Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:40](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][N:13]([CH3:40])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A suspension of 4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (18 mg), potassium carbonate (14 mg) and iodomethane (4.7 mg) in acetonitrile (2 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through Celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: benzene/acetone=2/1) to give 4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole (4 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:24](Br)[C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:31][C:26]5[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:24]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(Br)Br
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 16 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][N:16]=1)[CH3:2]
Reactant: CCc1cc(O)cc(C)c1OCCCCOc1ccc(C(F)(F)F)cn1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.6 g of 3-ethyl-5-methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]phenol and 0.23 g of potassium carbonate, to which a solution of 0.28 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.50 g of 3-ethyl-5-methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (64% yield), nD23.0 1.5170.
Reaction SMILES: I[C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CS(C)=O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[O:3][C:2]([C:20]3[NH:19][N:18]=[CH:22][CH:21]=3)=[N:6][C:5]=2[C:7]([NH2:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: COc1ccc(-c2oc(I)nc2C(N)=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(-c2oc(-c3ccn[nH]3)nc2C(N)=O)cc1
Temperature: 150 °C
Yield: 42.9 %

Procedure:
To a mixture of 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide (0.025 g, 0.07 mmol), 1H-pyrazole-5-boronic acid (0.020 g, 0.18 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.003 g, 0.004 mmol) in acetonitrile (2 mL) and DMSO (0.5 mL) was added a 1M sodium carbonate solution (0.1 mL, 0.1 mmol) and the reaction heated in the microwave at 150° C. for 15 minutes. A further portion of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.003 g, 0.004 mmol) was added and the mixture heated at 150° C. for a further 10 minutes in the microwave. The reaction was diluted with EtOAc and washed 1M sodium carbonate solution. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO4 and passed through a MP-SH resin cartridge (500 mg). The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(1H-pyrazol-5-yl)oxazole-4-carboxamide (0.008 g, 0.03 mmol, 38%) as a white solid. 1H NMR (DMSO) 3.84 (3H, s), 6.90 (1H, br. d), 7.09 (2H, d), 7.62 (1H, br. s), 7.67 (1H, br. s), 7.97 (1H, br. s), 8.27 (2H, br. d), 13.50 (1H, br. s). LCMS (2) Rt: 1.98 min; m/z (ES+) 285.
Reaction SMILES: CN([CH:4]=[C:5]([C:9](=[O:12])[CH2:10][CH3:11])[C:6](=O)[CH3:7])C.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C[O-].[Na+]>CO>[CH3:7][C:6]1[NH:18][C:16](=[O:17])[C:15](=[CH:4][C:5]=1[C:9](=[O:12])[CH2:10][CH3:11])[C:13]#[N:14]
Reactant: N#CCC(N)=O
Reactant: CCC(=O)C(=CN(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reaction time: 3 h

Procedure:
A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4 hexanedione. A mixture containing said 3-dimethylaminomethylene 2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 265°-268° C. with decomposition. The mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful; however, the two compounds should be separable.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[Br:19])[CH3:8])([CH3:4])([CH3:3])[CH3:2].NN>>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C:10]1[C:11]([Br:19])=[CH:12][CH:13]=[CH:14][C:15]=1[NH2:16])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: NN
Product: CN(Cc1c(N)cccc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
To a warm solution of (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester from Preparation 2 (589 mg, 1.71 mmol), and a small (catalytic) amount of Ra(Ni) in TBF/MeOH (8 ml/9 ml) was added H2NNH2 (110 μl, 3.5 mmol). With stirring, the solution was heated under reflux for an hour and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The concentrated filtrate was purified by flash chromatography to give (2-amino-6-bromo-benzyl)-methyl-carbamic acid tert-butyl ester (371 mg, 69%). 1H NMR (CDCl3, 300 MHz) δ: 1.48(s, 9H), 2.80(s, 3H), 4.67(s, 2H); 6.56(m,1H), 6.90(m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][NH:35][CH3:36].CCN(CC)CC>C(Cl)Cl.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([O:34][CH3:33])[CH3:36])=[O:8])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (5.0 g, 1.0 eq), EDCI (8.3 g, 1.2 eq) and HOBt (5.8 g, 1.2 eq) in 150 mL CH2Cl2 were added N-methoxymethanamine hydrochloride (4.2 g, 1.2 eq) and Et3N (14.5 g, 4.0 eq) at rt, the mixture was stirred at rt overnight, water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (3.5 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.82 (brs, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.72 (dd, J=9.6 Hz, 2.8 Hz, 1H), 6.32 (d, J=9.6 Hz, 1H), 3.59 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:22][C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:23]([NH:22][C:17]2[CH:16]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]3)[CH:20]=[CH:19][N:18]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Reactant: Nc1cc2ccccc2cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1
Yield: 36.7 %

