Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[C:17]([O:19]CC)=[O:18]>CO>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C@H:4]([CH3:3])[C@H:5]([C:17]([OH:19])=[O:18])[CH2:6]1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
An aqueous solution of sodium hydroxide (2N, 20 mL) was added to a solution of cis-1-tert-butyl 3-ethyl 4-methylpiperidine-1,3-dicarboxylate (2.5 g, 9.21 mmol) in methanol (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified to pH 2 using aqueous hydrochloric acid (1N) and was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:11][CH2:10]1.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: COc1ccccc1N1CCN(CCCc2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
2.3 Grams of 6-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril and 0.2 g of platinum black were suspended in 100 ml of methanol and the suspension was catalytically hydrogenated under 2 to 4 atmospheric pressure of hydrogen gas at a normal temperature. After the catalyst was removed by filtration, the filtrate was dried under a reduced pressure. The residue was recrystallized from isopropanol-diisopropyl ether to obtain 6-{3-[4-(2-methoxypheny)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 1.3 g. Melting point: 145°-146° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
Dissolve 4-(2-amino-ethyl)-benzonitrile hydrochloride (300 mg, 1.65 mmol) into saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over Na2SO4 and concentrate in vacuo to obtain 4-(2-amino-ethyl)-benzonitrile (205 mg, 85%). Dissolve 4-(2-amino-ethyl)-benzonitrile (200 mg, 1.37 mmol) in DCM (2 mL), add triethylamine (54 μL, 0.38 mmol) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (169 μL, 1.37 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (182 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: Cc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C
Yield: 67 %

Procedure:
Upon boiling a solution of 6.0 g 2-methylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 158° C. (ethanol) is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[NH:11][C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1.[CH3:31]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[N:11]([CH3:31])[C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1
Reactant: CI
Reactant: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
60% Sodium hydride (1.0 g) was suspended in dimethylformamide (hereinafter abbreviated as DMF) (5 ml) and under ice-cooling, a DMF solution (5 ml) of ethyl 7-(2-chloro-4-trifluoromethylphenoxy)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate (Compound 1) (0.8 g) was dropwise added thereto, followed by stirring for 10 minutes. Methyl iodide (0.4 g) was then added, the mixture was further stirred for 10 minutes, and to the reaction mixture was added water (20 ml) and the mixture was extracted twice with ethyl acetate (50 ml). The extract was washed with water and then saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was then evaporated under a reduced pressure and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.4 g of the title compound (colorless oil).
Reaction SMILES: F[C:2]1[C:3]([C:15]#[N:16])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[OH:17][NH:18]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:15]([NH2:16])=[N:18][O:17][C:2]=12
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Reactant: CC(=O)NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccncc1-c1ccnc2c(N)noc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.057 g, 0.267 mmol), N-hydroxyacetamide (0.060 g, 0.802 mmol), and potassium carbonate (0.222 g, 1.604 mmol) in DMF (Ratio: 7.0, Volume: 1.170 ml) and water (Ratio: 1.000, Volume: 0.167 ml) was stirred at 80° C. for 3 hr. The reaction mixture was filtered through a disposable fritted funnel. The filter cake was washed with EtOAc. Layers in the filtrate were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, concentrated, and further dried under high vacuum to afford the title compound as a brown solid (49 mg, 0.206 mmol, 77% yield). ESI MS (M+H)+=227.1.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)([OH:15])[C:25]([F:27])([F:26])[F:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)(=[O:13])=[O:12])=[O:24])=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCCC2
Yield: 56 %

