Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH3:19])[C:9](=[O:20])[C@H:8]1[CH2:21][CH3:22])=[O:6].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[OH:2][C:3]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH3:19])[C:9](=[O:20])[C@H:8]1[CH2:21][CH3:22])=[O:6]
Reactant: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O
Yield: 31 %

Procedure:
(3R)-4-(2,4-dimethoxybenzoyl)-1,3-diethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-4-(2,4-dihydroxybenzoyl)-1,3-diethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (31%). MS (ESI) m/z 359 ([M+H]+); MS (ESI) m/z 357 ([M−H]−); HRMS: calcd for C19H19FN2O4, 358.1329; found (ESI_FT), 359.13972.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(-n2nc3ccccc3n2)cc1
Temperature: 130 °C
Yield: 28.9 %

Procedure:
A mixture of 4-chloronitrobenzene (55.0 g, 349 mmol), benzotriazole (50.0 g, 420 mmol), potassium carbonate (200 g, 500 mmol), and NMP (500 mL) was stirred and heated under argon at 130° C. for 5 hours. Progress of the reaction was monitored by thin layer chromatography. The reaction mixture was poured onto crushed ice (2 kg). After all ice melted, the solid was filtered off and washed with water (200 mL). The product was suspended in methanol (1.5 L) and stirred for 30 minutes. The crystals were filtered off and dried in a vacuum oven. Column chromatography of the obtained material using silica gel and hot solution of ethyl acetate (1%) in toluene as an eluent gave 2-(4-nitrophenyl)-2H-benzo[d][1,2,3]triazole (24.24 g, 30% yield). 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=9.2 Hz, 2H, 4-nitrophenyl), 8.44 (d, J=9.2 Hz, 2H, 4-nitrophenyl), 7.93 (m, 2H, benzotriazole), 7.47 (m, 2H, benzotriazole).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)=[O:2].[CH3:14][N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([NH:15][CH3:14])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
2-(4-formylphenoxy)acetic acid was suspended in 20 mL of DCM at 0° C., and 0.5 mL of DMF was added followed by the dropwise addition of oxalyl chloride. The solution was allowed to warm to room temperature with stirring until gas evolution stopped and the solution was homogeneous. The solution containing the crude acid chloride was concentrated under vacuum and the residue resuspended in DCM, cooled to 0° C., and methylamine and DIEA were added. The mixture was allowed to warm to room temperature with stirring over 12 hours. The reaction mixture was then poured into 5% HCl, washed 3 times with EtOAc, dried over sodium sulfate, filtered and concentrated to a thick brown oil which was purified by column using DMC/MeOH to afford 2-(4-formylphenoxy)-N-methylacetamide (9) as an off white solid. NMR (CDCl3, 400 mHz), d═9.9 (1H, s), 7.88 (2H, d, J=8.6 Hz), 7.04 (2H, d, J=8.6 Hz), 6.6-6.5 (1H, BS, 4.54 (2H, s), 2.93 (3H, d, J=4.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[C:16]([O:18]C)=[O:17].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1c(C)nn(C)c1-c1ccc(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1C(=O)O
Temperature: 0 °C

Procedure:
A mixture of methyl 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole-4-carboxylate (i.e. the product of Step C) (12.33 g, 43.7 mol) and sodium hydroxide (1 N, 70 mL) in methanol (70 mL) was heated at reflux for 2 h. The reaction mixture was cooled to about 0° C., and then the pH of the reaction mixture was adjusted to 3 by the addition of aqueous hydrochloric acid solution (1 N). The reaction mixture was extracted with ethyl acetate (3×70 mL) and the combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a white solid (11.14 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:9][C:3]2[C:2]([Br:1])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1

