Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:28][OH:29])[CH2:23]5)=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.C=O.F[C:40](F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3SC(N4CCN(C)[C@@H](CO)C4)=NC3=O)=CC=2)C=N1>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:40])[C@@H:24]([CH2:28][OH:29])[CH2:23]5)=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:34])([F:35])[F:36])[CH:3]=1
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO
Agent: C=O
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one and formaldehyde following procedure used for compound of example 195.
Reaction SMILES: [BrH:1].BrBr.[NH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1>C(O)(=O)C>[BrH:1].[Br:1][CH:6]1[C:7](=[O:10])[CH2:8][CH2:9][NH:4][CH2:5]1
Reactant: O=C1CCNCC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1CCNCC1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.7 mL 33% HBr in acetic acid and 11.4 g bromine in 30 mL acetic acid were added slowly to a stirred solution of 10 g piperidin-4-one in 60 mL acetic acid at RT. The reaction mixture was stirred for additional 45 min at ambient temperature and the acetic acid was completely removed under reduced pressure. The residue was dissolved in 200 mL acetone and refluxed for 1 h, cooled, filtered and washed with acetone and dried to give 15.2 g of the desired product, (M+H)+: 180.
Reaction SMILES: [CH2:1]([S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][C:10]=1[O:31][CH3:32])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[Mn+2]>[CH2:1]([S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:19]=2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][C:10]=1[O:31][CH3:32])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1CCCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1cc(C=O)ccc1CCCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
7.9 g (9.1 mmol) of manganese oxide is added to a solution of 4.2 g (9.1 mmol) of 4-[3-(2-butoxy-4-hydroxymethyl-phenyl)-propyl]-2-methoxy-phenyl 1-butane sulfonate in 300 ml of dichloromethane. The reaction mixture is stirred for 15 hours at room temperature. The reaction mixture is filtered on Celite, and rinsed with dichloromethane. The solvents are evaporated. 3.95 g (94%) of 4-[3-(2-butoxy-4-formyl-phenyl)-propyl]-2-methoxy-phenyl 1-butane sulfonate is obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:20][O:21][CH2:22][C@H:23](O)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:5]=[C:4]([O:19][C@@H:23]([CH3:24])[CH2:22][O:21][CH3:20])[CH:3]=1
Reactant: COC[C@@H](C)O
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)cc(Br)c2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC[C@H](C)Oc1cc(Br)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
3-Bromo-5-[4-(methylsulfonyl)phenoxy]phenol (4.86 g, 14.2 mmol) synthesized in Example (1c) was dissolved in toluene (100 mL), and (R)-(−)-1-methoxy-2-propanol (1.77 mL, 18.1 mmol) and triphenylphosphine (4.10 g, 15.6 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 7.75 mL, 17.1 mmol) was added dropwise over 10 minutes and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (100 mL) and ethyl acetate (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (5.06 g, yield 86%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][S:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.ClCCl.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]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([S:11][CH3:10])[CH:13]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CSc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1cccc(Nc2cc(Cl)nc(Cl)c2)c1

Procedure:
To 2,6-dichloro-4-iodopyridine (1.3715 g, 5 mmol) dissolved in toluene (30 mL) were added 3-methylthioaniline (0.73 mL, 6 mmol), tris(dibenzylidene-acetone)dipalladium (90.6 mg, 0.1 mmol), 1,3-bis(diphenylphosphino)propane (80.0 mg, 0.2 mmol), and sodium-tert-butoxide (672.1 mg, 7 mmol). The resulting mixture was allowed to stir at reflux for 12-18 hours. The sample was diluted in dichloromethane and filtered through Celite™. The Celite™ was washed with dichloromethane and the filtrate was washed two times with water and one time with brine. The organic phase was dried over potassium carbonate and concentrated by rotary evaporation. The resulting sample (9) was dried for 12-18 hours under vacuum. The sample was used without purification.
Reaction SMILES: CC1(C)COB(C2C=CC(OC3CN(C(=O)C)C3)=CC=2)OC1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[Cl:33])[NH:29][CH:28]=[C:27]2[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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].C(OCC)(=O)C>[Cl:33][C:32]1[CH:31]=[C:30]2[C:26]([C:27]([CH:34]=[O:35])=[CH:28][NH:29]2)=[CH:25][CH:24]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)N1CC(Oc2ccc(B3OCC(C)(C)CO3)cc2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(Cl)ccc12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of 1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]azetidin-1-yl}ethanone (130 mg, 0.43 mmol) in toluene (5 mL) was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (134 mg, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.045 mmol), and 2 M aqueous potassium carbonate (0.86 mL, 1.72 mmol) and ethanol (1.7 mL). The mixture was degassed with nitrogen for 3 min and heated to 110° C. by microwave irradiation for 1 h. The mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL) and washed with brine (2×15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate=20:1 to 4:1) to give [(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde (70 mg, 44%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[N:10][C:11](OCC)=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cn1
Agent: [Pd]
Solvent: CO
Product: c1cncc(C(CC2CCCC2)c2cc3cccnc3[nH]2)c1
Temperature: 50 °C
Yield: 20.8 %