Procedure:
The title compound was prepared by the method of Example 1 in 56% yield from 5,6,7,8-tetrahydro-2-naphthalenesulfonamide and 4-chlorophenylisocyanate, m.p. 163-165° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:7])[CH3:6].BrBr>C(O)(=O)C>[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[N:20]=[C:21]3[S:1][C:2]([NH2:3])=[N:25][C:22]3=[CH:23][CH:24]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(Cl)cc1F
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Potassium thiocyanate (2.70 g, 27.8 mmol) was dissolved in acetic acid (190 mL), tert-butyl{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (2.40 g, 6.78 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the solution was added dropwise a solution (20 mL) of bromine (1.13 g, 7.07 mmol) in acetic acid, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was purified by basic silica gel chromatography (15 g, ethyl acetate), and the eluted fraction was concentrated under reduced pressure to give the title compound (2.69 g, 97%) as a white powder.
Reaction SMILES: [Mg].[CH3:2][CH2:3][CH2:4]Br.[OH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Cl-].[NH4+]>O1CCCC1>[OH:16][C:9]([C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=1[OH:6])([CH2:2][CH2:3][CH3:4])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCCBr
Reactant: O=C(Cn1ccnc1)c1ccccc1O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)(Cn1ccnc1)c1ccccc1O
Yield: 28.4 %

Procedure:
To a tetrahydrofuran solution of Grignard reagent prepared from 73 mg of magnesium and 369 mg of n-propyl bromide, 202 mg of 1-(2-hydroxyphenacyl) imidazole (II) was added dropwise under ice-cooled conditions while stirring, and the mixture was refluxed for 2 hours. After icecooling, an aqueous solution of ammonium chloride was added to the mixture to decompose the surplus amount of the Grignard reagent and addition salts produced in the reaction. Extraction with chloroform was performed on this mixture and the chloroform layer was washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: chloroform) to produce 70 mg of the title compound at a yield of 29%.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17]>>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: NCc1ccccn1
Product: CCOC(CNCc1ccccn1)OCC
Yield: 65.9 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2-bromo-1,1-diethoxyethane (34.6 ml, 230 mmol) was reacted with 2-picolylamine (50 g, 460 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:ethanol=10:1) to obtain the title compound (34.0 g, 65%)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][N:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:1](=[O:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Acetic anhydride (8 mL) was slowly added to a solution of (8) (1.25 g, 2.03 mmol) in pyridine (50 mL) and CH2Cl2 (30 mL) which had been cooled to 0° C. Stirring was continued at 0° C. for 30 minutes and then at room temperature overnight. Solvents were removed under high vacuum, and the residue was dissolved in CHCl3 (120 mL), followed by washing with 0.5N HCl (2×40 mL) and saturated NaHCO3 (2×40 mL). After solvent removal, the crude oil was purified by silica gel column chromatography, eluting with 3:1 EtOAc/hexane, to furnish 0.8 g (60%) of (9) as an oil: NMR δ 1.40-1.80 (m, 12 H), 2.05 (s, 3 H), 2.20-2.50 (m, 6 H), 3.40-3.73 (m, 6 H), 4.75 (s, 6 H) , 7.32 (s, 15 H). Anal. (C38H48N4O6) C, H, N.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CC(OC)(C)C.C(#N)C>[CH2:1]([CH2:8][NH:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: OCCCCCCCCNCCc1ccccc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 96.5 %

Procedure:
A 2-L flask was charged with benzylmethylamine (270 g, 2.23 mol), sodium carbonate (157 g, 1.48 mol), sodium iodide (11.1 g, 0.074 mol), 8-chlorooctanol (122 g, 0.74 mol) and ACN (1000 mL) and the resulting suspension was stirred at 80° C. for 20-30 hours. The reaction mixture was then concentrated to a volume of about 500 mL and water (600 mL) and MTBE (1000 mL) were added. The MTBE layer was then separated and washed with water (500 mL). The MTBE solution was concentrated under vacuum and the resulting oil was then further concentrated by distillation under high vacuum to remove excess benzylmethylamine. N-methyl-2-pyrrolidone (300 mL) was then added to the remaining oil and this solution concentrated by distillation under high vacuum to provide an oil. The oil was dissolved in MTBE (1000 mL) and the resulting solution was washed with water (2×500 mL), brine (500 mL), dried with sodium sulfate (100 g), filtered and concentrated by distillation to afford the title compound as an oil (178 g, 96% yield, >95% purity).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[OH:29])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:49])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 70 %

