Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]>C(O)CCC>[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:6]2[C:5]([CH2:9][NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCc1ccc(NCc2cnc(Cl)nc2N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,4-Dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine (200 mg, 0.71 mmol) (from Example 38c supra) was dissolved in hot n-butanol (2 mL) (Aldrich). After cooling to room temperature, triethylamine (0.20 mL, 0.92 mmol) (Allied Signal) and (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (198 mg, 0.91 mmol) (from Example 9c supra) were successively added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (20% ethyl acetate in hexanes) to give (±)-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-{2-chloro-5-[(4-ethyl-phenylamino)-methyl]-pyrimidin-4-yl}-amine as a viscous oil. (Yield 272 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][C:16]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: CCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 20.4 %

Procedure:
First, 3-cyanophenylacetic acid (3 g, 0.019 mol) is heated under reflux in thionyl chloride (50 ml) for 90 minutes. The excess thionyl chloride is then removed by distillation and the residual acid chloride added in one portion to a solution. 1-phenylpentane (2.76 g, 0,019 moles) in methylene chloride (10 ml). Anhydrous aluminum chloride (2.98 g) is added in small portions over 10 minutes. The reaction mixture is then heated under reflux for 1 hour, cooled and poured into a mixture of ice water (250 ml) and concentrated hydrochloric acid (50 ml). The mixture is extracted with ether (2×100 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica (hexane: ethyl acetate at 90:10 ) to yield 3-(4-pentylphenacyl) benzonitrile (1.13 g, m.p. 73° C.). This nitrile is heated under reflux in a mixture of 75% sulfuric acid (8 g) and acetic acid (8 g) for 90 minutes. The reaction mixture is then diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane to provide 3-(4-pentylphenacyl)benzoic acid (0.97 g), m.p. 109°-111° C., which was identified by IR and NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[NH:11][C:12](N)=O)/[CH3:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:22]=[O:23])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=N\NC(N)=O)c1ccc(F)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of (E)-2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxamide (1 g, 5.12 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) at 5° C. was added phosphorous oxychloride (5 mL) dropwise. The resulting solution was stirred at 70° C. for 2 h. The reaction mixture was cooled to 0° C. and quenched by the addition of 15 mL of ice/water mixture. The pH value of the solution was adjusted to 7 with 4N sodium hydroxide solution. The resulting mixture was stirred at 70° C. for an additional 1 h. The reaction mixture was cooled back to room temperature. The precipitate was collected by filtration and dried in a vacuum oven to give 600 mg (62%) of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde as a gray solid. LCMS (method A, ESI): RT=1.23 min, m/z=191.0 [M+H]+.
Reaction SMILES: C(O[C:5]1[CH:19]=[CH:18][C:8]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])[CH:6]=1)(=O)C.Cl.[OH-:30].[Na+]>>[OH:30][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:8]2[CH:18]=[CH:19][CH:5]=[CH:6][C:7]=2[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])=[O:17])=[CH:12][CH:13]=1
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccccc2)c(CCC2CCCCN2C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(O)cc1

Procedure:
4'-Acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide suspended in 1N sodium hydroxide is stirred until solution takes place. The pH of the aqueous solution is adjusted to 9 with 6N hydrochloric acid and an oil precipitates which is extracted with ethyl acetate. The product isolated by removal of the ethyl acetate solvent is crystallized from ethanol to provide analytically pure 4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 178.5°-182.5° C. (corr.).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CSc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C=CC#N)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (5.3 ml) in tetrahydrofuran (10 ml) was added dropwise to an ice-cooled mixture of sodium hydride (60%, 1.3 g) in tetrahydrofuran (40 ml). The mixture was stirred at 5° C. for 15 minutes. To the resulting mixture was added a solution of 4-(methylthio)benzaldehyde (5 g) in tetrahydrofuran (10 ml) at 5 to 10° C. The mixture was stirred at ambient temperature for 5 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was washed with a small amount of ether and dried to give pale brown crystals of 3-[4-(methylthio)phenyl]acrylonitrile (4.7 g).
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([C@H:33]([NH:35][S@@](C(C)(C)C)=O)[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>CO>[F:8][C:9]1[CH:10]=[C:11]([C@H:33]([NH2:35])[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen chloride 4.0 M in 1,4-dioxane (0.04 mL, 0.2 mmol) was added to a solution of (R)-N-((R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethyl)-2-methylpropane-2-sulfinamide (0.0301 g, 0.06 mmol) in MeOH (5 mL). The yellow reaction mixture was allowed to stir at ambient temperature for 18 h. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine. MS (ESI) m/z: calculated: 389.1; Observed: 390.1 (M++1).
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C2CCCN2)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate C-15 was treated with TFA:CH2Cl2 (3:7) at 0° C. The solution was warmed to room temperature and the progress of the reaction was monitored by MS analysis. After 1 h the reaction was complete and the solvent was removed under reduced pressure using a rotatory evaporator. The product C-16 was precipitated with Et2O and collected by filtration.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]=1[C:13]#[N:14]>CN(C=O)C.O>[O:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]=1[C:13]#[N:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(F)cccc1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Oc2ccccc2)cccc1N1CCCCC1
Reaction time: 1 h

