Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4](F)[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F-].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[OH:25]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[O:25][C:4]1[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7](=[C:2]([F:1])[C:3]=1[O:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[Cl:17])[C:8]#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(F)c(Oc2cc(Cl)ccc2Cl)c(Oc2cc(Cl)ccc2Cl)c(F)c1C#N
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a separable flask of glass provided with a stirrer, a thermometer, a water separation tube, and a cooling tube and having an inner volume of 300 ml, 242.5 gr of acetone and 19.1 gr (0.0955 mol) of tetrafluorophthalonitrile were placed, to dissolve tetrafluorophthalonitrile in acetone homogeneously. Next, the resultant solution and 134 gr (0.2306 mol) of potassium fluoride were added together and the resultant reaction slurry was retained at −5° C. To this reaction slurry, 34.1 gr (0.2092 mol) of 2,5-dichlorophenol dissolved uniformly in 30.5 gr of acetone was added dropwise over a period of one hour. The reaction proceeding during the dropwise addition was continued with the reaction product cooled from the exterior so as to keep the interior temperature thereof in the range of −5° C. to 0° C. After the dropwise addition was completed, the reaction mixture was retained for additional two hours. After the reaction was completed, the contents of the flask were cooled to 20° C. and filtered to separate the solid component.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[CH:22]=1.[Br:35][C:36]1[N:41]=[C:40]([CH:42](O)[CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=[CH:38][CH:37]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:35][C:36]1[N:41]=[C:40]([CH:42]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[CH:22]=2)[CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CO[Si](C)(C)C(C)(C)C)c2cccc(Br)n2)cc1C
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a solution of Ph3P (1.10 g, 4.19 mmol) in dry THF (30 mL), was treated with ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (696 mg, 3.31 mmol) and 1-(6-bromo-2-pyridinyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethanol (1.00 g, 3.01 mmol) and the resulting solution cooled to 0° C. (ice/water bath) under nitrogen. DIAD (0.829 ml, 4.21 mmol) in THF (30 ml) was then added drop-wise over 2 h using a syringe pump. The resulting mixture was then allowed to warm to ambient temperature over 22.5 h and was then reduced under vacuum to give an orange oily residue. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient, 1:1 to 0:1) afforded the title compound (429 mg).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[NH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=3)[CH2:4][CH2:3]1>CCO.[Ni]>[CH3:1][C:2]1([C:5]2[NH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=3)[CH2:4][CH2:3]1
Reactant: CC1(c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC1(c2cc3cc(N)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of 2-(1-methylcyclopropyl)-5-nitro-1H-indole (0.70 g, 3.2 mmol) in EtOH (20 mL) was added Raney Nickel (100 mg) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to afford 2-(1-methyl-cyclopropyl)-1H-indol-5-ylamine (170 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.65 (brs, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.14 (s, 1H), 3.45 (brs, 2H), 1.47 (s, 3H), 0.82-0.78 (m, 2H), 0.68-0.63 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CB1N2CCCC2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)C2CCCN12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -5 °C
Reaction time: 5.5 h

Procedure:
(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (13.87 g, 37.54 mmol) was dissolved in dichloromethane (40 mL). Into a separate flask were added borane-methyl sulfide complex (3.6 mL, ˜38 mmol), 1.0 M®-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene (1.9 mL, 1.9 mmol) and dichloromethane (20 mL). This mixture was cooled to −5° C. (ice/methanol bath) and the ketone solution was added drop-wise via cannula over 5 min. The reaction was stirred at −5° C. for 5.5 h and then quenched by slow addition of methanol (9 mL), 5% hydrogen peroxide solution (30 mL) and 1 M aqueous sulfuric acid (20 mL) respectively. The reaction was poured into water (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), 0.1 N hydrochloric acid (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated to afford (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one, which was used in subsequent reactions without further purification; Rf 0.14 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 7.19 (d, J=7.3 Hz, 2H), 7.02 (t, J=8.9 Hz, 2H), 4.72-4.61 (m, 2H), 4.21-4.13 (m, 2H), 3.27 (dd, J=13.2, 3.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.74 (dd, J=13.2, 9.6 Hz, 1H), 2.27 (br s, 1H), 1.88-1.66 (m, 4H) ppm; MS [M−OH]+354.0.
