Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16].[Li]CCCC.[CH3:22][S:23]SC.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:23][CH3:22])[C:4]=1[CH2:15][OH:16]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(CO)c(SC)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Following the procedure of Flader et al.,22 alcohol 26 (0.521 g, 2.39 mmol) was dissolved in THF (9.0 ml) in a flame-dried 25 mL round bottom flask under Argon, and then cooled to 0° C. At 0° C. nBuLi (2.5 M in hexanes, 2.4 ml, 6.0 mmol) was added slowly, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. Dimethyldisulfide (0.50 mL, 5.6 mmol) was added slowly at room temperature and the reaction was stirred for another 30 minutes at room temperature before being poured into water, acidified with 2 M HCl, and extracted with ethyl acetate. The organic fractions were combined and washed with brine, dried over MgSO4, and filtered. The resulting solid was purified via flash column chromatography (1:4 EtOAc:hexanes) to afford 56 (0.446 g, 1.69 mmol, 71%) as a green solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.Cl.[CH:21]1([C:26]2[N:27]=[C:28]([NH2:31])[S:29][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:26]2[N:27]=[C:28]([NH:31][C:4]([C:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=4)[CH:9]=[C:8]([CH3:19])[N:7]=3)=[O:5])[S:29][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1nc(C2CCCC2)cs1
Agent: Cl
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2nc(C3CCCC3)cs2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Cyclopentyl-thiazol-2-ylamine, hydrochloride instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=383 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].Cl.C(N(CC)CC)C.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:28][C:29]([CH3:34])([CH3:33])[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19])=[O:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc2ccn(CCCN)c(=O)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(CCCNC(=O)C(C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of methyl 2-(3-aminopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.13 g, 0.44 mmol) dissolved in methylene chloride (8 mL) was added triethylamine (0.18 mL, 1.3 mmol) and 2,2-dimethylpropanoyl chloride (0.08 mL, 0.66 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (40% to 90% EtOAc/hexanes) to afford methyl 2-{3-[(2,2-dimethylpropanoyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.14 g, 92%). LC-MS: (FA) ES+ 345.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Dimethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.070 g, 0.166 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1.0 mL). The resulting reaction mixture is stirred at room temperature for 5 hours. Concentrated to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.030 g). 1HNMR (400 MHz, DMSO-d6) δ: 2.44 (s, 6H), 3.90 (bs, 2H), 4.28-4.30 (m, 1H), 4.31-4.33 (m, 0.5H), 4.41-4.45 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.0 Hz, 1H), 5.93 (d, J=4.56 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.53 (d, J=8.16 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.11-8.13 (m, 1H), 8.84-8.87 (m, 2H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.C1COCC1>S(Cl)(Cl)=O>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: Nc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.1 %

Procedure:
A suspension of 3,5-dichloroisonicotinic acid (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) δ 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[C:15](OC)([CH3:17])[CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][CH:15]([CH3:17])[CH3:16])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: COC(C)(C)OC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
4,5-difluoro-2-nitroaniline (3.48 g, 20 mmol), 2,2-dimethoxypropane (11.9 mL, 100 mmol), and trifluoroacetic acid (1.6 mL, 21 mmol) were dissolved in toluene (40 mL) and stirred at room temperature for 1 h. A boron-pyridine complex (2.12 mL, 21 mmol) was slowly added. The reaction mixture was stirred for 20 h. The solvent was evaporated in vacuo, and the residue was taken up into water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (30:1) to give 2.42 g (56%) of the title compound as a bright orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[C:14]1([CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:21](=[O:22])[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:24][CH3:25])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(NC(=O)C(CC)c3ccccc3)sc2c1
Reaction time: 16 h

Procedure:
6-Ethoxy-benzothiazol-2-ylamine (39 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25%), ESI-MS m/z calc. 340.1, found 340.9 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([NH:19][CH:20](NC=O)NC=O)=O.CN(C)C=O>O>[C:1]1([C:7]2[C:8](=[O:16])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:20][NH:19][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNC(NC=O)NC=O
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c[nH]cc1-c1ccccc1

Procedure:
A 1.4 g. portion of 1,3-diphenyl-2-propanone was mixed with 1.0 g. of tris(formylamino)methane in 20 ml. of dimethylformamide. The reaction mixture was stirred at reflux temperature for 3 hours. The mixture was then cooled to approximately room temperature, and poured into water. The precipitated solids were separated by filtration, and the solids were suspended in chloroform. The chloroform was then filtered, and the solids remaining were washed first with water, and then with chloroform. The yield was about 100 mg. of 3,5-diphenyl-4(1H)-pyridone, m.p. greater than 335° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (90 mg, 0.22 mmol) in EtOH (10 ml) was added 10% palladium on activated carbon (90 mg). The resulting suspension was shaken on a Parr hydrogenator at 60 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (90 mg, 100%), which was used without further purification.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9]([C:11]1([CH2:21]Br)[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].O>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1([CH2:21][S:3][C:1](=[O:4])[CH3:2])[CH2:20][CH2:19][C:14]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C1(CBr)CCC2(CC1)OCCO2
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CSC(C)=O)CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 101.6 %

