Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.021 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 1.52 (m, 2 H), 2.08 (s, 6 H), 2.72 (m, 2 H), 2.80 (m, 2 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.85 (d, J=9.19 Hz, 1 H), 4.01 (s, 2 H), 4.22 (m, 2 H), 5.05 (d, J=5.88 Hz, 1 H), 6.71 (d, J=9.93 Hz, 1 H), 6.92(m, 3 H), 7.26 (m, 8 H), 7.45 (d, J=9.56 Hz, 1 H), 7.85 (m, 5 H), 8.62 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3c(F)cc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)cc(F)c3n2CCc2ccc(C(F)(F)F)nc2)C1
Reaction time: 0.17 h
Yield: 2.9 %

Procedure:
To a solution of 8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.26 mmol) in NMP (3.0 ml), powdered KOH (705 mg, 12.57 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (435 mg, 2.5 mmol) was added slowly to the above solution and stirred for 24 h at 25 deg C. After completion of the reaction (monitored by LCMS), DM water was added to the crude and extracted with the ethylacetate. The organic layer was separated, dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([Cl:18])(=[O:17])=[O:16])[CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:19][C:9]1[CH:10]=[C:11]([S:15]([Cl:18])(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc(CBr)c1

Procedure:
N-Bromosuccinimide (6.27 g, 0.035 mole), m-toluenesulfonyl chloride (6.72 g, 0.035 mole), and benzoyl peroxide (0.67 g, 0.0019 mole) were combined in CCl4 (40 mL) and heated at reflux 2 h. The reaction mixture was filtered and washed with CCl4. The filtrate was concentrated to give m-bromomethylbenzenesulfonyl chloride, 9.74 g, as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][C:21]([NH2:23])=O)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][C:21]#[N:23])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)C(CC(N)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)C(CC#N)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Reaction time: 2 h

Procedure:
A solution of racemic 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanamide, 164a, (0.250 g, 0.668 mmol) in pyridine was cooled to 0° C. and treated with trifluoroacetic acid anhydride (0.278 mL, 2.003 mmol). After 2 hours at 0° C., the reaction was concentrated to dryness and the residue was purified by silica gel chromatography (EtOAc) to afford 150 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.41 minutes (M+H) 357.47.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](Br)[CH:34]([CH3:36])[CH3:35]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:33]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CBr
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 100 °C

Procedure:
A glass vial was charged with 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared as described in Example 3; 41.60 mg, 120 μmol), tetrabutylammonium iodide (8.85 mg, 24.0 μmol), cesium carbonate (58.6 mg, 180 mol), DMF (0.48 mL), and isobutyl bromide (16.3 μl, 150 μmol). The vial was sealed and placed in a 90° C. oil bath for 15 h. Additional portions of cesium carbonate (40 mg) and isobutyl bromide (16 uL) were added, and the vial was heated in a Biotage Initiator microwave reactor for 1.5 h at 100° C. The mixture was then partitioned between EtOAc (10 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel (eluting with 0-80% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-iso-butyloxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as an oily tan solid. MS m/z=403.2 [M+H]+. Calc'd for C23H23N4O3: 403.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:18](=[C:19]([O:21]C)[CH:20]=1)[O:17][CH2:16][C@H:15]1[C@@:6]2([CH3:26])[CH2:7][CH2:8][C@@H:9]2[C@:14]1([CH3:23])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:25])[CH3:24].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:18](=[C:19]([OH:21])[CH:20]=1)[O:17][CH2:16][C@H:15]1[C@@:6]2([CH3:26])[CH2:7][CH2:8][C@@H:9]2[C@:14]1([CH3:23])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:25])[CH3:24]
Reactant: COc1cc(OC)c2c(c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (1R,10R,11S,16S)-4,6-dimethoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 42) (0.186 g, 0.519 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. under nitrogen, BBr3 (1.0 M in CH2Cl2, 0.54 mL, 0.54 mmol) was added dropwise. The solution was stirred at room temperature for 6 h. The reaction was quenched at 0° C. with anhydrous MeOH (6 mL) and evaporated. The residue was co-evaporated with MeOH (4×20 mL) and dried in vacuo. Purification by column chromatography on silica gel (Hexanes/EtOAc, 10:1) gave a product, which was triturated with MeOH (4.5 mL) to afford (1R,10R,11S,16S)-4-methoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-6-ol (Compound No. 44) (86 mg, 49%) as a white solid. 1H NMR (CDCl3): δ 6.38 (d, 1H), 6.24 (d, 1H), 5.49 (s, 1H), 4.40 (dd, 1H), 4.16 (dd, 1H), 3.71 (s, 3H), 2.25 (dd, 1H), 1.78-1.38 (m, 9H), 1.29 (s, 3H), 1.16 (m, 1H), 1.05 (m, 1H), 0.94 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H). MS m/z 345 (C22H32O3+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[CH3:17][C:18](N(C)C)=[O:19]>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([C:18](=[O:19])[CH3:17])=[CH:8]1
Reactant: Cc1ccc2c(ccn2C)c1
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cn(C)c2ccc(C)cc12
Reaction time: 0.17 h

