Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([Br:33])(Br)(Br)Br.OC[CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]>ClCCl>[Br:33][CH2:29][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2c(n1)CC(=O)N2CCCO
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(n1)CC(=O)N2CCCBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon and in an anhydrous medium, 1.50 g (3.76 mmol) of 1.2-bis-diphenylphosphinoethane are added at 0° C. to a solution of 1.25 g (3.76 mmol) of carbon tetrabromide in 20 ml of dichloromethane. After 10 minutes at 0° C., 417 mg (1.88 mmol) of the compound obtained in Step D dissolved in 10 ml of dichloromethane are added to the mixture. The mixture is stirred for 30 minutes at 0° C., and then for 3 hours at room temperature. After hydrolysis of the reaction mixture, the organic phase is dried over magnesium sulphate, filtered and concentrated. Purification by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) yields the title compound in the form of a white solid.
Reaction SMILES: P(Br)(Br)[Br:2].C1C=CC=CC=1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([I:26])=[C:22]([CH:25]=1)[CH2:23]O>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([I:26])=[C:22]([CH:25]=1)[CH2:23][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)ccc1I
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(I)c(CBr)c1
Yield: 247.4 %

Procedure:
A mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared while cooling and while stirring it is treated dropwise at a maximum temperature of 10° C. with 108.3 g of 5-chloro-2-iodobenzyl alcohol. Then, it is stirred for 4 hours at room temperature and for 1 hour at 50° C. After cooling, it is diluted with 120 ml of chloroform, the mixture washed with 25 ml of 5% hydrochloric acid, a 5% sodium hydroxide solution and with water, dried with magnesium sulfate and evaporated. There are obtained 126 g (95%) of crude 5-chloro-2-iodobenzyl bromide melting at 75°-79° C. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C([O:11][C:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]3)=[N:18][N:17]2[CH:40]=1)=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:12]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]([F:36])([F:38])[F:37])[CH2:26][CH2:27]4)=[N:18][N:17]3[CH:40]=2)=[O:11])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(Nc1ccc(Cl)cn1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 24 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 5-chloropyridin-2-ylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 24% yield (0.028 g). m.p. 265-268° C. 1H NMR (300 MHz, CDCl3) δ 9.78 (s, 1H), 8.35 (d, J=7.6 Hz, 1H), 8.27-8.25 (2H), 7.81-7.52 (m, 5H), 7.42-7.31 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.9 (d, J=7.6 Hz, 1H), 4.08-3.97 (m, 1H), 3.95-3.83 (m, 1H), 3.72-3.55 (m, 2H), 3.53-3.43 (m, 2H), 3.37-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 160.7, 154.9, 149.7, 146.7, 137.8, 137.3, 135.8, 134.2, 132.4, 129.5, 127.2, 127.2, 126.9, 126.8, 126.7, 126.5, 125.4, 118.9, 114.5, 112.3, 46.2, 46.18, 45.6, 41.2. MS (ES+) m/z 530.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].[H][H].C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[OH:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C#N)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCCc1cc(C#N)ccc1O
Reaction time: 1.33 h
Yield: 99.6 %

Procedure:
A Parr hydrogenation shaker was charged with a solution of 29.76 g (187 mmol) of the product of Step A in 100 mL of ethanol and 3.00 g of a 10% palladium on carbon catalyst was added. The flask was mounted in the hydrogenation appartus, freed of air, pressurized with hydrogen (40 psig) and shaken 80 minutes. At the end of this preiod, TLC analysis (15% ethyl acetate/hexane) indicated that the reaction was complete and the reaction mixture was filtered and evaporated. The product was dried in vacuo to afford 30.01 g (99%) of the title compound as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)CCl
Product: CC(C)(C)NC(=O)CN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl-chloride and N-tert-butylamine in an analogous manner as described in example 21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([OH:25])=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][CH2:52][C:53]([OH:55])=[O:54]>CN(C)C=O.C(N(CC)CC)C>[CH3:50][N:51]([C:23](=[O:25])[CH2:22][C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)[CH2:52][C:53]([OH:55])=[O:54]
Reactant: CC(C)C(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)cc1
Reactant: CNCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)N(C)CC(=O)O)cc2Cl)cc1
Reaction time: 24 h

Procedure:
