Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: OB(O)c1cccs1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 115.2 %

Procedure:
To a stirred solution of 5-bromo-2-nitroaniline (10.3 g, 47.3 mmol, 1 eq.), thiophen-2-ylboronic acid (9.08 g, 70.9 mmol, 1.5 eq.) and tetrakis(triphenylphosphine)palladium(0) (5.46 g, 4.73 mmol, 0.1 eq.) in THF (150 mL) was added a solution of sodium carbonate (7.27 g, 68.6 mmol, 1.45 eq.) in water (15 mL). The resulting mixture was warmed to 90° C. for 18 h. The reaction was then diluted with EtOAc and water and filtered through Celite. The organic layer was separated and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to afford 2-nitro-5-(thiophen-2-yl)aniline (12.0 g, 79% yield).
Reaction SMILES: [Na+].[Na+].[CH2:3]([S:9]([O-:12])(=[O:11])=[O:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6]>O>[CH2:3]([S:9]([OH:12])(=[O:11])=[O:10])[CH2:4][S:5]([OH:8])(=[O:7])=[O:6]
Reactant: O=S(=O)([O-])CCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCS(=O)(=O)O
Yield: 137.5 %

Procedure:
A solution of 3 g of 1,2-ethanedisulphonic acid disodium salt in 10 ml of water is introduced slowly into 200 ml of Dowex® 50 W×8 resin, and the product is eluted with 200 ml of demineralized water. The eluate is diluted by adding EtOH and concentrated under vacuum. 3.35 g of the expected product are obtained in the form of an oil which crystallizes at RT.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:36][CH2:35][CH2:34][CH2:33][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Cl[C:41](=[O:50])[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:39]=[CH:38][CH:37]=[C:8]([C:9](=[O:10])[NH:11][C:12]3[S:13][C:14]4[CH2:36][CH2:35][CH2:34][CH2:33][C:15]=4[C:16]=3[C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=3)[CH:7]=2)[C:41](=[O:50])[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCC(=O)Cl
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(CNC2CC2)c1
Product: CCOC(=O)CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(Cc4ccncc4)cc2)CCCC3)c1)C1CC1
Yield: 69.2 %

Procedure:
By using 120 mg of 2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 120 mg of ethyl 5-chloro-5-oxopentanoate, the reaction similar to Preparation Example 13 was performed, thereby obtaining 105 mg of ethyl 5-(cyclopropyl {3-[(3-{[4-(pyridin-4-ylmethyl)phenyl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}amino)-5-oxopentanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])=[CH:25][CH:24]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])=[CH:27][CH:28]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc(N)cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Yield: 80 %

Procedure:
Next, 13.60 mmol of 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline, 0.22 of 10% Pd/C, and 150 ml of ethanol were added into a bottle. Next, the mixture was heated to reflux, and 7 ml of hydrazine monohydrate was added slowly to the mixture from a dropping funnel over a period of 1 hrs under dry nitrogen. After a further 12 hrs of reflux, the mixture solution was filtered to remove Pd/C, and the filtrate was cooled to precipitate. The crude product was collected by filtration and recrystallization from ethanol to afford 4-Amino-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline as a white crystal with a yield of 80%. The 4-amino-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline had a melt point of 95° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:32]C=2C=1.C(N(CC)C(C)C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([C:23]([NH2:32])=[O:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)nn1-c1cccc(-c2ccccc2Cl)c1
Reactant: On1nnc2ccccc21
Agent: CCN(CC)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)nn1-c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
To a solution of the carboxylic acid (0.062 g, 0.17 mmol) in DMF (1 ml) were added pyBOP (0.138 g, 0.26 mmol), HOBT (0.035 g, 0.2 mmol), diethylisopropylamine (0.147 ml, 0.87 mmol) and ammonium chloride (0.056 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 16 hours, then cooled and partitioned between ethylacetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by silica-gel chromatography (3:2 hexanes/ethylacetate) yielded the product (0.062 g, 64%) as a solid.
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[CH:6]=1
Reactant: O[C@@H](CCl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cncc([C@@H]2CO2)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a solution of (R)-2-chloro-1-pyridin-3-ylethanol (2.0 g, 12.7 mmol) in acetonitrile (100 ml) is added potassium carbonate (7.02 g). The mixture is refluxed for 2.5 hours, and cooled to room temperature. The mixture is filtered, and the filtrate is distilled off under reduced pressure. The resultant is purified by silica gel column chromatography (methanol/chloroform=1/100) to give the title compound (R)-(pyridin-3-yl)oxirane (1.46 g, yield: 94%) as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6]2([O:18][CH2:17][CH2:16][O:9]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: OCCO
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
4-cyano-4-phenylcyclohexanone (5.97 g, 30 mmole) was taken up in toluene (200 ml) and ethylene glycol (4 ml, 71.6 mmole) was added. After addition of p-toluenesulfonic acid (86 mg, 0.5 mmole) the reaction mixture was heated to the boil in a water separator. The course of the reaction was followed by thin layer chromatography. After 20 hours no starting product could be detected any longer by thin layer chromatography. After cooling, the toluene solution was extracted by shaking with water (5×30 ml) and saturated aqueous NaCl solution (3×20 ml) and dried over Na2SO4. After removing the solvent on a rotary evaporator the desired ketal was obtained in a yield of 6.8 g (94%) as a white solid with a melting point of 108°-110° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:24][C@@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1.O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:24][CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][OH:30])=[N:3][C:4]=2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(Nc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Reactant: CC(C)[C@@H](N)CO
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)C(CO)Nc1nc(Nc2cccc([N+](=O)[O-])c2)c2ncn(C(C)C)c2n1
Yield: 3.1 %