Procedure:
Phosphoryl chloride (2.1 ml) was added dropwise to ice-cooled, dimethylacetamide (20 ml) and the solution was stirred at ca.0° for 10 min. A solution of 1,5-dimethyl-1H-indole (2.5 g) in dimethylacetamide (5 ml) was added, and the resulting solution was stirred at 85° for 2 h, then cooled, and partitioned between sodium carbonate (2N; 500 ml) and ethyl acetate (2×300 ml). The combined organic extracts were washed with water (300 ml), dried and evaporated in vacuo to give an oil, which was purified by FCC eluting with chloroform:hexane (1:1) to give the title comound as a solid (1.5 g), m.p. 119°-121°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([Cl:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pt]=S.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:23])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2[N+](=O)[O-])CC1
Agent: S=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A round bottom flask is charged with 5% platinum sulfide on carbon (0.20 g, 0.039 mmol). The flask was evacuated and refilled with argon three times. To the flask is added 4-(5-chloro-3-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.80 g, 8.17 mmol) as a solution in a 1:1 mixture of ethyl acetate:methanol (100 mL). The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 2.0 g of 4-(3-amino-5-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a dark solid in 80% yield.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[N:16]#[C:17]Br>C(#N)C>[CH:7]1([N:6]=[C:2]2[N:3]([C:17]#[N:16])[CH2:4][CH2:5][S:1]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: N#CBr
Reactant: c1ccc2c(c1)CCC2NC1=NCCS1
Solvent: CC#N
Product: N#CN1CCSC1=NC1CCc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
A suspension of 0.70 g (3.2 mmol) (4,5-Dihydro-thiazol-2-yl)-indan-1-yl-amine, 0.52 g (4.8 mmol) cyanogen bromide and 1.56 g (4.8 mmol) CsCO3 in 10 ml acetonitrile—was stirred at 20° C. for 16 hours. The suspension was filtered and the solvent evaporated. The crude product was purified by flash chromatography using EtOAc/n-hexane (1:5) as eluent to yield 0.50 g of 2-(Indan-1-ylimino)-thiazolidine-3-carbonitrile (white crystals, m.p. 90-91° C.). 1H-NMR (400 MHz, CDCl3): 2.0-2.15 (1H, m); 2.40-2.50 (1H, m); 2.85-2.95 (1H, m); 3.0-3.10 (1H, m); 3.35-3.45 (2H, m), 3.90-4.0 (2H, m), 4.65 (1H, t), 7.10-7.30 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([C:6](=O)[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.CC1(C)C2C(C(=O)C(=O)CC2)C(C)(C)C1C.[CH2:47]([NH2:50])[CH2:48][NH2:49].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>COCCOCCOC>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([C:6]3[N:49]=[CH:48][CH:47]=[N:50][C:7]=3[CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: CC1C(C)(C)C2CCCC(=O)C2C1(C)C
Reactant: NCCN
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Agent: CC1C(C)(C)C2CCC(=O)C(=O)C2C1(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: COCCOCCOC
Product: CC1C(C)(C)C2CCc3nccnc3C2C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-octahydro-inden-4-one is first prepared by the hydrogenation of 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF). 1,1,2,3,3-Pentamethyl-hexahydro-indene-4,5-dione is subsequently prepared with 1,1,2,3,3-pentamethyl-octahydro-inden-4-one (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-hexahydro-indene-4,5-dione (10 g, 0.04 mol), ethylene diamine (NH2CH2CH2NH2) (2.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The reaction mixture is then cooled to 25° C. and further oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 g, 0.045 mol) for another 8 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 7,7,8,9,9-pentamethyl-5,6a,7,8,9,9a-hexahydro-6H-cyclopenta[f]quinoxaline (˜10 g) is obtained.
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.[C:13]([NH:20][CH2:21][C:22](O)=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1.NN.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:22]([CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:33][N:32]=2)[N:31]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: *CC*
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
A 2-L round bottom flask equipped with a magnetic stirbar was charged with di(1H-imidazol-1-yl)methanone (121 g, 749 mmol) and acetonitrile (500 mL). The stirred slurry was cooled by immersing the flask in an ice bath. A solution of N-Boc glycine (125 g, 714 mmol) in acetonitrile (500 mL) was added via a 500-mL addition funnel over the course of 30-45 min. The mixture was aged for 1 h while a 5-L, 3-neck, round bottomflask equipped with a mechanical overhead stirrer and a thermocouple w/adapter was charged with 1-(6-chloropyridazin-3-yl)hydrazine (108 g, 749 mmol) and acetonitrile (900 mL) and cooled to <5 deg C. in an ice bath. The cold solution of the acylimidazole was then transferred via a polyethylene cannula into the thick suspension of the hydrazine over a period of 30-45 min). The ice bath was removed, and the mixture was allowed to warm. After 2.5 h of stirring, 4-methylbenzenesulfonic acid hydrate (143 g, 749 mmol) was added. The flask was then equipped with a heating mantle and a reflux condenser and was heated to reflux (82 deg C.) for 13 h, then cooled back to about 60 deg C. At this point, the warm solution was vacuum filtered through paper. The brown filtrate was then concentrated by rotary evaporation. The resulting thick yellow-brown slurry was stirred in an ice bath and diluted with ACN (about 100 mL). After stirring for 1 h, the solids were isolated by vacuum filtration, washed with ice-cold 1:1 ACN/H2O (2×150 mL) and air-dried on the filter until a freely flowing solid was obtained (159 g, 78.5% yield).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@:7]2(C(OC)=O)[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1.C(S)CCCCCCCCCCC.CC(C)([O-])C.[Na+]>CN(C)C=O>[CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1
Reactant: CC[C@H]1C[C@@H]2CN3CCc4c([nH]c5ccc(OC)cc45)[C@](C(=O)OC)(C2)[C@H]13
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCCCS
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13
Temperature: 115 °C
Reaction time: 6 h

