduced pressure. 4.8 g (41.4% of theory) of 4,5-dibromo-thiophene-2-carboxylic acid t-butyl-amide of melting point 190° C. are obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([NH:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C[C@@H](CO)NCc2ccccc2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl)benzamide (207 mg) and benzaldehyde (106 mg) in 1,4-dioxane (5 ml) was refluxed for 3 hours, and the mixture was evaporated in vacuo. To the residue in methanol (5 ml) was added sodium borohydride (15 mg) on ice-cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (S)-N-[4-[2-(benzylamino)-3-hydroxypropyl]phenyl]benzamide (250 mg) as colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([SH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24]I>O1CCCC1>[CH3:24][S:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2
Reactant: SC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 60% sodium hydride (245 mg) and anhydrous tetrahydrofuran (20 mL) under an argon atmosphere was added dropwise the solusion of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinoline-6-thiol (0.45 g) obtained in Example 28 in anhydrous tetrahydrofuran (20 mL) at room temperature. After stirring for 1 hr at room temperature, methyl iodide (0.95 mL) was added dropwise and the mixture was stirred for 30 min. Ice water was added to the reaction solution and stirred; thereafter, the mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as colorless crystals (356 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@H:3]([CH2:7][OH:8])[CH:4]([CH3:6])[CH3:5].[CH3:10]I.[F:12][P-:13]([F:18])([F:17])([F:16])([F:15])[F:14].[H+]>ClCCl>[OH:8][CH2:7][CH:3]([N+:2]([CH3:10])([CH3:9])[CH3:1])[CH:4]([CH3:6])[CH3:5].[F:12][P-:13]([F:18])([F:17])([F:16])([F:15])[F:14]
Reactant: CI
Reactant: CC(C)[C@@H](CO)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: CC(C)C(CO)[N+](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
58.5 g (0.5 mol) valinol are dissolved in 115 g (2.5 mol) formic acid and cooled to 0° C. 1.2 mol formaldehyde are added to this mixture and heated until carbon dioxide formation is complete on the boiling water bath. The solution is acidified with hydrochloric acid and the solvents removed by vacuum. The residue is dissolved in 50 ml water, made basic with 25% sodium hydroxide solution and extracted with diethyl ether. The extracts are dried via sodium sulfate and the solvent removed under vacuum. Distillation (33 mbar/80° C.) yields 53.7 g (82%) N,N-dimethylvalinol as a colourless oil. 50 g (0.38 mol) N,N-dimethylvalinol are dissolved in 100 ml dichloromethane, mixed with 56.8 g (0.4 mol) methyl iodide and stirred at room temperature for 12 h. The solvent is removed under vacuum, the residue is dissolved in 200 ml water and mixed with ice cooling with 0.4 mol hexafluorophosphoric acid in an aqueous solution. The reaction mixture is washed repeatedly with water and the solvent removed under vacuum. The yield of (1-hydroxymethyl-2-methyl-propyl)-trimethylammonium-hexafluorophosphate is 107 g. The enantiomer excess in the product is >95%.