Procedure:
(2-Chloro-9-isopropyl-9H-purin-6-yl)-(3-nitro-phenyl)-amine (333 mg, 1 mmol), D-valinol (310 mg, 3.0 mmol), and DBU (457 mg, 3.0 mmol) were stirred in NMP (5 mL) overnight at 150° C. under N2. After cooling, the mixture was diluted with H2O (40 mL) and was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine, treated with decolourising charcoal and MgSO4, filtered, and evaporated. The residue was redissolved in DMSO/H2O and chromatographed (Vydac 218TP1022; 9 mL/min, 27.5-37.5% MeCN in 0.1% aq CF3COOH over 40 min). Appropriate peak fractions were pooled and lyophilized to afford the title compound as an orange solid (12.3 mg). Anal. RP-HPLC (Vydac 218TP54; 1 mL/min): tR=15.8 min (27.5-37.5% MeCN in 0.1% aq CF3COOH over 20 min); purity>95% (λ=214 nm). DE-MALDI-TOF MS: [M+H]+=398.5 (C19H25N7O3=399.5).
Reaction SMILES: [Cl:1]CCCO[C:6]1[CH:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:7]=1[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:11]=1)=[O:9].Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[I-].[K+].Cl>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:29]2[CH:30]=[CH:6][C:7]([C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:11]=3)=[O:9])=[CH:27][C:28]=2[O:9][CH2:8][CH2:7][CH2:6][N:53]2[CH2:54][CH2:55][N:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][CH3:42])[CH2:51][CH2:52]2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)cc2OCCCCl)c2ccccc21
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Yield: 142.6 %

Procedure:
Ethyl 4-{3-[3-chloropropoxy-4-(4-ethylphenyl)methylaminobenzoyl]indol-1-yl}butanoate (44.5 g) was dissolved in N,N-dimethylformamide (230 ml), and 1-(2-methoxyphenyl)piperazine hydrochloride (36.2 g), potassium iodide (52.5 g), and triethylamine (46 ml) were added to the solution. The resultant mixture was stirred at 90° C. for one hour. The reaction mixture was cooled and poured into ethyl acetate (230 ml) and 1N hydrochloric acid (460 ml) was added. Crystals so precipitated were collected by filtration and recrystallized from 90% ethanol, to thereby obtain 42.6 g of ethyl 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy)benzoyl}indol-1-yl}butanoate hydrochloride as colorless crystals.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=CC=CC=1C(O)=O)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1Oc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C(O)c1ccccc1Oc1ccccc1
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccccc1Oc1ccccc1
Reaction time: 36 h
Yield: 78 %