Reaction SMILES: C1C2C(=CC=CC=2)C=C[C:2]=1[C:11](=[O:26])[CH2:12][C:13]([O:15][C:16]([CH3:25])([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:17]=[CH2:18])=[O:14].CC(O)(CCC=C(C)C)C=C.C=C1OC(=O)C1>>[O:26]=[C:11]([CH3:2])[CH2:12][C:13]([O:15][C:16]([CH3:25])([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:17]=[CH2:18])=[O:14]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Agent: C=C1CC(=O)O1
Agent: C=CC(C)(O)CCC=C(C)C
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O

Procedure:
The pro-accord 3,7-dimethyl-1,6-octadien-3-yl 3(β-naphthyl)-3-oxo-propionate, which is a β-ketoester pro-accord, is prepared by treating 3,7-dimethyl-1,6-octadien-3-ol (linalool), which is a fragrance raw material according to the present invention, with diketene under suitable conditions to form intermediate 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate, which is subsequently treated with 2-naphthoyl chloride to yield the pro-accord. 3,7-Dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate when exposed to suitable conditions (e.g., exposure to nascent moisture) breaks down to release a mixture of linalool and methyl β-naphthyl ketone, both of which are fragrance raw materials as defined herein.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)COCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
A solution of 500 mg of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)] in 10 ml of tetrahydrofurane was treated at room temperature with 57 mg of sodium hydride (55% dispersion in oil) and stirred for 1 h. Thereafter, 183 mg of chloroacetamide were added and the mixture was heated to reflux for 48 h. For the working-up, the cooled mixture was treated with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a gradient of dichloromethane to a 4:1-mixture-mixture of dichloromethane and methanol as the eluent. After crystallisation from ether, there were obtained 29 mg (5% of theory) of 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-acetamide as a white solid; MS: m/e=307 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)cc1

Procedure:
78.1 mg of solid beige-coloured 3-{4-[3-(3-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]-pyridine-2-carboxamide and 3-fluoro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cncnc1
Product: Cc1c2n(c3c(-c4cncnc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (25 mg, 33%), MS (ISN) m/z=302.4 [(M−H)+], mp 325° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1COCC1.O>[NH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH:2]=[O:1])[CH:7]=2)[NH:11][N:10]=1
Reactant: Nc1n[nH]c2ccc(C3OCCO3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-1H-indazol-3-amine (75 mg, 0.36 mmol) in THF (5 mL) and H2O (0.5 mL) was added p-toluene sulfonic acid (25 mg) and the reaction was stirred overnight at room temperature. Ethyl acetate (75 mL) was added and the solution was washed with sat. sodium bicarbonate (5 mL), brine (2×5 mL), dried over MgSO4 and concentrated to give the title compound as an orange solid (52 mg, 89%). 1H NMR (400 MHz, CD3OD) δ 9.68 (s, 1H), 8.94 (s, 1H), 8.18 (d, 1H, J=7.6 Hz), 7.68 (d, 1H, J=8.4 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[Si:27]([O:34][CH2:35][C@H:36]([O:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[C:46]([CH:49]=O)[CH:45]=[CH:44]2)[CH3:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Si:27]([O:34][CH2:35][C@H:36]([O:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[C:46]([C:49]1[N:6]3[CH:5]=[C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]3=[N:10][N:11]=1)[CH:45]=[CH:44]2)[CH3:37])([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 9B, Steps A-E; 0.32 g, 0.84 mmol) and (R)-8-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)quinoline-2-carbaldehyde (0.29 g, 0.84 mmol) in ethanol (4.2 mL, 0.84 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.2 mL) and iodosobenzene diacetate (0.30 g, 0.92 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.29 g, 49%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH2:3][CH2:2]1.[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C(O)CNC(=O)OC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{[(Tetrahydro-2H-pyran-4-yloxy)carbonyl]amino}acetic acid, 563 mg (2.06 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 563 mg (1.65 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were suspended in 10 ml of dichloromethane. 0.23 ml (1.65 mmol) of triethylamine was added to the obtained suspension, and they were stirred at room temperature overnight. 20 ml of dimethylformamide was added to the reaction mixture, and they were stirred at 50° C. for 3 hours. 263 mg (1.37 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 50 mg (0.41 mmol) of 4-dimethylaminopyridine and 0.19 ml (1.37 mmol) of triethylamine were added to the reaction mixture, and they were stirred at 50° C. overnight. The resultant mixture was concentrated under reduced pressure and then ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane:ethyl acetate=3:1 to 1:2) to obtain the title compound.