Procedure:
A mixture containing 5-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-1H-pyridin-2-one (prepared as in Example 108, 100 mg, 0.33 mmol) and 10% palladium on activated carbon (80 mg) in methanol (20 mL) was heated at 50° C. under hydrogen (5 atm) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-(2-cyclopentyl-1-pyridin-3-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine (20 mg, 10%): LC/MS m/e calcd for C19H21N3 [M+H]+ 292.40, observed 292; 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (m, 2H), 1.49 (m, 2H), 1.58-1.90 (m, 5H, H), 2.16 (m, 1H), 2.30 (m, 1H), 4.43 (t, J=7.8 Hz, 1H), 6.54 (s, 1H), 7.32 (dd, J=6.1, 7.6 Hz, 1H), 7.48 (m, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.23 (m, 2H), 8.58 (d, J=4.4 Hz, 1H), 8.73 (s, 1H), 12.00 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 4 and 4-iodophenol (5.08 g) were dissolved in tetrahydrofuran (100 mL), triphenylphosphine (6.06 g) and diethyl diazodicarboxylate (4.02 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (7.5 g) as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=3[Cl:28])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Yield: 98 %

Procedure:
Add pyridine (0.66 mL, 8.21 mmol) to a solution of 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 2.0 g, 6.84 mmol) in dichloromethane (35 mL) at 0° C. Stir and add 2-chloro-4-fluorobenzoyl chloride dropwise (1.45 g, 7.52 mmol). Stir at 0° C. for 30 min and 1 hr. at room temperature. Dilute with dichloromethane (30 mL) and wash with sodium hydroxide (1N, 2×25 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexanes [20-40%] to give the title compound (3.0 g, 98%). Mass spectrum (ion spray): m/z=449.0 (M+1); 1H NMR (CDCl3): 7.87 (bs, N—H), 7.80 (dd, J=6.1 Hz, 8.6 Hz, 1H), 7.48 (s, 1H), 7.28-7.24 (m, 1H), 7.21 (dd, J=2.5 Hz, 8.4 Hz, 1H), 7.11 (td, J=2.2 Hz, 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.73 (dd, J=2.2 Hz, 8.4 Hz, 1H), 4.52 (septet, J=3.6 Hz, 1H), 3.69 (ddd, J=3.7 Hz, 7.7 Hz, 13.6 Hz, 2H), 3.35 (ddd, J=3.9 Hz, 7.7 Hz, 13.6 Hz, 2H), 1.97-1.89 (m, 2H), 1.81-1.72 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:20]1([S:26][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 70 °C
Yield: 96.9 %

Procedure:
To a solution of 12.0 g (41.6 mmol) of N-[(4-fluorophenyl)sulfonyl]glycine, 1,1-dimethylethyl ester from Example 5a and 12.8 mL (125 mmol) of thiophenol in 80 mL of anhydrous dimethylformamide, previously degassed by passing nitrogen through the solution, was added 17.3 g (125 mmol) of powdered potassium carbonate. The mixture was vigorously stirred and warmed to 70° C. and maintained there for 13 hours, cooled and ethyl acetate and water added. The organic layer was separated, washed four times with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford crude product. This was triturated with diethyl ether and hexanes, and the solids filtered and air dried to yield 15.3 g of title compound N-[[4-(phenylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, m/e=386 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:12][N:13]([CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)[C:9](=[O:10])[O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1CCNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27 %