Procedure:
Prepared by the method of Example 1 using 3-bromo-5-methyl-2-pyrazinamine and 5-chloro-2-thienylsulphonyl chloride
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1F
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a solution of Boc-Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 0.525 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added, stirred for 15 min. and then evaporated to remove the solvent under reduced pressure. The residue was mixed with methylene chloride, washed with a saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=40:1:0.1) to give Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (235 mg, 85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][NH:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.[F-].[K+]>CS(C)=O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])=[N:7][C:2]=1[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:24])#[N:23]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(C#N)cc2F)c1
Reactant: CNCC(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(C#N)cc2F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
A mixture of 3-(6-chloro-5-cyano-3-fluoro-pyridin-2-ylamino)-N-methoxy-4-methyl-benzamide (55.6 mg, 0.166 mmol), N-methyl-neopentylamine (70 mg, 0.511 mmol), diisopropylethylamine (0.1 mL) and potassium fluoride (12 mg) in DMSO (1 mL) was heated to 150° C. overnight. The product (3.9 mg, 5.9%) was isolated after purification by HPLC. C21H26FN5O2 MS m/e=400 (M+H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:12][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:3])[CH:11]=1
Reactant: CC(C)=CCBr
Reactant: O=Cc1ccc(O)cc1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)=CCOc1ccc(C=O)c(O)c1
Yield: 17.3 %

Procedure:
A solution of 6 g (0.11 mol) of potassium hydroxide, 22.7 g (0.1 mol) of benzyltriethylammonium chloride, and 14 g (0.1 mol) of 2,4-dihydroxybenzaldehyde was concentrated in vacuo. The residue was suspended in 100 ml of ethyl acetate and 11.7 ml (0.1 mol) of dimethylallyl bromide was slowlv added to the solution. The mixture was extracted with 100 ml of water, and the organic phase was dried and concentrated in vacuo to give 3.568 g of a residue, from which 4.738 g (20%) of 4-(3-methyl)-but-2-enyloxy-2-hydroxybenzaldehyde identical to that previously described by S. Khan, and M. Krishnamurti in Indian J. Chem. 22B (1983), 276 was purified by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 200 g) using petroleum ether-ethyl acetate (9:1) as an eluent.
Reaction SMILES: [OH-].[K+].[ClH:3].C[O:5][C:6](=[O:23])[CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.Cl>C(O)C.CCOCC>[ClH:3].[CH3:22][N:20]([CH3:21])[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][CH:8]([CH2:7][C:6]([OH:23])=[O:5])[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
1.7 M KOH (70.5 ml, 120 mmol) was added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid methyl ester hydrochloride (1.79 g, 5.77 mmol) in ethanol (80 ml). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was taken up in water. The aqueous phase was extracted with ether, and 5.5 M hydrochloric acid (23.6 ml, 130 mmol) was added. After concentration of the aqueous phase, the residue was extracted with ethanol, the potassium chloride which remained was separated off and the filtrate was concentrated. The product was thereby obtained as a colourless, oily compound in a yield of 95% (1.62 g).
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23]([O:25]C)=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Li+]>O.CO>[CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23]([OH:25])=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1nc(NC(=O)c2cc([N+](=O)[O-])cn2C)sc1CCC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.6 %

Procedure:
Methyl 5-isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylate (660 mg, 1.74 mmol; see step (iii) above) was suspended in a mixture of water (25 mL) and methanol (5 mL) containing lithium hydroxide (125 mg, 5.21 mmol). The reaction mixture was stirred vigorously for 48 h at room temperature. Some of the methanol was removed under partial reduced pressure at 50° C. The cooled solution was extracted with ether and the ethereal layer was discarded. The aqueous layer was cooled to 0° C. and acidified by adding HCl (Concentrated) dropwise with stirring. The pale yellow solid was filtered off, washed with water and dried overnight at 45° C. under reduced pressure to give the sub-title compound (584 mg, 92% yield), m.p.=296-300° C.
Reaction SMILES: Cl[C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:3]3[C:7]([N:8]=[C:9]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=24)=[CH:6][CH:5]=[N:4]3)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1c2c(nc3ccnn13)CCCCC2
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCCC4)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (221 mg, 1.0 mmol) in toluene (4 mL) was added 4-benzyloxyphenyl boronic acid (100 mg, 2.0 mmol), tetrakis(triphenylphosphine) palladium (5.7 mg, 0.0047 mmol), and 2M aq Na2CO3 (1.0 mL, 2.0 mmol). The reaction was flushed with argon and stirred at 80° C. overnight. The solution was cooled, followed by dilution with EtOAc (3 mL). The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated. The residue was purified via flash chromatography (5-30% EtOAc/Hexane) to provide 10-(4-benzyloxy-phenyl)-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (200 mg, 54% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:17].[N+]([O-])(O)=[O:19]>C(O)(CC)C>[CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:19].[OH2:17].[OH2:3].[OH2:3].[Al:6]
Reactant: O=[N+]([O-])O
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: CCC(C)O
Solvent: O
Product: [Al]
Reaction time: 3 h