Procedure:
1-Boc-4-(2-chloropyridin-4-ylmethyl)piperazine (500 mg, 1.63 mmol) (Preparation B-14) was mixed with 3-aminoisoquinoline (234 mg, 1.0 equiv), Pd2(dba)3 (148 mg, 0.1 equiv), xantphos (140 mg, 0.15 equiv), and Cs2CO3 (735 mg, 1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound (250 mg, yield 61%) was obtained as yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]>>[C:10](=[O:11])([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCc1ccsc1
Product: O=C(OCCc1ccsc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using the method of Example 7a, 3-thiopheneethanol was treated with 4-nitrophenyl chloroformate to afford, after purification by flash chromatography (EtOAc:hexane (1:9)), the title product (56%); TLC, Rf =0.25, EtOAc:hexane (1:9).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[OH:14])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)[O:14][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O[Si](C)(C)C(C)(C)C)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(5-Benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.537 g, 1.26 mmol), tert-butyldimethylsilyl chloride (0.209 g, 3.78 mmol) and imidazole (0.095 g, 3.78 mmol) were combined in DMF (8 mL) and stirred at room temperature for 72 hours. Standard aqueous workup and silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([O-:18])=[O:17].[K+].OS(O)(=O)=O>>[N+:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)=[CH:2][CH:3]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCN1CCCC(c2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCN1CCCC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To ice cooled 3-phenyl-1-propyl-piperidine (4.6 g, 19.73 mmol) and KNO3 (2.254 g, 22.29 mmol) was added concentrated H2SO4. The reaction mixture was allowed to warm to room temperature and stirred for another 30 minutes. To the reaction mixture was added cautiously ice and subsequently the pH was adjusted to 9-10. The aqueous phase was extracted several times with ethyl acetate. The organic phases was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (5.2 g, 81% purity).
Reaction SMILES: [CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH2:16][OH:17])[CH2:14][CH2:13][CH2:12][CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].C[C@@H]1[C@@]2(CO)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2O)=CCC1>>[CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
In the same manner, substituting 4-androstene-17β,19-diol for the 1α-methyl-4-androstene-17β,19-diol above results in the preparation of 4-androstene-17,19-dione.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)n(C)c2c1
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc2nc(-c3ccc4oc(=O)n(C)c4c3)c(C)n2c1
Yield: 77.9 %

Procedure:
5-(3,6-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.85 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-3-methyl-2-benzoxazolinone (2.3 g) and 2-amino-5-methylpyridine (2.6 g). mp. 247°-249° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH:10]1([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=2[F:9])[NH2:5])[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: Nc1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(F)c(C2CC2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60.7 %

Procedure:
Mix 3-bromo-4-fluoro-aniline (415 mg, 2.18 mmol), cyclopropylboronic acid (244 mg, 2.84 mmol), K3PO4 (1.62 g, 7.64 mmol), triphenylphosphine (61 mg, 0.22 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), toluene (12 mL) and water (1 mL) under N2, stir at 100° C. for 16 hrs. Cool the reaction to 25° C., add water (10 mL), extract with EtOAc (10 mL×2). Combine the organic layers; wash with brine (15 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, PE:EtOAc=2:1) affords the target compound (200 mg, 61%).
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28](=[O:30])[CH3:29]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][C:28](=[O:30])[CH3:29])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 60 °C
Yield: 32.4 %

