Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:2].[O-][CH2:16]C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:16])([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) was added sodium ethoxide (0.22 ml) and 0.5 ml ethanol. A solid precipitates. The solution was stirred at room temperature for 1 h, iodomethane was added and the suspension stirred at room temperature for 3 h. Concentration in vacuo and purification by HPLC gave the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:19]1([CH2:20][CH2:21][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 60 °C
Yield: 73.8 %

Procedure:
To a 50 mL round bottom flask is added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by 4-tert-butylcyclohexanone (1.43 g, 9.3 mmol). MeOH (20 mL) is added to give a clear solution, followed by pyrrolidine (1 mL). A condenser is attached to the RB flask, and the resulting solution is heated at 60° C. for two hours. MeOH is removed and the residue is redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL), and 1 N HCl (10 mL), and dried over Na2SO4. Solvent is removed in vacuo to give 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.41 g, 74%), which is used for the next step without purification.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH2:34])[N:27]=1>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:22]([NH:21][S:18]([CH2:17][C:8]2[C:7]([S:4]([N:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:20])=[O:19])=[O:23])[N:27]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
A solution of the sulfonyl isocyanate from Example 16 (approximately 1.3 g) and 0.56 g of 4,6-dimethoxy-2-aminopyrimidine in 6 ml methylene chloride was stirred overnight at room temperature. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Trituration of the residue with warm n-butyl chloride/ethyl acetate gave a cream-colored solid. The yield of the title compound, m.p. 175°-180°, was 1.1 g; IR(nujol): 1720, 1730 cm-1 ; NMR(CDCl3 /DMSO-d6): δ 2.8 (6H, s, SO2N(CH3)2), 3.7-4.0 (9H, s, CO2CH3 and OCH3 's), 5.8-6.0 (3H, two singlets, --CH2 -- and heterocyclic ring H), 7.55-8.4 (3H, m), 10.5 (1H, br s, NH), 12.5 (1H, br s, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1.B([O-])([O-])O[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:39]([O:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:13]=[CH:14][C:15]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][CH:17]=4)[CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=3[CH:26]=2)=[CH:34][CH:33]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(N)(=O)=O)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of methyl 7-bromo-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g), 4-(2-butoxyethoxy)phenyl borate (0.22 g), 1M potassium carbonate solution (3 ml), ethanol (5 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere for 3 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1.[OH:35]O>C(O)(=O)C.O>[CH3:34][S:33]([C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:4]2[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: OO
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(SC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of example 16 (35 mg, 0.078 mmol) was dissolved in acetic acid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution in water, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 36 mg of the title compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[C:13]1(N)[CH:18]=[CH:17][CH:16]=C[C:14]=1[NH2:19]>C(O)(=O)C.O>[CH:11]1[C:1]2[C:2](=[O:4])[N:19]=[C:14]3[CH:13]=[CH:18][CH:17]=[CH:16][C:5]3=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1N
Solvent: O
Solvent: CC(=O)O
Product: O=c1nc2ccccc2nc2ccccc12
Temperature: 75 °C
Yield: 96 %