Procedure:
Resolved (+) voacangine (200 mg, 1 equivalent) and 1-dodecanethiol (1.5 equivalent) in dimethyl formamide (DMF, 1.2 mL) was added to a mixture of sodium tertiary butoxide (1.5 equivalent) in DMF (0.8 mL) at 100° C. and the reaction mixture stirred in the dark at 110-120° C. for 6 h and then at room temperature for about 12 h. Volatiles were removed in vacuum, and after aqueous work-up, (+) ibogaine was isolated by extraction with dichloromethane. The organic portion was washed with water and dried over MgSO4. Volatiles were removed to provide ibogaine as a foamy solid (140 mg). A solution of ibogaine thus obtained, in dichloromethane (DCM, 1.4 mL), was added to a 1 molar BBr3 (1.5 equivalent) solution in DCM at 0-5° C. over a 2 h period to provide a suspension, which was stirred at room temperature for 12 h. Then, the reaction mixture was cooled to 0-5° C. and MeOH (0.6 mL) was added to it drop wise over a period of 15 minutes and the resulting mixture stirred at room temperature for 12 h. Volatiles were removed in vacuum, and the residue was separated by column chromatography on silica gel using 5% MeOH/CHCl3 as the eluent to obtain (+) noribogaine (70 mg) as a foamy solid. Specific rotations determined for the naturally occurring (−) enantiomers, and the synthetic (+) enantiomers made according to this invention are tabulated below, which demonstrate the stereochemistry and enantiomeric purity of the synthetic enantiomers prepared according to this invention.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:11]([OH:14])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(F)cc1F
Product: O=C(O)C=Cc1ccc(F)cc1F
Yield: 77 %