Procedure:
Potassium thioacetate (1.0 g) was added to a solution of 8-bromomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) in DMF (30 ml) and the solution was heated at 80° C. for 4 h. The mixture was then added to water (100 ml) and extracted with ether. The solvent was washed with water, bicarbonate solution and brine, then dried (MgSO4) and evaporated to give the title compound (1.0 g) as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6](/[N:8]=[C:9](\[NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=2)/[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12]O)=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6](/[N:8]=[C:9]2\[NH:16][C:17]3[N:21]([N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:18]=3)[CH2:12][C:11]([CH3:15])([CH3:14])[NH:10]\2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)N/C(=N/C(=O)c1ccc(F)cc1)Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)Cn2nc(-c3ccc(F)cc3)cc2N/C(=N\C(=O)c2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of (Z)-4-fluoro-N-(((3-(4-fluorophenyl)-1H-pyrazol-5-yl)amino)((1-hydroxy-2-methylpropan-2-yl)amino)methylene)benzamide (25 mg, 0.06 mmol) in anhydrous THF (0.5 mL) under a nitrogen atmosphere was added triphenylphosphine (19 mg, 0.07 mmol) followed by diisopropyl azodicarboxylate (DIAD) (14 μL, 0.07 mmol). The reaction mixture was stirred at room temperature for 30 minutes and purification by silica chromatography (EtOAc:hexanes) afforded the title compound (21 mg, 88% yield). LCMS (ESI). found (M-H)−, 394.15; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.35 (s, 1H), 8.18 (m, 2H), 7.75 (m, 2H), 7.31 (m, 4H), 7.17 (s, 1H), 3.75 (s, 2H), 1.39 (s, 6H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[CH2:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (−50° C.) suspension of methyltriphenylphosphonium bromide (1.2 g, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium bis(trimethylsilyl)-amide (3.4 mL, 3.4 mmol), and the resulting mixture was stirred for 1 h at room temperature. The resulting cloudy yellow solution was re-cooled to −30° C., and 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (0.5 g, 1.68 mmol) was added. The resulting slightly yellow solution was stirred at room temperature for 3 h, then diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and purified by column chromatography on silica gel using 15-30% ethyl acetate in hexanes as eluant to give 471 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[CH3:23]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 8 h

Procedure:
10.0 g of 11β-fluoroandrost-4-ene-3,17-dione [U.S. Pat. No. 3,966,713 (1976)] is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 8 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is chromatographed on silica gel with an acetone-hexane gradient. Yield: 7.8 g of 11β-fluoro-3-methoxyandrosta-3,5-dien-17-one as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27]1.CCN=C=NCCCN(C)C>>[O:26]1[CH2:30][CH2:29][CH:28]([C:31]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:32])[CH2:27]1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)C1CCOC1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)C4CCOC4)c3)c2c1
Yield: 15.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with tetrahydro-3-furoic acid (0.10 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 40 mg (15% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.7 (t, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4 (s, 1H), 3.9 (m, 1H), 3.82–3.68 (m, 2H), 3.3–3.1 (m, 2H), 2.2–2.0 (m, 2H); ES-MS (m/z) 351 [M+H]+.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: NCCN
Solvent: CCO
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
95% Ethanol (0.5 mL) was added to a mixture of nickel (II) chloride (105 mg, 0.81 mmol) and sodium borohydride (15 mg, 0.40 mmol). The mixture immediately turned black. After 15 min at rt, ethylene diamine (86 μL, 1.29 mmol) was added. After 15 min at rt, a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (from Example 1, step 3, 43.3 mg, 0.16 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 16.7 mg (38%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1cncc1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added 5-[(aminooxy)methyl]-1-methyl-1H-imidazole 100 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 101 (0.40 g, quantitative yield) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl.[CH3:10][C:11](=O)[CH:12]=[CH:13][CH3:14].[OH-].[Na+]>C(OCC)(=O)C>[CH3:10][C:11]1[CH:12]=[C:13]([CH3:14])[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1O
Reactant: CC=CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
In a three-necked flask were placed 33 g of o-aminophenol and 207 g of concentrated hydrochloric acid and the mixture was heated to the reflux temperature and stirred for 1 hour. To the mixture being heated under reflux was slowly added 51 g of 3-penten-2-one with a purity of 65% over 2 hours and stirring was continued for another 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 300 ml of a 48% aqueous solution of NaOH was added until the aqueous phase became alkaline. Ethyl acetate was added further, the organic layer was recovered and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by gas chromatography, recrystallized from hexane and the crystals collected by filtration were washed with hexane and dried at 80° C. under reduced pressure to give 18.9 g of 2,4-dimethyl-8-quinolinol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>>[CH3:23][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1cc(C)cc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cc(C)cc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.53 mmol) and 1-iodo-3,5-dimethylbenzene (0.08 mL, 0.55 mmol) according to the general procedure IC to give 128 mg (83%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.59 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.21-7.19 (m, 2H), 7.07-7.05 (m, 2H), 6.90-6.89 (m, 2H), 6.78-6.77 (m, 1H), 2.72-2.67 (t, 2H, J=7.8 Hz), 2.42-2.37 (t, 2H, J=7.8 Hz), 2.05 (s, 6H); 13CNMR (CDCl3) δ 173.1, 140.7, 137.8, 131.7, 130.1, 129.2, 128.3, 122.9, 121.4, 89.4, 88.6, 51.6, 35.4, 30.8, 21.1; ESI-MS m/z 315.1 (MNa+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10][CH3:11].[C:14]1(/C=C/C(=O)C)[CH:19]=CC=C[CH:15]=1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[C:9]1[CH:19]=[CH:14][CH:15]=[CH:11][CH:10]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5) using (3E)-4-phenyl-3-buten-2-one (20 g, 137 mmol). LCMS E-S (M+H)=215.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.2-12.3 (br s, 1H), 7.88-8.00 (br s, 3H), 7.43-7.51 (m, 3H), 7.29-7.38 (m, 2H), 6.08 (s, 1H), 3.67-3.70 (m, 2H), 2.23 (s, 3H).