Procedure:
Aluminum sec-butoxide was prepared in accordance with the process described in U.S. Pat. No. 4,242,271. A 75% mixed solution of this aluminum sec-butoxide in sec-butyl alcohol was hydrolyzed at 85° C. with a mixed solution of sec-butyl alcohol containing 30% of water to obtain an alumina slurry. After the alumina slurry was aged at 125° C. for 3 hours in an electromagnetically stirring autoclave, water was immediately added to the alumina slurry until a solids content was 20%, and the thus-treated alumina slurry was cooled. The pH of the alumina slurry was adjusted with a 3.8% aqueous solution of nitric acid to obtain Alumina Hydrate 6A. Alumina hydrate A obtained by drying colloidal sol of this alumina hydrate was determined by X-ray diffractometry and found to have a pseudoboehmite structure. At this time, the BET specific surface area was 175 m2/g, and the pore volume was 0.65 ml/g. Incidentally, the specific surface area and pore volume were determined by the following respective methods.
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[CH:4]1[C:3]2[CH:8]=[CH:9][C:10]3[C:11]4[CH:4]=[CH:3][CH:2]=[CH:15][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[O:1][C:5]=1[CH:6]=[O:7]
Reactant: OCc1cc2ccc3ccccc3c2o1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 134.9 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added naphtho[1,2-b]furan-2methanol (11A, 4.8 g, 24.2 mmol), barium manganate (Aldrich, 12.4 g, 48 mmol) and dry CH2Cl2 (500 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plug of SiO2 to remove inorganic salts and polar materials. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH2Cl2 /pentane to give after drying 4.02 g (84.7% yield) of phenanthro[1,2-b]furan-2-carbaldehyde, mp 123°, (C,H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([CH2:5]O)[OH:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>C(O)C.[Pd]>[C:7]([NH:11][CH2:5][C@H:3]([OH:4])[CH2:2][OH:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: O=C[C@H](O)CO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC[C@H](O)CO

Procedure:
30 g of (R)-glyceraldehyde, 36 cc of tert. butylamine in 800 cc of ethanol are hydrogenated over 8 g of 10 % palladium/carbon with H2 for 4 hours, the catalyst is filtered off and the solution is concentrated. (S)-1-tert.butylamino-2,3-dihydroxy-propane is obtained from ethyl acetate/ether (2:1) in the form of crystals having a M.P. of 76°-81°. [α] 20546 = -11.8° (c = 2.0; methanol).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10](O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.ClC(OC)=O.N1C=CC=CC=1.CO.[CH3:35][O:36][C:37]([O:39][C@H:40]1[CH2:45][CH2:44][C@H:43]2[C@H:46]3[C@H:56]([CH2:57][CH2:58][C@:41]12[CH3:42])[C@:54]1([CH3:55])[C:49](=[CH:50][C:51](=[O:59])[CH2:52][CH2:53]1)[CH2:48][CH2:47]3)=[O:38]>C1(C)C=CC=CC=1>[CH3:35][O:36][C:37]([O:39][C@H:40]1[CH2:45][CH2:44][C@H:43]2[C@H:46]3[C@H:56]([CH2:57][CH2:58][C@:41]12[CH3:42])[C@:54]1([CH3:55])[C:49](=[CH:50][C:51](=[O:59])[CH2:52][CH2:53]1)[CH2:48][CH2:47]3)=[O:38].[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@:20]3([CH3:21])[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH:9]=[CH:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: COC(=O)Cl
Agent: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2