Procedure:
Cbz-Cl (7.2 ml, 21.259 mol, 1.5 eq., 50% solution in toluene) was added at 0° C. to a mixture of 4-(methylamino)piperidin-2-one (1.814 g, 14.173 mmol, 1.0 eq.) and K2CO3 (3.91 g, 28.346 mmol, 2.0 eq.) in THF (50 ml) and the mixture was stirred for 14 hours at RT. After monitoring by TLC, the reaction mixture was diluted with DCM (300 ml), washed with water and saturated NaCl solution (in each case 150 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox, 1% MeOH in DCM). Yield: 27% (1.0 g, 3.82 mmol)
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:7][CH3:8].[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([CH:29]=[O:30])=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[C:11]([O:10][C:6](=[O:9])[CH:7]([CH3:8])[CH:29]([C:19]1[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[OH:30])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Reactant: CCC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C(=O)OC(C)(C)C)C(O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A first intermediate compound, 7-Chloro-3-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: Diisopropyl amine (freshly distilled over sodium, 12.8 mL, 91.4 mmol, 2.2 equiv.) was dissolved in Et2O (40 mL) and cooled to −78° C. Butyl lithium (2.5 M solution in hexane, 37.0 mL, 91.4 mmol, 2.2 equiv.) was added slowly under nitrogen atmosphere. The mixture was stirred for 15 min and t-butyl propionate (13.8 mL, 91.4 mmol, 2.2 equiv.) was added as a solution in dry THF (20 mL). The reaction mixture was stirred for 30 min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (10.0 g, 42.0 mmol, 1.0 equiv.) was added as a solution in a minimum amount of dry THF (35 mL). A bright yellow precipitate was formed within 10 min and stirring became difficult. The reaction was allowed to warm up to RT. The reaction mixture turned dark red and was poured into saturated NH4Cl (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. 3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester was obtained as a yellow thick syrup which upon drying under high vacuum became a foamy solid (20.0 g, crude). The product was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=O)[CH:4]=1.[CH:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)(=O)C>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[C:12](\[CH2:13][CH2:14][CH2:15][CH3:16])/[CH:11]=[O:17])[CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: CCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCC/C(C=O)=C\c1cccnc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
6.0 g (0.15 mol) of sodium hydroxide were added to a solution of 160.5 g (1.5 mol) of pyridine-3-carbaldehyde in 750 ml of methanol. Thereafter, 150.0 g (1.5 mol) of hexanal were added dropwise in the course of 3 hours at room temperature. Stirring was carried out for 1 hour, the pH was brought to 6 with acetic acid and the solvent was then evaporated under reduced pressure. The residue was taken up in a water/dichloromethane mixture and the organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure. Distillation gave 190 g (67% of theory) of E-2-(3-pyridylmethylidene)-hexanal as a yellow oil of boiling point 132°-134° C./2 mbar.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1cc(N2CCOCC2=O)ccc1N
Yield: 60 %

Procedure:
A solution of 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile (1.1 g) in THF (80 ml) was hydrogenated at 1 atm in the presence of Pd/C 10% (350 mg) at room temperature. The reaction mixture was filtered through decalite and precipitated (AcOEt/heptane) to yield 2-amino-5-(3-oxo-morpholin-4-yl)-benzonitrile as a white solid (580 mg). MS: 218.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]1[O:38][C:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=2)=[N:28][N:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2nnc(/C=C/C(=O)NNC(=O)c3ccc(C#N)cc3)n2-c2ccccc2Cl)nc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nnc(/C=C/c3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Reaction time: 2 h

Procedure:
(E)-N′-(3-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)acryloyl)-4-cyanobenzohydrazide 10 was dissolved into dichloromethane (10 mL) and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give (E)-4-(5-(2-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)benzonitrile as a yellow solid. Yield: 0.035 g, 12.7%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: Brc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Br)cc1

Procedure:
Bromobenzene (0.5 mL), acryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (1207.0 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)CCN.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]>[Cu]I.O1CCOCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])[CH:15]=1
Reactant: O=C1CCCN1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccnc1
Temperature: 125 °C
Yield: 93.7 %

Procedure:
In a sealed flask, a stirred mixture of CuI (37 mg, ˜0.2 mmol) and potassium carbonate (2.70 g, 19.5 mmol) was degassed for 15 min. N,N-dimethylethylenediamine (146 μL, ˜1.0 mmol), 3-iodopyridine (2.00 g, 9.8 mmol), 2-pyrrolidinone (˜1 g, 11.7 mmol) and 1,4-dioxane (10 mL) were added, respectively (A. Klapars, J. C. Antilla, X. Huang S. L. Buchwald J. Am. Chem. Soc. 2001, 123. 7727-7729). The flow of nitrogen was removed, and the reaction mixture was then heated at 125° C. for 18 h. After cooling to room temperature the reaction mixture was filtered, rinsed with ethyl acetate, and concentrated. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 5/95) to afford title compound 349 (1.49 g, 94% yield) as a yellow oily liquid. MS (m/z): 163.1 (M+H)+.
Reaction SMILES: [CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@H:14](O)[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:67]>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@@H:14]([Cl:67])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
24 g of 3β-tribenzylsilyloxy-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in a mixture of 250 ml of methylene chloride, 250 ml of carbon tetrachloride, and 125 ml of pyridine and stirred with 24 g of triphenylphosphine for 3 hours. The mixture is then washed with water, dried over sodium sulfate, and concentrated under vacuum. After chromatography on silica gel with hexane-acetone, 19.8 g of 3β-tribenzylsilyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one is obtained.