Procedure:
To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (500 mg, 1.668 mmol) in DMF (8162 μl) was added K2CO3 (692 mg, 5.00 mmol) followed by 1-chloropropan-2-one (178 μl, 2.502 mmol). This was heated to 60° C. for 30 min. The crude sample was purified via Biotage normal phase chromatography (25 g SNAP column, 0%-65%, 65%. hex/EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-one (192 mg, 0.540 mmol, 32.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 2.27 (s, 3H) 5.21 (s, 2H) 7.64 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.67 (s, 1H) 8.93 (d, J=4.80 Hz, 1H). MS: m/z: 356.1 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH2:13][CH2:12]1)C)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:6][NH:7][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH2:13][CH2:12]1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC[C@H]1CC[C@H](/C=C/CO)CC1

Procedure:
A solution of 200 mg (0.672 mmol) trans{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester in 2 ml 4M hydrogen chloride solution in dioxane was stirred for 30 minutes at room temperature. The reaction mixture was then concentrated under reduced pressure. The crude HCl-salt was triturated two times with dry ether and the crystalline product then dried for several hours at 45° C. and 15 mbar to give 155 mg (98.6%) of pure trans-3-[4-(2-methylamino-ethyl)-cyclohexyl]-(E)-prop-2-en-1-ol HCl-salt as colorless cristalls, MS: 198 (MH+).
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:25]([NH2:27])=[O:26])[CH:10]=[CH:11][C:12]=3[C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[NH:7][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(Cl)Cl>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:12]1[CH:11]=[CH:10][C:9]([C:25]([NH2:27])=[O:26])=[C:8]2[C:13]=1[C:14]1[CH2:15][CH2:16][CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][C:6]=1[NH:7]2
Reactant: CC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-acetyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Example 27-1, 30 mg, 0.081 mmol) and sodium borohydride (6.2 mg, 0.163 mmol) in methanol (1 mL) was stirred at rt for 1 h. The mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by preparative HPLC to provide two diastereomers of 5-(2,6-difluorophenyl)-2-(1-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide. Each one was partitioned between 1 M aqueous sodium hydroxide and DCM, followed by drying and concentration, to provide the separated racemic diastereomers of 5-(2,6-difluorophenyl)-2-(1-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide. The more polar diastereomer (Example 28-1) was a white solid (10 mg, 33%). 1H NMR (400 MHz, chloroform-d) δ 1.26 (d, J=6.59 Hz, 3H) 1.30-1.43 (m, 1H) 1.78-1.89 (m, 1H) 1.97-2.05 (m, J=12.74 Hz, 1H) 2.14-2.22 (m, 1H) 2.24-2.35 (m, 1H) 2.57 (dd, J=16.04, 10.77 Hz, 1H) 2.81 (dd, J=16.48, 5.05 Hz, 1H) 3.70-3.79 (m, 1H) 6.96-7.04 (m, 3H) 7.32-7.41 (m, 2 H) 10.05 (s, 1H). Mass spectrum m/z 371.1 (M+H)+. The less polar diastereomer (Example 28-2) was a white solid (8 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 1.26 (d, J=6.15 Hz, 3H) 1.34-1.40 (m, 1H) 1.42-1.53 (m, 1H) 1.75-1.90 (m, 2H) 2.24-2.35 (m, 1H) 2.68 (dd, J=16.26, 10.11 Hz, 1H) 2.94 (dd, J=16.26, 5.27 Hz, 1H) 3.80 (s, 1H) 6.96-7.05 (m, 3H) 7.34-7.40 (m, 2H) 10.05 (s, 1H). Mass spectrum m/z 371.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O)(=O)=O.II.[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24]>O.C1(C)C=CC=CC=1>[C:26]([CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:25][CH2:23][CH3:24])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: II
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), methanesulfonic acid (20 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with toluene (2×500 ml). The combined organic layers were washed with brine and concentrated under vacuum to yield 4-((carboethoxy)methoxy)benzaldehyde as an oily material (400 g, Y=94%, P=99%).