Reaction SMILES: [Br-].[C:2]([N:5]1[CH2:9][CH2:8][CH:7]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]1=[O:29])(=[O:4])[NH2:3].[CH2:30]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[OH:41])[CH:36]=O)[CH3:31].C(N(CC)CC)C.[OH-].[Na+].Cl>C(O)C.C(OC(C)C)(C)C.C(OCC)(=O)C>[C:2]([N:5]1[CH2:9][CH2:8][C:7](=[CH:36][C:35]2[CH:38]=[CH:39][C:40]([OH:41])=[C:33]([O:32][CH2:30][CH3:31])[CH:34]=2)[C:6]1=[O:29])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: NC(=O)N1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCOc1cc(C=C2CCN(C(N)=O)C2=O)ccc1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a solution of 939 mg (2 mmol) of (1-carbamoyl-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide in ethanol (16 ml) were added 332 mg (2 mmol) of 3-ethoxy-4-hydroxybenzaldehyde and 558 μl (4 mmol) of triethylamine, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was evaporated to give a residue, which was dissolved in diisopropyl ether and treated with 4 ml of 1N aq. sodium hydroxide. The aqueous layer was made acid with 1N hydrochloric acid under ice-cooling and the product was dissolved in ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was crystallized from a dichloromethane/n-hexane mixture to give 143 mg of the objective compound (Ia-19) in 26% yield.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)=[N:12][C:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=3[NH:1][C:19]=2[CH:18]=1
Reactant: COCCOc1ccc(-c2nc(-c3ccc(OC)cc3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Solvent: Clc1ccccc1Cl
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)cc(-c3ccc(OC)cc3)nc12
Yield: 71 %

Procedure:
A solution of methyl 3-azido-2-(4-(2-methoxyethoxy)phenyl)-6-(4-methoxyphenyl)-isonicotinate (42 mg, 0.097 mmol) in 1,2-dichlorobenzene (2 mL) was heated at 160° C. for 10 min. The solvent was removed under a stream of nitrogen and the residue was purified by radial chromatography (step gradient elution with hexane containing 10 to 50% EtOAc) to give methyl 7-(2-methoxyethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (28 mg) as a solid. MS (ESI) m/z 407.2 (M+H). 1H NMR (CDCl3) δ ppm 9.38 (1H, s), 8.29 (1H, d, J=8.24 Hz), 8.13 (1H, s), 8.10 (2H, d, J=8.55 Hz), 7.03 (2H, d, J=8.55 Hz), 6.94-7.02 (2H, m), 4.19-4.28 (2H, m), 4.07 (3H, s), 3.88 (3H, s), 3.79-3.84 (2H, m), 3.49 (3H, s).
