Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[S:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18][CH3:19]>>[I-:18].[CH2:1]([N+:8]1[CH:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11][C:12]=1[S:13][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)C1CCC(=S)N1Cc1ccccc1
Product: COC(=O)C1CCC(SC)=[N+]1Cc1ccccc1
Product: [I-]

Procedure:
Methyl 1-benzyl-5-thioxo-2-pyrrolidinecarboxylate (16.5 g, 66.2 mmol) in iodomethane (70 mL) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. 1H NMR (CDCl3) δ 2.24 (m, 1H), 3.04 (s, 3H), 3.16 (m, 1H), 3.25 (m, 1H), 3.63 (s, 3H), 4.29 (dd, 1H), 4.72 (d, 1H), 4.89 (dd, 1H), 5.14 (d, 1H), 7.43 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][NH2:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:22]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.S([O-])([O-])(=O)=O.[Mg+2].[CH:34](=[N:36]O)[CH3:35].ClN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][N:17]3[C:22]4([CH2:26][CH2:25][CH2:24][CH2:23]4)[O:27][N:36]=[C:34]3[CH3:35])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1CCCC1
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN1C(C)=NOC12CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A mixture of 2-(4-chloro-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethylamine (1.00 g, 3.28 mmol), cyclopentanone (0.32 mL, 3.6 mmol), and magnesium sulfate in dichloromethane was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) along with N-hydroxyethanimidoyl chloride, which was prepared from acetaldehyde oxime (242 mg, 4.10 mmol) and N-chlorosuccinimide (537 mg, 4.10 mmol) according to the method described in Part G of Example 10. The resulting solution was cooled in an ice bath and triethylamine (0.69 mL, 4.9 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred overnight. The work-up and purification procedures described in Part G of Example 10 were followed to provide 770 mg of 4-chloro-2-(ethoxymethyl)-1-[2-(3-methyl-1-oxa-2,4-diazaspiro[4,4]non-2-en-4-yl)ethyl]-1H-imidazo[4,5-c]quinoline as a clear, colorless oil.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:17]CC)(=O)[CH:14]=[O:15]>C1COCC1>[CH2:3]([C:14]([OH:15])([CH:13]([OH:17])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC/C=C\CCCBr
Reactant: CCOC(=O)C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(O)C(O)(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (263 mg, 10.9 mmol) and a stirbar. The flask was dried with a heat gun for 5 minutes, cooled under nitrogen before THF (5 mL) and a small grain of iodine was added. A solution of (Z)-1-bromodec-4-ene 3 (2 g, 9.1 mmol) in THF (5 mL) was added slowly. The solution was stirred at room temperature for 2 hours then ethyl glyoxylate (0.375 mL, 1.82 mmol, 50% solution in toluene) was added. Upon completion, the solution was quenched with saturated ammonium chloride solution (5 mL) and stirred until the excess magnesium had dissolved. The solution was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% Hexanes to 20% EtOAc in hexanes) to afford (6Z,16Z)-11-((Z)-dec-4-enyl)docosa-6,16-diene-11,12-diol 29 as a colorless oil (700 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:22][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CC(C)=O>[C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20][CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)-c1cc(C(=O)OC(C)(C)C)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CSc1ncc2ccc3sc(C(=O)OC(C)(C)C)cc3c2n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2-Methylsulfanyl-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (9.0 g, 26.91 mmol) and DDQ (12.22 g, 53.82 mmol) were suspended/dissolved in dry dioxane (100 mL) and heated at reflux for 1 hour. Further DDQ (12.22 g, 53.82 mmol) was added and the resulting suspension was heated at reflux for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure and then partitioned between EtOAc and saturated Na2CO3. The aqueous layer was further extracted with EtOAc (3×200 mL) and the combined organics were washed with saturated Na2CO3 (2×250 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The deep brown gum obtained was redissolved in hot acetone, silica (˜60 mL) was added and the resultant suspension was concentrated under reduced pressure. The solid obtained was subjected to column chromatography (gradient elution, 20-30% acetone in hexanes, ˜600 mL silica) giving a light brown solid (6.50 g, 73% yield). ). MS (ES+) 333. δH (CDCl3) 1.7 (9H, s), 2.8 (3H, s), 7.8 (1H, d), 7.9 (1H, d), 8.8 (1H, s), 9.2 (1H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH:6]=[N:7][NH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][O:11][N:10]=1>C1(C)C(C)=CC=CC=1>[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:9]1[NH:8][N:7]=[C:6]([C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:10]=1
