Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:32]/[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:35][CH:34]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)CC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: O=Cc1ccc(OCc2ccccn2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Temperature: 70 °C
Yield: 71.9 %

Procedure:
In a 20 mL reaction vessel were placed 31.0 mg (136 μmol) of 6-(1H-indol-6-yl)hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 41.3 mg (72% yield) of the title compound as a yellow powder.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[CH3:11][O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCCO)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a cold (−15° C.) solution of Z-Glu-OMe (1.5 g) in THF (70 mL) was added N-methylmorpholine (0.616 mL) followed by isobutyl chloroformate (0.731 mL) dropwise. After 30 min stirring at −15° C., NaBH4 (576 mg) was added, followed MeOH dropwise. The reaction mixture was stirred at −10° C. for 15 min and quenched by the addition of 1M KHSO4 solution. The mixture was extracted with EA. The org. phase was washed with water, dried (Na2SO4) and evaporated off to give 1.5 g of the crude product as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 4 (3.5 g, crude material), morpholine (0.99 g), potassium carbonate (2.89 g), and potassium iodide (1.66 g) in DMF (22 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated to a residue. The crude material was purified by flash chromatography (silica gel, 30-50% ethyl acetate/hexanes) to yield compound 5 as a yellow solid.
Reaction SMILES: [OH-].[Na+].[N:3]1([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([C:15]4[CH:16]=[C:17]([NH:26]C(=O)C)[CH:18]=[C:19]([N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)[CH:20]=4)[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1>C(O)C.C(OCC)(=O)C>[N:3]1([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([C:15]4[CH:16]=[C:17]([CH:18]=[C:19]([N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)[CH:20]=4)[NH2:26])[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(-n2cccc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Yield: 85 %

Procedure:
A mixture of 10% NaOH (5 ml) and the compound of Example 96 (1.45 g, 3.79 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was removed under reduced pressure and the residue was purified by column chromatography over silica gel to give the product in 85% yield (1.1 g).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]([CH3:55])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C@@:33]3([O:51][CH3:52])[CH2:37][N:36](C(OCC[Si](C)(C)C)=O)[C@H:35]([C:47]([O:49][CH3:50])=[O:48])[CH2:34]3)=[CH:29][CH:28]=2)=[C:23]([CH:53]=[CH2:54])[CH:22]=1>C1COCC1>[CH3:55][N:20]([CH3:19])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C@@:33]3([O:51][CH3:52])[CH2:37][NH:36][C@H:35]([C:47]([O:49][CH3:50])=[O:48])[CH2:34]3)=[CH:31][CH:32]=2)=[C:23]([CH:53]=[CH2:54])[CH:22]=1
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1cc(N(C)C)ccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
TBAF (1.0M in THF, 1.7 mL, 1.7 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-1,2-dicarboxylate (231 mg, 0.440 mmol) in THF (5 mL) and stirred at r.t. for 1 hr. The reaction was evaporated to give crude (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (167 mg, 0.439 mmol, 100% yield) as an orange oil used directly in next steps with no purification. LCMS: rt=1.01 min. [M-OMe]+=349; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 μL; wavelength=220.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
A solution of (2S,4R)-1-benzyl-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (320 mg) in a mixture of methanol (5 ml) and 1N-sodium hydroxide (3 ml) was stirred at room temperature for 3 hours and the volatile solvent was evaporated in vacuo. Water (20 ml) was added to the residue and the aqueous solution was adjusted to pH 7 with 1N-hydrochloric acid. The precipitated solid was collected by filtration and dried in vacuo to give (2S,4R)-1-benzyl-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (176 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(O)[CH2:3]1.O=P(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3]1
Reactant: CC1(C)CC(C)(C)CC(O)(C#Cc2ccccn2)C1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C=C(C#Cc2ccccn2)CC(C)(C)C1
Yield: 79.3 %