Procedure:
This synthesis is depicted in FIG. 2. Several methods are known for the conversion of testosterone into Androsta-4,16-dien-3-one (Brooksbank et al., Biochem. J. (1950) 47:36). Alternatively, thermolysis (460°) of the methyl carbonate of testosterone gives Androsta-4,16-dien-3-one in 90% yield. 17β-Methoxycarbonyloxy-androst-4-en-3-one (IV) was prepared from testosterone (III. Fluka) with methyl chloroformate/pyridine (a) in 76% yield (after recrystallization from MeOH). M.p. 140°-141°, [a]D =+95.4° (C=1.10) - IR. (CDCl3): 1740s, 1665s, 1450s, 1280s, 1H-NMR. (360 Mhz): 0.87 (s, 3 H); 1.20 (s, 3 H); 3.77 (s, 3 H); 4.53 (br. t, J=8, 1 H); 5.75 (s, 1 H). A solution of the methyl carbonate IV in toluene was pyrolyzed (b) as described for 1. Recrystallization of the crude product from acetone at RT. gave pure ketone 4 in 90% yield. M.p. 127°-129.5°, [a]D =+118.9° (c=1.32) ([3]: m.p. 131.5°-133.5° (hexane), [a]D16 +123°±3.5° (c=1.03)). - IR. (CDCl3): 3050w, 1660s, 1615m. - 1H-NMR. (360 Mhz): 0.82 (s, 3 H); 1.22 (s, 3 H); 5.70 (m, 1 H); 5.73 (s, 1 H); 5.84 (m, 1 H).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:5](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].OO.[Li+].[OH-].S([O-])([O-])=[O:39].[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]([C@@H:4]([C@@H:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:5]([OH:6])=[O:39])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](c1ccc(F)cc1)c1cccc(F)c1
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1ccc(F)cc1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of the product from step 3 (0.7 g, 1.6 mmol) in 15 mL of THF and 5 mL of water was cooled to 0° C. in an ice-water bath. To the stirred solution was added hydrogen peroxide (0.7 mL of a 30% solution in water, 7 mmol) and LiOH (75 mg, 3.1 mmol), and the mixture was stirred at 0° C. for 45 min. The reaction was quenched by the addition of a solution of sodium sulfite (0.8 g, 7 mmol) in 5 mL of water, followed by a 0.5 M solution of aqueous NaHCO3 (16 mL, 8 mmol). The stirred mixture was warmed to ambient temperature and most of the THF was removed in vacuo. The aqueous mixture was extracted with two portions of dichloromethane to remove the chiral auxiliary. The aqueous phase was acidified to pH 1 with the addition of 6 N HCl and extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvent was removed in vacuo to give the title compound as a gum.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].Cl.[O:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]1>>[O:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:25]1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Reactant: N[C@H]1CCOC1
Agent: Cl
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@H]2CCOC2)nn1
Yield: 77 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) was converted, using (S)-tetrahydrofuran-3-amine hydrochloride instead of isopropylamine, to the title compound (100 mg, 77%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 3.5% methanol in dichloromethane). MS: m/e=361.0 [M+H]+.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1>C(Cl)(Cl)Cl.CC#N>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([N:30]([C:31]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[CH3:29])=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: CNc1ccc(C(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(N(C)C(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of acid 101 (0.5 g, 2.1 mmol) in CHCl3 (30 mL) and CH3CN (30 mL) at 0° C. was added oxalyl chloride (1.59 g, 12.6 mmol) and a catalytic amount of DMF. The resulting solution was stirred for 2 h at rt and concentrated in vacuo. The resulting residue was re-dissolved in CHCl3 and cooled to 0° C. To this mixture was added N-methyl-4-isopropyl aniline (0.78 g, 5.2 mmol) and the reaction was stirred overnight warming to rt. The reaction mixture was diluted with CHCl3 (30 mL) and washed with 1 N HCl (50 mL). The combined organic layers were washed with water (75 mL), dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel eluting with EtOAc/hexanes and EtOAc/MeOH to yield 393 as a light yellow solid (0.65 g, 84.4%). mp: 231-233° C. MS (APCI): m/z 370.2 [M+H]+. Anal. Calcd. For C19H23N5O3. 0.1H2O: C, 61.47; H, 6.30; N, 18.87. Found C, 61.28; H, 6.19; N, 18.57.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:30]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C21H25ClN6O2, 428.9