A solution of 3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetic acid (70 mg), 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (49 mg), 1-hydroxybenzo-triazole hydrate, (45 mg) in dimethyl formamide (2 mL) was stirred at room temperature for 0.5 hours followed by addition of a solution of methyl glycine hydrochloride (46 mg) and triethylamine (56 mg) in dimethylformamide (1 mL). After stirring for one day, the reaction mixture was concentrated. The residue was purified by HPLC as described for Examples 33–90, to give methyl N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine. The ester was hydrolyzed using the method described in Example 1(i) and purified as above, to give 25 mg (31%) of N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine, m/z 439.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH:18]([CH3:20])[CH3:19])[CH2:15][C:14](=[O:21])[CH2:13][CH:12]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:29]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:12]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH2:13][C:14](=[O:21])[NH:29][CH2:15][C@H:16]3[O:17][CH:18]([CH3:20])[CH3:19])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)OC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)O[C@@H]1CNC(=O)C[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Yield: 9.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(1-methylethoxy)-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (138.0 mg, 0.33 mmole) was treated with NaN3 (54.0 mg, 0.83 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.33 mL) (Aldrich) in acetonitrile (10 mL) at reflux for 6 hrs, followed by chiral chromatograph to give (3S,4S,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethoxy)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.0 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O3+H [(M+H)+]: 433.1080, Found: 433.1080; (3R,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethoxy)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.0 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O3+H [(M+H)+]: 433.1080, Found: 433.1080;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.C1COCC1.O.NN>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H]1[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
To a solution of 244 (0.40 g, 1.03 mmol) and MeOH:THF (1:1, 10 mL) was added hydrazine monohydrate (0.514 g, 10.3 mmol) and the reaction was stirred at 50° C. for 18 h. The reaction mixture was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 0.130 g (48.8%) of (S)-(3,4-dichlorophenyl)((R)-1-methylpyrrolidin-2-yl)methanamine (246).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(S(F)(F)[F:21])CC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([F:21])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2nccnc2F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1nccnc1C1(F)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.4 g, 2.018 mmol) in CH2Cl2 (6.73 mL) was cooled to 0° C. DAST (0.533 mL, 4.04 mmol) was added to the reaction mixture dropwise and the resulting mixture was allowed to stir at 0° C. for 2 hr. A solution of saturated sodium carbonate was added dropwise to the reaction mixture at 0° C. to quench the reaction. The heterogeneous mixture was stirred vigorously for 1 hr to ensure complete quenching. Mixture was transferred to a separatory funnel and the layers were separated after addition of more DCM and saturated bicarbonate solution. The organic layer was dried over magnesium sulfate and rotovapped to remove the volatile solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[OH:32])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(2-pyridin-2-yl-ethyl)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, LC at 215 nm; Rt 3.10: 98%, m/z (ES+): 436.4 (M+H).
Reaction SMILES: N1C=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])C=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].O.[C:22](#[N:24])[CH3:23]>>[CH2:11]([N:24]1[CH2:5][CH2:4][C:3]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC#N
Reactant: BrCc1ccccc1
Reactant: OCCCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCCCC1=CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
5.00 g (36.4 mmol) of 3-pyridinepropanol was dissolved in 150 ml of acetonitrile, 4.55 ml (38.3 mmol) of benzylbromide was added, and the mixture was heated at 70° C. After 2 hours, heating was stopped, and the mixture was evaporated. Then, the residue was dissolved in 100 ml of methanol, and the mixture was cooled to 0° C. 4.12 g (109 mmol) of sodium borohydride was added thereto. After completion of the reaction, 50 ml of water was added thereto, and the mixture was evaporated. Then, the residue waspartitionedbetween ethylacetateand brine. After drying the organic layer over magnesium sulfate, the mixture was evaporated, to give a crude product. The crude product was subjected to 150 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:6-1:1), to give 6.48 g (28.0 mmol, 77.0%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([I:15])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: Brc1ccc2oc3ccccc3c2c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccc(I)cc3c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-Bromodibenzofuran (2.5 g, 10.1 mmol), orthoperiodic acid (0.49 g, 2.15 mmol), iodine (1.02 g, 4.02 mmol), sulfuric acid, H2O (2 ml) and acetic acid (10 ml) are put into a reaction vessel and the mixture is stirred at 70° C. for 3 hours. After cooling to room temperature the reaction mixture is poured into water and filtered. The white solid is washed by methanol and the desired product is obtained (1.92 g, 51%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80°-90° C. overnight. The reaction mixture was poured into water (200 ml)NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191°-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH3:29]>C(O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:28]([CH3:29])=[N:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: CC=O