Reactant: COc1cccc(C=NNC2=NOCc3ccccc32)c1
Solvent: Cc1ccccc1C
Product: COc1cccc(-c2n[nH]c(-c3ccccc3CO)n2)c1
Temperature: 0 °C

Procedure:
A suspension of 16 g of 4-[2-(3-methoxybenzyliden)hydrazino]-1H-2,3-benzoxazine in 160 ml of anhydrous xylene is refluxed for 45 minutes and then cooled to about 0° C. The solid which precipitates is recovered by filtration and recrystallized from ethanol yielding 14.7 g of the compound of the title. M.p. 157°-59° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>C1(C)C=CC=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]2([C:14]3[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][CH:13]=3)[CH2:3][CH2:2][CH:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: CCCC1CCC(=O)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 91.5 %

Procedure:
1st stage 4-n-Propylcyclohexanone 650 g and phenol 1550 g were mixed, and hydrochloric acid gas was blown to the mixture with vigorously stirring at room temperature. The mixture was vigorously stirred for three hours and then left for 50 hours at room temperature. Meantime, the reaction solution was solidified. Warm water 1,000 ml and toluene 3,000 ml were added to the solid. The solid was heated and dissolved completely. The crystals deposited from the solution after cooling were filtered and washed with water and with toluene. After drying the crystals, white crystals 658 g of 1,1-bis(4-hydroxyphenyl)-4-n-propylcyclohexane was obtained by recrystallization from acetone.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].[N+:32](C1C=C(Cl)C=CC=1O)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([N+:32]([O-:34])=[O:33])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (1.0 g, 3.35 mmol) in butanone (35 ml) was added 2-nitro-4-chlorophenol (0.639 g, 3.69 mmol), potassium carbonate (0.925 g, 6.7 mmol) and potassium iodide (0.556 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g, 93% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O>Cl.O.[Zn]>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][CH2:12]2
Reactant: COc1cc(Br)cc2c1OCCC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc2c1OCCC2
Yield: 47 %

Procedure:
According to the process of preparation I, from the amalgam of zinc prepared form 915 g (14 gram-atoms) of zinc, 91 g (3.8×10-1M) of mercurous chloride in 46 cm3 of concentrated hydrochloric acid and 1350 cm3 of water, after addition of 700 cm3 of water, 1100 cm3 of concentrated hydrochloric acid, 2500 cm3 of toluene and 450 g (1.8M) of 6-bromo-8-methoxy-4-chromanon (III1), 200 g (yield=47%) of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4OC(F)(F)F)noc3N)CC2)c1
Yield: 69.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (592 mg, 1.28 mmol, 70%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cn1c(C=O)cc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaBH3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOWCH2Cl2) gave the title compound (1.3 g. 65%) as a semi-solid: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[NH:9][C:10](=[NH:26])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O>[C:5]([O:4][NH:26][C:10](=[NH:9])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:7])[CH3:6]
Reactant: N=C(CC1(n2ccc3cccnc32)CCCC1)NO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)ONC(=N)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Acetic anhydride (11.2 mL, 118.61 mmol) was added to N-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine (400) (1.8 g, 6.98 mmol) and stirring was continued for 3 h at room temperature (TLC, ethyl acetate, Rf=0.5). Water (50 mL) was added, and the mixture was basified to pH 8 by solid NaHCO3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 2-(1-{1H-pyrrolo[2,3-b]pyridin-1-yl}cyclopentyl)ethanimidamido acetate (401) (1.7 g, 81%) as an off-white solid.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].O.Cl>C1COCC1.CO>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.03 g (25.8 mmol) of sodium hydroxide were added to a solution of 715 mg (2.6 mmol) of (+/−)-ethyl (4-nitrophenyl)(cyclopentyl)acetate in 6 ml of THF/methanol (1:1), and the mixture was stirred at RT overnight. The reaction mixture was then poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated. The residue was taken up in 80 ml of diethyl ether, and 250 ml of petroleum ether were added. The precipitated solid was filtered off with suction and washed with petroleum ether. The product obtained in this manner was purified further by preparative HPLC. This gave 89.5 mg (14% of theory) of the title compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:5][CH:4]1[O:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:1][CH2:2][CH2:3]1