Procedure:
The title compound II-ah was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 70/30). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.61 (1H, s), 3.29 (1H, dd), 2.61-1.03 (19H, m), 0.88 (3H, s), 0.79 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][N:29]2C(OC(C)(C)C)=O)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
(R)-tert-Butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate (0.0389 g, 0.0680 mmol) was dissolved in dioxane (1 mL) and treated with 4M hydrogen chloride in dioxane (0.425 mL, 1.70 mmol). The solution was stirred at ambient temperature overnight. The reaction was concentrated in vacuo, resuspended in dioxane and concentrated in vacuo. The residue was concentrated from MeOH (3 times) and then dissolved in MeOH. The solution was then added dropwise to Et2O to afford (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-morpholin-3-yl)ethanone dihydrochloride (20 mg, 54%). m/z 472.1/474.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1H), 7.48 (d, 2H), 7.40 (d, 2H), 5.13-5.07 (m, 1H), 4.50 (d, 1H), 4.15-4.05 (m, 1H), 4.01-3.55 (m, 13H), 3.53-3.39 (m, 1H), 2.83-2.73 (m, 1H), 1.65-1.56 (m, 1H), 1.23 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH3:13])=[CH:9][N:10]=2)[N:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.Cl>CCOCC>[ClH:1].[CH3:13][O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: NCCCN1CCOCC1
Reactant: COCc1cnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCOCC
Product: COCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 31 %

Procedure:
Prepared from 6-chloro-3-(methoxymethyl)imidazo[1,2-b]pyridazine (8a) and 3-morpholinopropylamine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (35 mg, 31%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=9.8 Hz, 1H), 7.54 (s, 1H), 6.80 (d, J=9.8 Hz, 1H), 4.76 (s, 2H), 3.90-3.89 (m, 4H), 3.51 (t, J=6.5 Hz, 2H), 3.38 (s, 3H), 3.26-3.23 (m, 6H), 2.18-2.13 (m, 2H); 13C NMR (125 MHz, CD3OD) δ 154.7, 136.5, 128.7, 125.7, 124.2, 115.0, 64.3, 62.2, 57.3, 55.9, 52.5, 38.7, 23.6; HPLC tR=8.1 min (Synergi), 95.2%; ES-MS: (M+H)=306 m/z.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][CH:9](C)CCN>>[CH2:8]([CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:1][NH2:7])[CH3:9]
Reactant: CCCCCCN
Reactant: CC(C)CCN
Product: CCCCC(CC)CN

Procedure:
n-hexylamine and/or 3-methyl-butylamine
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[C:10]([C:11]([O:13][CH2:14]C)=[O:12])=[C:9]([C:16](OCC)=[O:17])[O:8][N:7]=1>CO>[CH:1]([NH:4][C:16]([C:9]1[O:8][N:7]=[C:6]([CH3:5])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:17])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1onc(C)c1C(=O)OCC
Reactant: CC(C)N
Solvent: CO
Product: COC(=O)c1c(C)noc1C(=O)NC(C)C

Procedure:
2.9 g of isopropylamine are added dropwise to 10 g of diethyl 3-methylisoxazole-4,5-dicarboxylate, dissolved in 100 ml of methanol, and the mixture is then refluxed. After 7 hours the mixture is evaporated down and the remaining oil is chromatographed over silica gel (using 9:1 toluene/acetone). Methyl 5-isopropylaminocarbonyl-3-methylisoxazole-4-carboxylate is obtained as colorless crystals of melting point 64°-66° C. (compound No. 1005).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: CCCCCCCC(I)I
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.44 ml of diiodooctane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C32H36F2INO3 (647) MS (ESI): M+-18
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 4-nitrobenzylalcohol (10.0 g), tert-butyl-dimethylsilyl chloride (11.8 g), imidazole (11.2 g) and DMF (50 ml) was stirred at room temperature for 1.5 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/7) to give tert-butyldimethyl-4-nitrobenzyloxysilane (17.5 g) as pale yellow oil.