Reaction SMILES: [CH3:1][CH2:2][CH2-:3].[Mg+2].[Br-].[F:6][C:7]1[CH:32]=[CH:31][C:10]2[S:11][C:12]([C:15]3[N:19]4[N:20]=[C:21]([CH3:29])[CH:22]=[C:23]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[C:18]4=[N:17][C:16]=3[CH3:30])=[C:13]([CH3:14])[C:9]=2[CH:8]=1>C1COCC1>[F:6][C:7]1[CH:32]=[CH:31][C:10]2[S:11][C:12]([C:15]3[N:19]4[N:20]=[C:21]([CH3:29])[CH:22]=[C:23]([C:24]([OH:28])([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[C:18]4=[N:17][C:16]=3[CH3:30])=[C:13]([CH3:14])[C:9]=2[CH:8]=1
Reactant: CCCC(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Reactant: [CH2-]CC
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
N-Propylmagnesium bromide (0.601 g, 4.09 mmol) is added dropwise to a solution of 1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl]-butan-1-one (1.08 g, 2.72 mmol) in THF (27 mL) at 0° C. The reaction is stirred at room temperature overnight. The mixture is quenched with ammonium chloride, extracted with ethylacetate, dried over sodium sulfate, filtered, and concentrated to dryness. The crude is purified by ISCO (5% EtOAc/Hexane) to give the title compound (280 mg, 24%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 6.7 (s, 1H), 6.4 (s, 1H), 2.6 (s, 3H), 2.5 (s, 3H), 2.3 (s, 3H), 2.0 (m, 3H), 1.5 (m, 1H), 1.3 (m, 4H), 0.9 (t, J=7.3, 6H) ppm. Mass spectrum (m/e): 426 (M+1).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]([O:19][C@@H:20]1[CH2:33][C:32]2[C@@:23]([CH3:39])([C@@H:24]3[C@@H:29]([CH2:30][CH:31]=2)[C@@H:28]2[CH2:34][CH2:35][C:36](=O)[C@@:27]2([CH3:38])[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)=[O:18].C([C:44]1[CH:49]=[C:48](C)[CH:47]=[C:46](C(C)(C)C)[N:45]=1)(C)(C)C.O1CCCC1>C(Cl)Cl>[CH3:16][C:17]([O:19][C@@H:20]1[CH2:21][C:22]2[C@@:23]([CH3:39])([C@@H:24]3[C@@H:29]([CH2:30][CH:31]=2)[C@@H:28]2[CH2:34][CH:35]=[C:36]([C:47]4[CH:48]=[CH:49][CH:44]=[N:45][CH:46]=4)[C@@:27]2([CH3:38])[CH2:26][CH2:25]3)[CH2:32][CH2:33]1)=[O:18]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
Trifluoromethanesulphonic anhydride (45.4 mL) is dropped into a solution of prasterone acetate (100 g) and 2,6-di-tert-butyl-4-methylpyridine (58 g) in methylene chloride (1 L) at −5° C., maintaining the temperature between −5° C. and 0° C. and stirring at said temperature for about 5 h. The mixture is then concentrated under vacuum, and the concentrate is taken up in n-hexane (about 1500 mL) to obtain a precipitate which is isolated by filtration. The filtered solution is washed with a 1N hydrochloric acid solution (about 1.5 L) and then with a sodium chloride saturated aqueous solution (500 mL). The organic phase is added with potassium carbonate (50 g), and the resulting suspension is stirred for about 15 h at room temperature, then filtered. After removal of the solvent under vacuum an oil (about 110 g) is obtained, which is taken up with tetrahydrofuran (1.5 L). The solution is degassed and diethyl(3-pyridyl)borane (54.5 g), bis(triphenylphosphine)palladium II chloride (1.8 g) and a 2M sodium carbonate aqueous solution (500 mL) are added in sequence in an inert gas environment. The resulting mixture is refluxed for about 1 h, then cooled to room temperature, and ethyl acetate (1 L) and water (1 L) are added. The aqueous phase is back-extracted with ethyl acetate (0.5 L), and the combined organic phases are concentrated under vacuum to obtain crude abiraterone acetate as oil (230 g; purity about 88%; assay 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][C:3]=1[CH3:11].Br.[OH2:13]>CS(C)=O>[CH3:11][C:3]1[CH:4]=[C:5]([C:8](=[O:9])[CH:10]=[O:13])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O
Reactant: CC(=O)c1ccc(C)c(C)c1
Agent: Br
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)C=O)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
3,4-dimethylacetophenone (13.52 mmol, 2.0 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (5.4 mL) was gradually added at room temperature. After 16 hours of stirring at 70° C., the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a white solid (1.234 g, yield 57%).