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: C=CCOC(=O)c1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 36 h
Yield: 45.1 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 39.95 mmol, 1.0 equiv) in ethanol (250 mL) were added copper(II) acetate (14.51 g, 79.90 mmol, 2.0 equiv) and acetaldehyde (44.1 mL, 0.20 mol, 5.0 equiv; 20% solution in water) and the reaction mixture heated to refluxe for 36 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4, concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (3:7→1:9) to obtain 7.2 g (45%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO): δ 1.46 (s, 9H), 1.88-1.91 (m, 2H), 2.14-2.20 (m, 2H), 2.63 (s, 3H), 2.97 (br s, 2H), 4.13-4.15 (m, 2H), 4.58 (t, J=11.5 Hz, 1H), 4.81 (d, J=4.6 Hz, 2H), 5.28 (d, J=10.4 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 6.03-6.10 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 8.14 (s, 1H). MS (ISP): 400.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:8]([CH2:15][OH:16])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10])[CH3:7]>>[CH2:6]([C:8]([CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10])[CH3:7]
Reactant: CCCCC(C=O)(CC)CO
Reactant: CS(=O)(=O)Cl
Product: CCCCC(C=O)(CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylemine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([N:14]2[C:22](=[O:23])[C:21]3[C@H:20]4[C:24]([CH3:26])([CH3:25])[C@:17]([CH3:27])([CH2:18][CH2:19]4)[C:16]=3[NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+]>[CH3:5][O:23][C:22]1[N:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]=[C:16]2[C:21]=1[C@H:20]1[C:24]([CH3:26])([CH3:25])[C@:17]2([CH3:27])[CH2:18][CH2:19]1.[CH3:5][N:15]1[C:16]2[C@:17]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:20]([CH2:19][CH2:18]3)[C:21]=2[C:22](=[O:23])[N:14]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c2c(nn1-c1ccccc1)[C@@]1(C)CC[C@@H]2C1(C)C
Product: Cn1c2c(c(=O)n1-c1ccccc1)[C@@H]1CC[C@@]2(C)C1(C)C
Reaction time: 0.17 h
Yield: 35 %
Yield: 17 %

Procedure:
Dimethyl sulfate (66 μL, 0.7 mmol) was added to (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 7; 185 mg, 0.7 mmol) in 1 M NaOH (5 mL). The mixture was vortexed and then heated with a heat gun for 30 sec., then shaken for 10 min, and extracted twice with dichloromethane. TLC indicated that the sodium hydroxide solution still contained starting material so a further quantity of dimethyl sulfate (150 μL, 1.6 mmol) was added and the mixture was vortexed, heated with a heat gun for 30 sec and then heated for 90 min at 100 degrees. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were evaporated and purified by column chromatography, eluting initially with 50% ethyl acetate/hexanes and later with 12.5% methanol/ethyl acetate to give (4R,7S)-3-methoxy-7,8,8-trimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (70 mg, 35%) as a yellow solid, and (4R,7S)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (33 mg, 17%) as a white solid. APCI-MS (M+H) 283.
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=O)[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([C:36]#[N:37])(OCC)(OCC)=O>>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([C:36]#[N:37])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following a procedure similar to that described in Example 2(c), but using 100 mg of N-t-butyl-3-oxo-4-androstene-17β-carboxamide (prepared as described in Preparation 1), 0.2 ml of diethyl cyanophosphate and 200 mg of a boron trifluoride-diethyl ether complex, 86 mg of the title compound were obtained as a crystalline substance, melting at 198° to 200° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
Piperidine (0.133 g, 1.56 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.448 g, 2.34 mmol) were added to a methylene chloride solution (30 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.293 g, 0.783 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) to obtain the titled compound (0.152 g, 0.345 mmol, 44%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]3(O)[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:36][CH:35]=4)(O)[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:46]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:37]2[CH:36]=[CH:35][C:34]([C:26]3[C:25]4[C:20]([C:19]([C:16]5[CH:15]=[CH:14][C:13]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=6[C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:18][CH:17]=5)=[C:32]5[C:27]=3[CH:28]=[CH:29][CH:30]=[CH:31]5)=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:39][CH:38]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: OC1(c2ccc(-c3ccccc3-c3ccccc3)cc2)c2ccccc2C(O)(c2ccc(-c3ccccc3-c3ccccc3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2ccccc2-c2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5-c5ccccc5)cc4)c4ccccc34)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
9,10-bis(4-(2-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (4.9 g, 7.3 mmole) was suspended in acetic acid (70 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (50 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (4.6 g, 88%) was obtained.