Procedure:
A mixture of isatoic anhydride (1 mol) and 1,2 phenylenediamine (1.1 mol) in aglacial acetic acid (60%) was heated at 75° C. for 3 hrs. The resulting mixture was diluted with water and solid filtered to obtained dibenzo[b,e][1,4]-diazepine-11-one in 96% yield.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[C:17]([CH3:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:19][CH3:20])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[C:17]([CH3:18])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[S+](C)C
Reactant: COc1cc(C=O)c(C)cc1C#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2CO2)c(C)cc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (1.20 g, 30.0 mmol) in THF (300 ml) was added dropwise a solution of trimethylsulfonium iodide (8.74 g, 42.8 mmol) in DMSO (80 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxy-5-methylbenzonitrile (5.00 g, 28.5 mmol) in THF (60 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-5-methyl-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 6.88 (s, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.25 (s, 1H), 2.65 (d, J=2.6 Hz, 1H), 2.37 (s, 3H); LC/MS: (IE, m/z) [M+1]+=190.0; tR=2.85 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.O[NH:25][C:26](=[NH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][N:33]=[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:25]=1
Reactant: O=C(O)c1ccco1
Reactant: N=C(NO)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: c1cncc(-c2noc(-c3ccco3)n2)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Furan-2-carboxylic acid (0.8 g; 7 mmol) in 15 ml of dichloromethane was cooled to 0° C., and 0.76 g of 1,3-dicyclohexylcarbodimide (4 mmol) was added slowly. The reaction mixture was stirred at 0-5° C. for 2 hours and filtered. The filtrate was evaporated, the residue was dissolved in 15 ml of pyridine and added 0.43 g of N-hydroxy-nicotinamidine (3.2 mmol). The reaction mixture was heated at reflux until the reaction was finished (measured by TLC), then cooled to room temperature and poured into 100 ml of water. The precipitate was isolated by filtration and dried under vacuum. The product was isolated by column chromatography. Yield 0.23 g (15%). Mp. 110-114° C.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCC(F)(F)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25]Br>>[CH3:31][O:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1cc(CBr)cc(OC)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 59.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (252 mg, yield: 59.1%).
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Co:10](Cl)Cl.C([O-])(=O)C.[Na+]>CO.O>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Co:10]
Reactant: Cl[Co]Cl
Agent: CC(=O)[O-]
Agent: O=c1cccccc1O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [Co]

Procedure:
To a solution of tropolone (244 mg) in methanol is added a solution of cobalt (II) chloride (129 mg) in water and then sodium acetate (164 mg). The precipitate is recovered by filtration and recrystallized from ethanol-ethyl acetate to give 206 mg of tropolone cobalt complex as brown powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[N:13]=[CH:12][NH:11][C:10]=1[CH3:9])=[S:23]
Reactant: CN=C=S
Reactant: Cc1nc[nH]c1CSCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1nc[nH]c1C
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g) in acetic acid (200 ml) was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride m.p. 189°-192°. Potassium carbonate (7.75 g) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g) in water (120 ml). The solution was stored at room temperature for 15 minutes and methyl isothiocyanate (5.15 g) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5°. The product was collected and recrystallised from water to give N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, m.p.150°-152°.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>C(#N)C.C(=O)([O-])O.[Na+]>[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(N)c1NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
N-Chlorosuccinimide (74.1 g, 555 mmol) was added to a stirred solution of methyl 3-amino-2-[(3-hydroxypropyl)amino]benzoate (81.9 g, 370 mmol) in acetonitrile (1480 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. Additional N-chlorosuccinimide (9.88 g, 74.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-45% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (15.7 g, 60.8 mmol, 16%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH2:10]([N:12]([CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:11].O.[OH-].[Na+]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:28]([N+:12]([CH2:10][CH3:11])([CH3:6])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:29]
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC[N+](C)(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium fluoroborate (3.81 g, 25.6 mmol) was added to a solution of N,N-diethyl-3-[S-(4-nitrophenyl)sulfonimidoyl]-1-propanamine (7.7 g, 25.6 mmol) in methylene chloride (50 mL) maintained at -20° C. After 15 min the reaction mixture was warmed to 0° C. for 30 min and then to ambient temperature for 1 h. Water (100 mL) was added to the reaction mixture, and the reaction mixture was made basic with 10% sodium hydroxide. The biphasic mixture containing insoluble material was filtered. The solid that was collected by filtration was recrystallized from a methanol/ethanol mixture. The white solid that formed was collected by filtration to give 0.51 g(4.9%), mp 125°-126.5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH:13]=[CH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:15].[Na+].OO.[Cl-].[Na+]>O1CCCC1.C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=CC1CC1CO[Si](C)(C)C(C)(C)C
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-vinylcyclopropylmethyl t-butyldimethylsilyl ether (17.1 g, 81 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to 0° C. A borane-dimethylsulfide complex (2.5 g, 33 mmol) was added thereto, and the mixture was stirred for one hour. Ethanol (38 ml), 3N sodium hydroxide (38 ml) and 30% hydrogen peroxide (18.2 ml) were added thereto, and the mixture was stirred for 30 minutes. The saturated sodium chloride aqueous solution was added thereto, and the product was extracted with ethyl acetate, then dried over anhydrous magnesium sulfate and concentrated. Then, it was purified by silica gel column chromatography to obtain 2-(2-hydroxyethyl)cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, yield: 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16]2[N:17]=[C:18](Cl)[N:19]=[CH:20][C:15]=2[C:14](=[O:22])[C:13]([C:23](=[O:25])[NH2:24])=[C:12]1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[NH2:26][C:12]1[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:27])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:16]2[N:17]=[C:18]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:39][CH:38]=3)[N:19]=[CH:20][C:15]=2[C:14](=[O:22])[C:13]=1[C:23](=[O:25])[NH2:24]
Reactant: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 120 °C
Yield: 19.6 %