Procedure:
To a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF was added NaH (60%, 6.0 mmol) at 0° C. The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-1-yl)benzonitrile (CAS#646989-68-6) (612 mg, 3.0 mmol) was added and the reaction stirred for 48 h at RT. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 2-phenoxy-6-(piperidin-1-yl)benzonitrile as an off-white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>ClCCl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:13]([NH:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])=[O:15])[C@@H:10]([CH3:12])[OH:11]
Reactant: CCOC(=O)CN
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Yield: 85.4 %

Procedure:
Boc-threonine (produced by Wako Pure Chemical Industries Ltd.) (11.0 g, 50 mmol) and glycine ethyl ester hydrochloride (produced by Wako Pure Chemical Industries Ltd.) (8.4 g, 60 mmol) were dissolved in dichloromethane (250 mL). After triethylamine (8.4 mL, 60 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 12.4 g, 60 mmol) and hydroxybenzotriazole (9.2 g, 60 mmol) were further added thereto, the mixture was reacted at room temperature for overnight with stirring. After completion of the reaction, reaction mixture was filtered, and then the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the product was crystallized from hexane, to obtain Boc-Thr-Gly-OEt (1) (13.0 g) (yield; 85.1%).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.C([CH2:14][NH2:15])O.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:14][NH2:15]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: NCCO
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition was prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol was employed in place of the Bisphenol-A, 20.1 g of ethanolamine was employed in place of the 2-(methylamino)ethanol, and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product was dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution was adjusted to 3.0 with phosphoric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[NH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:23]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: NNCc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Cl)cc1-c1nc(-c2cc(Cl)ccc2O)n(Cc2ccccn2)n1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 5 h with 1.7 g of 2-hydrazinomethylpyridine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridin-2-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 227-229 C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([CH3:22])=[CH:7][CH2:8][C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[C:11](=[O:20])[C:10]=1[CH3:21])([OH:3])=[O:2].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:9]([CH2:8][CH:7]=[C:6]([CH3:22])[CH2:5][CH2:4][C:1]([O:3][CH3:23])=[O:2])=[C:10]([CH3:21])[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC1=C(OC)C(=O)C(CC=C(C)CCC(=O)O)=C(C)C1=O
Solvent: CO
Product: COC(=O)CCC(C)=CCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Reaction time: 4 h
Yield: 448.7 %