Procedure:
A mixture of 2-phenoxybenzyl alcohol (4.0 g, 20.2 mmol, prepared by the reduction of commercially available 2-phenoxybenzoic acid with LiAlH4 /THF) and 150 mL CH2Cl2 was treated with pyridinium dichromate (11.39 g, 30.3 mmol) at 25° C. and stirred for another 36 hours. The mixture was filtered through d.e. and then through a pad of silica gel to produce 3.11 g (78%) of title compound as a yellow oil. 1H NMR (CDCl3) δ6.8 (d, 1H), 6.9 (d, 1H), 7.0 (m, 2H), 7.1 (m, 2H), 7.2 (m, 1H), 8.9 (m, 1H), 10.2 (s, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][N:10]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]([CH2:14][OH:15])[CH2:12][OH:13].N1C=CN=C1>CN(C)C=O>[Si:1]([O:13][CH2:12][C@@H:11]([CH2:14][OH:15])[N:10]([CH3:9])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C(CO)CO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN([C@H](CO)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 39.2 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (3.53 g, 23.43 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a solution of N-methyl-N-(4-phenoxybenzenesulfonyl)serinol (8.32 g, 24.66 mmol), which is the product of Example 67(2), and imidazole (4.13 g, 61.65 mmol) in N,N-dimethylformamide (200 ml) at room temperature with stirring. The mixture was further stirred for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure. To the residue, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (4.15 g, yield 38%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NCCC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 20, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 3,3-dimethyl-butyraldehyde.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=1.[CH3:24][CH:25](O)[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH:25]([O:20][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:24]
Reactant: CC(C)O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)OC(C)C)cn1
Reaction time: 15 h
Yield: 76.6 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (258 mg, 1.25 mmol) and 4-dimethylaminopyridine (12 mg, 0.10 mmol) in dichloromethane (4 mL) was added dropwise to a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) and 2-propanol (0.06 g, 1.0 mmol) in dichloromethane (4 mL) at room temperature. After 15 h, the mixture was filtered and the filtrate was concentrated and purified by chromatography (SiO2, heptane:ethyl acetate 100:0 to 8:2) to give the title compound (270 mg, 77%) as a colourless oil. MS: m/e=353.1 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C@:20]([CH3:24])([C@@H:21]([CH3:23])[CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]3)[CH2:9][CH2:8]2)(=O)C.[I:26]N1C(=O)CCC1=O>CO>[I:26][C@@H:22]1[C@H:21]([CH3:23])[C@@:20]2([CH3:24])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])=[CH:6][C:5]1=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CO
Product: C[C@H]1[C@@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
3.42 g (10 mmol) of 3-acetoxy-1α-methyl-androsta-2,4-dien-17-one (DE-A 3715869) is dissolved in 40 ml of absolute methanol. 2.25 g (10 mmol) of N-iodosuccinimide is added under nitrogen atmosphere and it is stirred for 1 hour at room temperature. The reaction mixture is added with stirring in 70 ml of ice water and the product is extracted with ethyl acetate. The organic phase is washed with 50 ml of water and dried on sodium sulfate. After chromatography of the crude product on silica gel with ethyl acetate/hexane as mobile solvent, 2.36 g (55.4% of theory) of 2α-iodo-1α-methylandrost-4-ene-3,17-dione is obtained as solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15]C(C)(C)[O:17][C@:13]32[C@H:8]([C@H:9]([C:21]([CH3:25])=[C:22]([F:24])[F:23])[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:4][C@@H:5]1[C:6]([CH3:26])=[CH:7][C@@H:8]2[C@@:13]([OH:17])([C@@H:12]([CH3:20])[CH2:11][CH2:10][C@H:9]2[C:21]([CH3:25])=[C:22]([F:24])[F:23])[C@H:14]1[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=C(F)F)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=C(F)F)CC[C@H](C)[C@@]2(O)[C@H]1O
Yield: 54.7 %

Procedure:
A solution of the product of (3aS,4R,6aS,7R,10S,10aS)-7-(2,2-difluoro-1-methylvinyl)-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 151, 400 mg) and para-toluenesulfonic acid in methanol (20 ml) was stirred at room temperature for 24 hours. The reaction mixture was quenched with excess aqueous sodium hydrogen carbonate, diluted with water and extracted with diethyl ether (2×). The combined organic phases were washed with concentrated aqueous sodium chloride, dried (Na2SO4) and evaporated. The solid residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (5:95 and then 10:90) to give the product as a white solid (195 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1.C(O)C.O>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC1c2ccccc2-c2c(-c3nc4ccc(Br)cc4[nH]3)cccc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
Stir, at ambient temperature, a mixture of 390 mg of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in a mixture of 2 ml of acetic acid, 2 ml of ethanol and 2 ml of water in the presence of 65 mg of powdered zinc. After half an hour, add a further 65 mg of powdered zinc and maintain the stirring for approximately 3 hours. Add Celite, filter over sintered glass and wash the precipitate with 200 ml of a mixture of methanol and dichloromethane (20/80 by volume). Evaporate the filtrate to dryness under vacuum, add twice 50 ml of toluene and, each time, re-evaporate to dryness under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane and a 7N solution of ammonia in methanol (90/10 by volume). In this way, we obtain 69 mg of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-amine, in the form of a beige foam with the following characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([OH:20])([C:23]([F:25])([F:24])[F:22])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)c2c1OCO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at −70° C., for 1.5 hours at −0° C., for 1 hour a and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.