Procedure:
3,3,5,5-Tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (200 mg, 0.78 mmol) was dissolved in pyridine. POCl3 (153 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 6 h. After cooling, the POCl3 and pyridine were removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 hexane:ethyl acetate to afford 2-[(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)-ethynyl]pyridine (148 mg, 80% yield) as a light tan solid. M.p. 55-56° C. 1H NMR (CDCl3, 300 MHz) Δ8.56 (m, 1H), 7.62 (m, 1H), 7.40 (d, J=7 Hz, 1H), 7.18 (m 1H), 6.09 (s, 1H), 2.00 (s, 2H), 1.35 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([N:50]=[C:51]=[O:52])=[CH:46][CH:45]=1.ClCCl>O>[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])=[CH:46][CH:45]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Solvent: O
Solvent: ClCCl
Product: CN(C)c1ccc(NC(=O)Nc2ccc3c(c2)CCN3c2nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c2ncn3C(=O)OC(C)(C)C)cc1
Reaction time: 20 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 32.2 mg of 4-dimethylaminophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 20 hours at ambient temperature, 0.5 ml of water is added, and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 55 mg of expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:20]=[C:21](Br)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:19]1[CH:24]=[C:23]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 76.3 %

Procedure:
A mixture of 3A (1.46 g, 6.9 mmol) and 3-nitrobromobenzene (0.81 g, 4.0 mmol) in DME (40 mL) and 2.0 M Na2CO3 (8.0 mL) was degassed by bubbling argon for 5 min. To this solution, Pd(PPh3)4 (280 mg, 0.25 mmol) was added. The mixture was heated at 90° C. for 5 h. After cooling to rt, it was extracted with EtOAc and dried over Na2SO4. The product was purified by silica gel chromatography (CH2Cl2/hexanes=1/5) to give 4A (880 mg, 75% yield) as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.37 (s, 9H) 6.28 (t, J=3.52 Hz, 1H) 6.33 (dd, J=3.52, 1.76 Hz, 1H) 7.41 (dd, J=3.52, 1.76 Hz, 1H) 7.59 (m, 1H) 7.73 (d, J=7.91 Hz, 1H) 8.16 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CC(O)=O.[Pt](=O)=O>[CH:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: c1ccncc1
Reactant: C=CC
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCCCC1
Yield: 137.9 %

Procedure:
A solution of O-protected pyridine propene (1.5 g, 5.7 mmol) and platinum(IV) oxide (258 mg) in MeOH (20 mL) and AcOH (4 ml) was hydrogenated 6 h at 40 psi. The final solution was filtered over CELITE, rinsed with MeOH then concentrated. The residue was diluted with 1 N NaOH, extracted with DCM and AcOEt, and the combined organic layers were dried over Na2SO4 and concentrated. The residue was quickly passed through a plug of silica gel (eluting hexanes/AcOEt 8:2) to provide 1.0 g (65%) of O-protected isopropyl piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.C[N:23](C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:23])=[O:13])[S:10][C:3]=12
Reactant: CN(C)C=O
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc2nccc(Cl)c2s1
Yield: 100 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (1.0 g, 4.7 mmol), thionyl chloride (7.0 mmol, 3.5 mL), CH2Cl2 (40 mL), and DMF (0.4 mL) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, the resulting residue was suspended in CH2Cl2 (60 mL), and NH3 gas was bubbled through the mixture for 10 min. The reaction mixture was filtered to give the title compound as a white solid (1.17 g, 100%). MS: 213.0/215.1 (MH+); HPLC Rf: 3.44 min; HPLC purity: 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: Cc1cccc(Br)n1
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(C#N)c2ccc(F)cc2)n1
Yield: 83.8 %

