Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH2:30][CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCCC)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:9](/[CH2:15]CO)\[C:10]([O:12][CH2:13]C)=[O:11])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[C:9]2\[C:10](=[O:11])[O:12][CH2:13][CH2:15]\2)/[C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(Cl)cc2)cc1

Procedure:
The moist product from Example 64 is heated under reflux in 1.5 1 of toluene in the presence of 1 g of paratoluenesulfonic acid. The water and ethanol are removed with the aid of a Dean Stark apparatus and then about 11 of toluene is evaporated off. After returning to room temperature, the crystals formed are filtered off and washed with a minimal amount of butan-2-one, then dried to give 261.5 g of (Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonylphenyl) methylidene)dihydro-furan-2-one in the form of crystals melting at 188°-190° C.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)=CN=1)=O.Cl[C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)[CH:26]=[CH:27][C:28]=1Cl.FC(F)(F)C1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:49][C:32]1[C:33]([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:40][CH2:39]2)=[O:37])=[N:34][CH:35]=[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:23][C:24]=2[C:18]([F:21])([F:20])[F:19])[CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2C(F)(F)F)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 2-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as off-white amorphous solid. MS: 418.2 (MH+).
Reaction SMILES: [ClH:1].C(N1CCCC(O)(C2C=CC=CC=2)C1)(C)C.Cl.[C:19]([N:23]1[CH2:28][CH2:27][CH2:26][C:25](O)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24]1)([CH3:22])([CH3:21])[CH3:20]>>[ClH:1].[C:19]([N:23]1[CH2:28][CH2:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)N1CCCC(O)(c2ccccc2)C1
Agent: CC(C)N1CCCC(O)(c2ccccc2)C1
Agent: Cl
Product: CC(C)(C)N1CCC=C(c2ccccc2)C1

Procedure:
By following the procedure indicated in step (d) of Preparation II and replacing the N-isopropyl-3-hydroxy-3-phenylpiperidine hydrochloride with the N-tert.-butyl-3-hydroxy-3-phenylpiperidine hydrochloride, the N-tert.-butyl-3-phenyl-1,2,5,6-tetrahydropyridine hydrochloride was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)C5CC5)CC4)[nH]c3cc2Cl)CC1
Yield: 46 %

Procedure:
To a mixture of [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36, 150 mg, 1.0 eq.) and cesium carbonate (243 mg, 2.0 eq.) in acetonitrile (8 mL) was added cyclopropane carbonylchloride. The reaction mixture was refluxed 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between tert-butylmethylether and water. The aqueous layer was extracted with tert-butylmethylether and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel with a 98:2 to 95:5:0.25 gradient of dichloromethane/methanol/ammonia as eluant, to afford 59 mg (46%) of the title compound as a light-yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20]C)=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[NH4+].[Cl-].[C:29]1(C)C=CC=CC=1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:20])=[CH:16][CH:17]=2)[C:12]1=[O:22])([O:3][CH3:29])=[O:2]
Reactant: Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(Cc1ccccc1C(=O)O)C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1ccccc1CC1Cc2ccc(O)cc2C1=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of the product of Step 2 (25 g, 84.5 mmol) in toluene (1.2 L) at 60° C. was added AlCl3 (45 g, 338 mmol) in portions. The mixture was stirred at 60° C. for 14 hrs. NH4Cl solution was added and the mixture was extracted with EtOAc. The crude concentrated extract was treated with excess CH2N2 in Et2O. Chromatography of the resulting product on silica gel (eluted with 30% EtOAc/hexane) gave 17.5 g (70%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=O)[CH:9]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[BH4-].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCNCC1c1ccc(Cl)cc1
Yield: 69.5 %

Procedure:
Solution of 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)-piperazin-2-one (500 mg, 1.6 mmol) and acetic acid (929 μl, 16 mmol) were added to a refluxed solution of sodium borohydride (608 mg, 16 mmol) in 1,4-dioxane (5 ml) and reflux was continued. The reaction was quenched by water and extracted with dichloromethane and washed with brine and dried. After removal of the solvent, residue was purified by silica gel column chromatography to give 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (330 mg, 69%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]I)(=[O:8])=[O:7])[CH3:3].[C-:16]#[N:17].[K+].CS(C)=O>O.C1OCCOCCOCCOCCOCCOC1>[C:16]([CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][S:6]([N:5]=[CH:4][N:2]([CH3:3])[CH3:1])(=[O:8])=[O:7])#[N:17]
Reactant: [C-]#N
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)CCC(C)(C)CC#N
Temperature: 100 °C
Reaction time: 14 h
Yield: 84.7 %