Procedure:
A mixture of 0.60 g (1.51 mmol) of the product prepared in step 11.3 and 0.53 g (3.02 mmol) of 4-morpholin-4-ylphenylamine in 6.5 mL of NMP is placed in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM machine, Discovery model) and the mixture is heated under pressure at 120°C. for 60 minutes at a power of 75 W, and then cooled to room temperature. 15 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained by suction and then dried in an oven. The crude solid is triturated in methanol, drained by suction and dried in an oven under vacuum. 0.159 g of the expected product is obtained in solid form. Yield=20%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(Cl)cc1
Yield: 26.6 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.21 g of sodium hydride (60% in oil), and 1.44 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.47 g of 2-(4-chlorobenzyl)-2-(3,3,4,4,4-pentafluorobutyl)malononitrile (the present compound (23)).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20].O>CS(C)=O>[I:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[N:19]([CH3:20])[CH3:18]
Reactant: CNC
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
1-Fluoro-3-iodo-5-nitrobenzene (500 mg, 1.87 mmol), and potassium carbonate (260 mg, 1.88 mmol) were suspended in DMSO (7 ml) and dimethylamine (2M in THF, 3 ml, 6 mmol) was added. The vial was sealed under argon and stirred for 15 min at 125° C. under microwave conditions. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate (3×40 ml). The organic phase was washed with brine (1×100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to obtain 320 mg (59% yield) of the title compound as a brown solid. Purity 100%.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:38]=[CH:39][S:40][CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[CH:39][S:40][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cscn1
Product: C[C@@H](c1ccc(-c2cscn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=O.CC(=O)[C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](CC(=O)CC2)CC3)CC1.C(Cl)(=O)C([Cl:50])=O>C1C=CC=CC=1>[Cl:50][C:21]([C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][C:12](=[O:20])[CH2:13][CH2:14]1)[CH2:9][CH2:8]3)=[O:23]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)Cl)CC[C@@H]12

Procedure:
A solution of 5α-androstan-3-one 17β-carboxylic acid (2.25 g., corrected for the presence of 15% 5α-pregnan-3,20-dione as an impurity) and oxalyl chloride (4.5 ml.) in dry benzene (150 ml.) was refluxed for 1.5 hours, and then evaporated to dryness to afford crude 17β-chlorocarbonyl-5α-androstan-3-one. This acid chloride in benzene (15 ml.) was shaken with 880 ammonia (24 ml.) and water (15 ml.) for 5 minutes. After a further 30 minutes of standing at room temperature the precipitated amide was filtered, washed with water and dried. Recrysyallisation from dichloromethane/petrol afforded title compound (1.18 g.) m.p. 259°-262°. A further recrystallisation from dichloromethane/petrol provided an analytically pure sample; m.p. 276°-277°; [α]D + 51.5°, (c 0.6%).