Procedure:
To a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-6-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. under argon atmosphere, and the mixture was heated to reflux for 3 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 2-(α-cyano-4-fluorobenzyl)-6-methylpyridine (5.51 g) as yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11]>[Zn].N>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: N
Agent: [Zn]
Product: Fc1cc(F)c(F)nc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
80 g of pentafluoropyridine (Janssen) and 111.5 g of zinc power were added to 560 ml of 20% aqueous ammonia. The resulting mixture was stirred at room temperature for 5 hours, and then gently refluxed to remove water using a Dean-Stark trap, to obtain 60.4 g (yield: 84.5%) of the title compound.
Reaction SMILES: N1C=CC(OCC#C)=CC=1.[Li]CCCC.[CH3:16][C:17](=[O:38])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@@H:25]([CH2:26][C:27](=O)[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH3:16][C:17](=[O:38])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C#CCOc1ccncc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of propargyl 4-pyridyl ether (prepared according to (Thummel et al, J. Org. Chem. 1978, 43 4882) (173 mg, 1.3 mmol) in dry THF (15 mL) was treated with n-BuLi (2.5M in THF, 1,3 mmol, 0.52 mL) at −70° C. After stirring the mixture at −75° C. for 0.5 hr, a solution of 5β-pregnan-3,20-dione, cyclic 20-(1,2-ethanediyl acetal) (180 mg, 0.5 mmol) in THF (15 mL) was added and the mixture was stirred at −78° C. for 20 min. The cooling bath was removed and the stirring was continued at rt for 1 hr. The mixture was quenched with NH4Cl solution (2 mL). The solvent was removed and the residue was then dissolved in acetone (25 mL). After adding 2N HCl (2 mL) the s olution was stirred at rt for 20 min. Sat. NaHCO3 soln. was added to neutralize the acid. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product (250 mg). This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with CH2Cl2:acetone mixture (90:10) gave 3α-hydrocy-3β-[3-4′-pyridinyloxy)-1-propynyl]-5β-pregnan-20-one (145 mg) as a colorless solid; mp 84-90° C.; TLC Rf (CH2Cl2:acetone 85:15)=0.17.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(Cc2ccccc2)CCN1C

Procedure:
To a solution of 2-[1-(1-methylpiperazine-2-yl)-ethylamino]-4-[benzimidazol-1-yl]-pyrimidine (EXAMPLE 20; 3 mg) in 4 mL of DMSO was added benzyl bromide (2 μL) and K2CO3 (2.2 mg). The mixture was stirred for 2d at room temperature, then diluted with 5 mL of EtOAc and poured into 10 mL of 1N HCl. The phases were separated and the aqueous phase was basified (pH>11) with 5N NaOH and extracted with 4×5 mL of EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2—MeOH to provide 1.9 mg of the title compound. Mass spectrum (ESI) 428.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=2)[O:13][CH2:14][CH:15]=O)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[CH3:19][O:18][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[C:6](=[O:7])[C:2]([CH3:1])([CH3:32])[N:3]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[C:4]2=[O:20])=[CH:17][C:12]=1[O:13][CH2:14][CH2:15][NH:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCC=O
Product: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCCNC1CCN(C)CC1

Procedure:
The title compound was prepared in analogy to example 51e by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-acetaldehyde as starting material and 4-amino-1-methylpiperidine instead of morpholine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]2[CH:12]=[C:11]([CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH2:66][NH2:67])([CH3:65])[CH2:62][CH2:63][CH3:64])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH3:65])([CH2:62][CH2:63][CH3:64])[CH2:66][NH:67][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:57])([CH3:56])[CH3:55]
Reactant: Cc1cc(OCc2ccccc2)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 240 mg (0.81 mmol) of 7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 139A) in 12 ml of tetrahydrofuran was admixed with 132 mg (0.97 mmol) of 1-hydroxy-7-azabenzotriazole and 186 mg (0.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was admixed with 0.422 ml (2.43 mmol) of N,N-diisopropylethylamine and 210 mg (0.97 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A. The mixture was stirred at room temperature for a further 18 hours, and the contents were then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane/ethyl acetate, gradient 0% to 50%), which gave 370 mg (65% yield, 71% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:26]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[Cl:27].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:27])=[C:16]([Cl:15])[C:26]=4[CH2:25][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589 =-6.87 (c=0.44, methanol).