Procedure:
A mixture of 1.85 g of 4-(N,N-dimethylaminomethylene)aminosulfonyl-1-iodo-2,2-dimethylbutane, 0.49 g of potassium cyanide, 0.06 g of 18-crown-6 and 30 ml of dimethyl sulfoxide was stirred at 100° C. for 14 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to silica gel (70 g) column chromatography and elution was carried out with ethyl acetate-hexane (9:1). The fractions containing the objective compound were pooled and concentrated and the residue was recrystallized from ethyl ether to provide 1.11 g of the title compound. m.p. 53°-54° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(F)c1
Product: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(F)c2)C1
Yield: 119.5 %

Procedure:
The title compound (D132) (108 mg) was prepared according to the experimental procedure described in Description 115 starting from methyl 5-fluoro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D71) (90 mg, 0.295 mmol) and 3-Fluorophenol (0.029 ml, 0.295 mmol).
Reaction SMILES: N1C=CC=CC=1N.[CH3:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.Cl[C:16]1[CH:21]=[C:20]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:19]=[CH:18][N:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([S:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:14][C:11]3[S:12][CH:13]=[C:9]([CH3:8])[N:10]=3)[CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(Sc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Nc1ccccn1
Product: COc1cccc(Sc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 61.6 %

Procedure:
Preparation of 4-(3-methoxyphenylthio)-N-4-methylthiazol-2-yl)pyridin-2-amine: Using the method of Example 3, Step B, 4-methylthiazol-2-amine (10.8 mL, 4.32 mmol), 2-chloro-4-(3-methoxyphenylthio)pyridine (0.989 g, 3.93 mmol), potassium phosphate (0.917 g, 4.32 mmol), Pd2(dba)3 (0.0899 g, 0.0982 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0625 g, 0.108 mmol) were reacted to provide 4-(3-methoxyphenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.798 g, 61.7% yield). 1H NMR (d6-DMSO) δ 11.08 (s, 1H), 8.09 (d, 1H), 7.45 (t, 1H), 7.14 (m, 2H), 7.11 (m, 1H), 6.77 (s, 1H), 6.61 (dd, 1H), 6.52 (s, 1H), 3.80 (s, 3H), 2.20 (s, 3H); Mass spectrum (apci) m/z=330.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:19]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:12]([N:11]=[N:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A solution consisting of 9.0 g. ethyl pyruvate (2,4,6-trichlorophenyl)hydrazone (mixed isomers) and 100 ml. carbon tetrachloride was chilled to minus 10° (-10° ) C. and 5 ml. chlorine gas was added. After allowing the reaction mixture to warm up to about 25° C., the carbon tetrachloride was removed by evaporation under reduced pressure. The oily residue that remained was dissolved in a mixture of benzene and technical hexane (1 part of benzene to 4 parts of the latter). This solution was poured onto a 50 cm. × 5 cm. column of silica gel and the chromatogram was developed with the solvent mixture. The first portion of eluate was discarded and the fractions containing the orange-red azo compound were saved. After removal of the solvents by evaporation at 100° C. and 10 mm. mercury pressure 6.9 g. ethyl 2-chloro-2-[(2,4,6-trichlorophenyl)azo]propionate was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(C(O)c2nc(C)c(C)s2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)c2nc(C)c(C)s2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)methanol (945 mg) was dissolved in chloroform (20 ml) to prepare a solution. Manganese dioxide (3.5 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure to give (4,5-dimethylfuran-2-yl)(4,5-dimethylthiazol-2-yl)-methanone (910 mg, yield 97%).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)[N:29]=1>C(Cl)Cl>[ClH:14].[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[C@@H:4]([NH:3][S:36]([C:33]2[CH:34]=[CH:35][C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][CH:27]=3)=[CH:31][CH:32]=2)(=[O:37])=[O:38])[CH2:5][NH:6][C:7]([C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[O:8])[CH2:22][CH2:21]1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Reactant: CN1CCN(C(=O)[C@@H](N)CNC(=O)c2ccc(Cl)s2)CC1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(S(=O)(=O)N[C@@H](CNC(=O)c3ccc(Cl)s3)C(=O)N3CCN(C)CC3)cc2)cs1
Reaction time: 16 h