Procedure:
To a solution of 6-(5-carboxy-3-methyl-2-pentenyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (93 mg) in methanol (3 ml) was added p-toluene sulfonic acid (10 mg). The mixture was stirred for 4 hours. The solvent was evaporated off under reduced pressure. The residue was dissolved in diethylether. The solution was washed with water and then dried. The solvent was evaporated off under reduced pressure. The residue was subjected to a column chromatography using silica-gel (3 g). From the fractions eluted with carbon tetrachloride-ethyl acetate (5:1) was obtained 2,3-dimethoxy-6-(5-methoxycarbonyl-3-methyl-2-pentenyl)-5-methyl-1,4-benzoquinone (84 mg). This product was treated in a conventional manner to produce 2,3-dimethoxy-6-(5-methoxycarbonyl-3-methyl-2-pentenyl)-5-methylhydroquinone, which was dissolved in pyridine (0.4 ml). The solution was cooled to about -10° C., to which was added chlorosulfonic acid (120 μl). The mixture was stirred for two days at room temperature. The reaction solution was made to pH 8- 9 with 1N potassium carbonate, then unreacted substances were removed by extraction with diethylether. The aqueous phase was subjected to evaporation to dryness under reduced pressure. The residue was subjected to column-chromatography using silica-gel (3 g). From the fractions eluted with methanol-chloroform (2:5) was obtained a mixture (24 mg) of potassium salts of 2,3-dimethoxy-6-(5-methoxycarbonyl)-3-methyl-2-pentenyl)-5-methylhydroquinone 1-sulfate and 4-sulfate.
Reaction SMILES: [N:1]([C@@H:4]1[C:21]2[C@:16]([CH3:24])([CH:17]3[CH2:23][C@@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)=[N+]=[N-].C(S)CCS.C(N(CC)CC)C>CO>[NH2:1][C@@H:4]1[C:21]2[C@:16]([CH3:24])([CH:17]3[CH2:23][C@@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](N=[N+]=[N-])C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](C[C@H](N)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
A mixture of 6α-azido-1,2β-methylenandrost-4-ene-3,17-dione (1695 mg, 5 mmol), 1,3-propanedithiol (0.25 ml, 2.5 mmol), triethylamine (0.35 ml, 2.5 mmol) and methanol (2.5 ml) is stirred for 6 hours at room temperature. Then the reaction mixture is evaporated in vacuo to dryness. The residue is taken up in ether, the etheral solution washed with water, dried and evaporated in vacuo. Column chromatography of the residue over silica gel affords the pure 6α-amino-1,2β-methylenandrost-4-ene-3,17-dione (1000 mg, 64%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[C:17]([O:24][CH2:25][CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:25]([O:24][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH:15]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:23]=[CH:22]2)[CH3:26]
Reactant: [H][H]
Reactant: CCOc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOc1cccc2ccc(N3CCNCC3)cc12

Procedure:
A solution of 24.9 g (0.072 mol) of 1-benzyl-4-(8-ethoxy-naphthalen-2-yl)-piperazine in 360 ml of ethanol is combined with 5 g of palladium on charcoal (10%) and stirred at a hydrogen pressure of 5 bar at ambient temperature. The catalyst is separated off, the filtrate is concentrated by evaporation and the residue is washed with diethylether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[C:18]2\[CH2:19][N:20]([CH:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[CH2:21][CH2:22][CH:23]\2O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:38]([S:40][CH:23]1[CH2:22][CH2:21][N:20]([CH:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:19]/[C:18]/1=[CH:17]\[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1)(=[O:41])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2O)c2ccccc21
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)indol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidin-4-ol (1.58 g) in toluene (32 ml) were added thioacetic acid (0.45 ml) and N,N-dimethylformamide dineopentyl acetal (1.75 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, to the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)indol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (0.66 g, yield: 38%) as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (296 mg, 1.25 mmol) in CH2Cl2 at 0° C. was added pyridine-3-sulfonyl chloride hydrochloride (279 mg, 1.31 mmol) followed by Et3N (0.36 mL, 2.6 mmol). The reaction was stirred at room temperature for 24 h and was quenched with a 1:1 solution of water and saturated aqueous NaHCO3. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (1:1 hexanes:EtOAc) provided the title compound as a white solid (369.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.75 (m, 1H), 8.09 (d, 1H), 7.44 (m, 1H), 7.15 (m, 1H), 6.76 (m, 3H), 5.23 (bs, 1H), 4.44 (s, 2H), 4.16 (d, 2H), 1.47 (s, 9H); MS 379 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:35]=C=O)=O.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:35])[C:13]3[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
A modification of the general method described in Part C of Example 3 was followed using 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline (2.6 g, 6.4 mmol) as the starting material and chloroform as the solvent. The reaction with trichloroacetyl isocyanate was not complete after one hour as evidenced by a TLC analysis. Additional trichloroacetyl isocyanate was added, and the reaction was stirred overnight. Following the reaction with sodium methoxide, the solid product was isolated by filtration and washed with methanol and a mixture of dichloromethane and water. The solid was isolated by filtration and recrystallized from 2-methoxyethyl ether. The crystals were dried under high vacuum to provide 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 183-184° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.N1C=CN=C1.N1C=CC=CC=1>C(OCC)C>[CH3:25][C:2]1([CH3:1])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([O:22][Si:27]([CH3:30])([CH3:29])[CH3:26])[CH2:20][CH3:21]
Reactant: CCC(O)(CC)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(CC)(CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C)O[Si](C)(C)C
Yield: 80.6 %

Procedure:
183 mg (0.52 mmol) of 51 is reacted with 171 mg (1.56 mmol) of trimethylchlorosilane, 140 mg (2.03 mmol) of imidazole and 0.21 ml of pyridine in 15 ml of diethyl ether analogously to 33., and 178 mg of the title compound is obtained as colorless oil.