Reactant: CC(O)CCS
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC1CCSC(c2ccccc2)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 5.8 grams (0.055 moles) of benzaldehyde is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 10.1 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[OH:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Reactant: C[Si](C)(C)Cl
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
Trimethylsilylchloride (3.27 mL, 25.8 mmol) was added to a solution of (3β,5α,25R)3-hydroxy-spirostan-11-one (4.0 g, 9.3 mmol) and triethylamine (6.5 mL, 46 mmol) in dichloromethane (60 mL) at room temperature. One gram of dimethyl aminopyridine was added and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with methanol (1 mL) and diluted with ethyl acetate, washed with water (5×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The product was triturated with methanol, filtered and dried to afford 3.94 g (85%) product as a white solid. 1H NMR (250 MHz, CDCl3) 6 4.5 (q, 1H, J=6Hz); 3.45 (m, 2H); 2.35 (t, 1H, J=10 Hz); 2.4 (dt, 1H, J=12.2 Hz); 2.2 (s, 2H); 2.1-1.1 (m, 12H); 1.02 (s, 3H); 0.9 (d, 3H, J=7.0 Hz); 0.78 (d, 3H, J=7 Hz); 0.69 (s, 3H); 0.1 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[O:16][C:15]([CH3:21])([CH3:20])[CH:14]4[O:22][CH:13]4[C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[NH3:26]>C(O)C>[NH2:26][CH:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([CH2:9][C:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:23])[CH:11]=2)[O:16][C:15]([CH3:21])([CH3:20])[CH:14]1[OH:22]
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C2OC21
Reactant: N
Solvent: CCO
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C(N)C1O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The N-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl) acetamide obtained above was immediately poured into a mixture of so much ethanol and 25%-strength aqueous ammonia solution (6:5 v/v) that a 0.2 M solution of the compound was obtained, and the resulting solution was stirred for 16 hours at 50° C. Then the solution was allowed to cool to room temperature, and the solvent was largely evaporated at reduced pressure. The remaining residue was chromatographed on silica gel (mobile phase: gradient dichloromethane/methanol/25%-strength aqueous ammonia solution 97.5:2:0.5 to 90:9.5:0.5 v/v/v). Drying of the product fractions yielded 7.3 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-4-chlorobenzyl acetamide, which was used without further purification for the subsequent reaction. The other regioisomer, 2-[3-amino-4-hydroxy-2,2-dimethylchromen-6-yl]-N-4-chlorobenzyl acetamide, was not observed.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A solution of 2.0 g (1 mmol) of 4-hydroxybenzophenone and 1.25 g (1.5 mmol) of trimethylacetyl chloride in 30 ml of pyridine was heated to 50° C. for 2 h. The reaction mixture was stripped of most of the pyridine and then slurried into water. The crude product obtained by filtration was air-dried and recrystallized from ethanol. The first crop (2.35 g, 79.9%, M.P.≅100°-102° C.) was used for analysis and biological evaluation.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:14]([CH3:25])[N:15]=[C:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:34]([NH2:36])=[O:35].O>CN(C)C=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:16]2[C:5]3[C:4]4[CH:3]=[C:2]([O:1][CH:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[C:34]([NH2:36])=[O:35])[C:11]([O:12][CH3:13])=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:14]([CH3:25])[N:15]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Reactant: NC(=O)C(Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(N)=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
4-(8-Hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (97.7 mg, 296 μmol) is dissolved in N,N-dimethylformamide (3.7 ml). Potassium carbonate (102 mg, 738 μmol) and 2-bromo-2-(4-fluorophenyl)acetamide (170 mg, 733 μmol) are subsequently added. The reaction mixture is stirred at 120° C. for 18 h. When the reaction is complete, the mixture is poured into water (50 ml) and extracted three times with ethyl acetate (50 ml each time). The combined organic phases are dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue is then suspended in a little 2-propanol, filtered off with suction and dried in a high vacuum, giving 2-[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-2-(4-fluorophenyl)acetamide (68 mg, 141 μmol) as a solid having a melting point of 249.2° C. MS: 482.1 (M+H+), TLC (HPTLC): Rf=0.31 (ethyl acetate/ethanol 8:1, parts by volume).