Procedure:
Intermediate 90 (0.2 g, 0.5 mmol) was dissolved in 10 ml DCM and TEA (0.35 ml, 2.5 mmol). Commercially available 4-(2-Methyl-thiazol-4-yl)-benzenesulfonyl chloride (130 mg, 0.47 mmol) in 5 ml DCM was slowly added at 0° C. and the reaction was stirred for 16 h. Then the solution was evaporated to dryness and purified by silica gel chromatography. The compound was dissolved in DCM, HCl (2 M in diethyl ether (500 ml)) was added and the solvents were evaporated to dryness.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:39])[C@:7]1([O:34][Si](C)(C)C)[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])(=[O:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][CH2:5][C:6](=[O:39])[C@:7]1([OH:34])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O[Si](C)(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A solution of (11β,16β)-9-fluoro-16-methyl-3,20-dioxo-11,17-bis[(trimethylsilyl)oxy]pregna-1,4-dien-21-yl acetate (26 g, ˜43 mmol) in 430 mL of tetrahydrofuran (THF) was cooled to 0° C. and neat acetic acid (4.95 mL, 86.5 mmol) was added followed by dropwise addition of a 1.0 M solution of tetra-n-butylammonium fluoride in THF (43.3 mL, 43.3 mmol). After stirring at 0° C. for 4 hours, the ice bath was removed and the reaction was allowed to warm to room temperature and stir for an additional 16 hours. Most of the THF was removed by rotary evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, sat. NH4Cl, water, sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give an off-white solid. Purification by flash chromatography through a 1.6 kg column of silica gel eluting with 4% MeOH in dichloromethane provided 16.1 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The above obtained crude 2,4-dibenzyloxybenzyl chloride [VII] was dissolved in dimethyl sulfoxide (150 ml) and then thereto was added sodium cyanide (4 g), followed by stirring for 2 hours at room temperature (20° C.). The reaction mixture was added to water (1 liter) and extracted with dichloromethane (1 liter). The dichloromethane extract was concentrated under reduced pressure and the residue was purified by a silica gel column [inner diameter: 10 cm, length 50 cm; developer: dichloromethane-hexane 1:1 (v/v) mixed solution] and furthermore, was recrystallized from diethyl ether-hexane 2:1 (v/v) mixed solution to obtain 2,4-dibenzyloxyphenylacetonitrile [VIII] (14.3 g, yield from [VI]: 70%). Melting point: 99°-100° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]#[N:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.N.[Ni]>[NH2:18][CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:7]([CH3:8])[C:6](=[O:19])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(Cc1cccc(CC#N)c1)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CN(Cc1cccc(CCN)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
tert-Butyl-N-[3-(cyanomethyl)benzyl]-N-methylcarbamate (preparation 14) (3 g, 11.5 mmol, slightly impure) was dissolved in ethanol saturated with NH3 (300 ml), treated with Raney® Nickel (500 mg) and stirred under a hydrogen atmosphere (60 psi, room temperature, 18 hr). The catalyst was removed by filtration under nitrogen, the solvent evaporated to dryness and the resultant crude product purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to give the desired product (2.40 g, 78%). 1H NMR (CDCl3) δ 1.20 (s, 2H), 1.50 (s, 9H), 2.70-2.90 (m, 5H), 3.00 (s, 2H), 4.20 (s, br, 2H), 7.05 (s, br, 3H), 7.25 (s, br, 1H). LRMS m/z=265.1 (M+1)+.
Reaction SMILES: [Na+].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O-:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2.P([O-])([O-])([O-])=[O:25].C1C=[N+]([C@H]2O[C@@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)([O-])=O)[C@H](O)[C@@H]2O)C=C(C(N)=O)C=1.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O>>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH:6]([OH:25])[CH2:7][CH2:8]2
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)[O-])oc13)CCCC2
Agent: NC(=O)c1ccc[n+]([C@H]2O[C@@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@H](O)[C@@H]2O)c1
Agent: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CC(O)CC2
Reaction time: 0.5 h

Procedure:
A mixture of 5 parts 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid sodium salt, 4 parts of 25% w/v supernatant liver fraction, 10 parts of phosphate buffer pH 7.4, one part of nicotinamide adenine dinucleotide phosphate and one part of glucose-6-phosphate was incubated in a shaking incubator at 37° C. for 30 minutes. The reaction was stopped and protein was precipitated by the addition of 5 parts of 2 N hydrochloric acid. The reaction mixture was extracted three times with 100 parts of diethyl ether and after being dried over anhydrous sodium sulphate the extracts were evaporated to dryness at room temperature in a current of air. The 5,7-dihydroxy-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid and the other dihydroxy compounds identified in Example 1 were isolated by the preparative layer chromatography technique described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50](=[NH:52])[NH2:51])[CH:46]=2)[CH:41]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50](=[NH:51])[NH2:52])[CH:46]=2)[CH:41]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CCCCCNC(=O)OCc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of 4.7 g of ε-benzyloxycarbonylaminocaproic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and stirred overnight at room temperature. The precipitate was separated by filtration and washed with a small volume of pyridine. The filtrate and the washings were added to stirred ethyl ether. The precipitated crystals were collected by filtration, recrystallized from an ethanol-ether mixture, and washed with acetone to obtain 6.2 g of white crystals of 6-amidino-2-naphthyl ε-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)(=[O:17])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (180 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL). DDQ (100 mg, 0.44 mmol) was added and stirred at room temperature for 4 h. The reaction was concentrated and purified by silica gel flash column chromatography (45% ethyl acetate in hexanes) to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (70%) as a white solid. 1H NMR (400 MHz, DMSO-D6) 11.72 (s, 1H), 8.07 (s, 1H) 7.65 (d, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 3H), 7.04 (d, 2H), 6.71 (m, 1H), 3.40-3.36 (m, 4H), 3.02-2.99 (m, 4H).