Procedure:
A disadvantage here is the high reaction temperature needed, the unsatisfactory yield and the difficult accessibility of the compounds of the formula (I). Monatshefte der Chemie 90, 680 (1959) describes the reaction of 2,4-difluorobenzaldehyde with acetic anhydride at 180° C., 2,4-difluorocinnamic acid being obtained in a 77% yield.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[S:31][CH:32]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([C:30]2[S:31][CH:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:13]4([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:21])=[CH:27][CH:26]=3)[N:29]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)OCc5ccccc5)CCCCC4)cc3)cs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)O)CCCCC4)cc3)cs2)CC1
Yield: 67 %

Procedure:
35 ml of 2N aqueous sodium hydroxide solution was added to a solution of 11.8 g (23.0 mmol) of 1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester in 120 ml of tetrahydrofuran, and the mixture was heated under reflux for 15 hours. Ether was added to the reaction solution to separate the aqueous layer. Concentrated hydrochloric acid was added to the separated aqueous layer to neutralize it, and the precipitated crystal was collected by filtration to obtain 6.60 g (67%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[CH2:8]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Brc1ccsc1
Reactant: CCCCCCBr
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccsc1
Reaction time: 2 h

Procedure:
3-Hexylthiophene was synthesized by coupling the Grignard reagent of 3-bromothiophene with 1-bromohexane using bis(1,3-diphenylphosphino)propane nickel(II)chloride as catalyst. The product was purified by fractional distillation under reduced pressure. Polymerization of the monomer was achieved by mixing a 0.1M solution of 3-hexylthiophene in chloroform with a 0.4M chloroform solution of anhydrous ferric chloride. The mixture was stirred for two hours prior to precipitation into acidified methanol. The solid product was filtered, washed with NH4OH, water and methanol. The crude polymer was dissolved in hot dichloromethane and insoluble products were removed by filtration. Low molecular products were removed by cooling the filtrate and adding methanol. The precipitate was filtered and dried in a vacuum oven. The polymer possessed IR bands at 3027, 2930, 2859, 1458, 819, and 725 cm-1. The polymer had a number-average molecular weight of 9300 and a polydispersity index of 2.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]([CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:19]([C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:27][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2nnc(Cc3ccncc3)c3ccccc23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g (3.91 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67.A1 in WO 98/35958) and 1.82 g (11.7 mmol) 4-tert-butylcyclohexylamine (trans-/cis-mixture) is stirred overnight at 120° C. The cooled reaction mixture is then distributed between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic phase is washed with water and brine, dried (MgSO4) and evaporated and the residue purified on silica gel by flash chromatography using dichloromethane/methanol (9:1) yielding the title compound as a trans-/cis-mixture: FAB MS (M+H)+=375. Separation of the isomers by reversed phase medium pressure chromatography (CH3CN/H2O/trace of TFA) gives the cis-isomer (m.p. 64-65° C.) followed by the trans-isomer (m.p. 132-134° C.).