Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+]([O-])=O.Cl.Cl.[NH2:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>C1COCC1.C(O)C.O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:17](=[O:18])[CH2:16][CH2:15][NH:14][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: NCCC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)CCNc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
6-Chloro-5-nitro-pyrimidin-4-ylamine (379 mg, 2.1 mmol) in THF (2 mL) was added to an ice cold solution of Example 9B (510 mg, 2.1 mmol) in THF (20 mL) and ethanol (20 mL). The mixture was stirred at 0 C for 20 min, at room temperature for 1 hr and heated at 75 C for 2 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL), concentrated, and filtered. The filter cake was washed with water and dried to give 0.55 g (83% yield) of the title compound. MS(ESI(+)) m/e 303.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[NH:7][C:8](=O)[C:9]3[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[C:9]2[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C2CCCC2)nc2c1CCC2
Product: Clc1nc(C2CCCC2)nc2c1CCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 2.2 %

Procedure:
A 250-mL round bottom flask was charged with crude 2-cyclopentyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (4.05 g) and POCl3 (22 mL, 23.8 mmol). The resulting mixture was stirred at 100° C. for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was poured into water (250 mL) and dichloromethane (50 mL) then treated with aqueous sodium hydroxide until the pH˜8. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extract was washed the saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica on chromatography using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.095 g, 3% over 2 steps) as a brown oil. MW=222.71. 1H NMR (CDCl3, 300 MHz) δ 3.31 (quin, J=2.4 Hz, 1H), 3.07 (t, J=7.8 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.22-2.00 (m, 4H), 1.98-1.76 (m, 4H), 1.75-1.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14]Cl.[I-:16].[Na+]>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH2:14][I:16]
Reactant: [I-]
Reactant: Fc1c(C(F)(F)F)cc(Cl)c(CCl)c1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1c(C(F)(F)F)cc(Cl)c(CI)c1F
Yield: 99.7 %

Procedure:
Treat a solution of 1-chloro-2-chloromethyl-3,4-difluoro-5-trifluoromethyl-benzene (1.0 g, 3.8 mmol) in acetone (10 mL) with sodium iodide (2.8 g, 19 mmol) and stir the reaction 1 hr at room temperature. Dilute the reaction in EtOAc (50 mL) and filter. Concentrate the filtrate to afford 1.35 g (100%) of product. 1H NMR (d6-CDCl3) δ 7.39 (d, 1H, J=5.7 Hz), 4.46 (d, 2H, J=2.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[NH:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.CC(C)([O-])C.[K+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:5]([CH2:34][O:33][CH2:31][CH3:32])[C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: CCOCCl
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(Sc2ccc(Cl)c(Cl)c2)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1c(Sc2ccc(Cl)c(Cl)c2)c(Br)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of 4-bromo-2-(p-chlorophenyl)-5-[(3,4-dichlorophenyl)thio]pyrrole-3-carbonitrile (0.644 g, 1.40 mmol) and potassium tert-butoxide (0.173 g, 1.54 mmol) in tetrahydrofuran is stirred at room temperature for 30 minutes, treated with chloromethyl ethyl ether (0.16 mL, 1.54 mmol), stirred overnight at room temperature, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ethyl acetate/hexanes solution to give the title product as a white solid (0.554 g, mp 105°-107° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][N:25]1[C:29]2[N:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1.N1CC=C(C2NC3N=CN=C(ON4C5=NC=CC=C5N=N4)C=3C=2)CC1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C>C(O)CCC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([O:24][N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[N:26]4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: On1nnc2cccnc21
Agent: C1=C(c2cc3c(On4nnc5cccnc54)ncnc3[nH]2)CCNC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(On4nnc5cccnc54)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.5 mg, 0.0343 mmol, 1 eq) and 1-hydroxy-7-azabenzotriazole (HOAt) (5.6 mg, 0.041 mmol, 1.2 eq) in n-butanol (1 mL) was stirred at 80° C. for 15 h. Solid that had formed during the course of the reaction was filtered over a Hirsh funnel and washed with minimal n-butanol. The filtrate was concentrated in vacuo. To a solution of the solid (3-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-b]pyridine) (6.4 mg, 0.015 mmol, 1 eq) in DMSO (1 mL), di-tert-butyldicarbonate (5.0 mg, 0.023 mmol, 1.5 eq) and DiPEA (20 μL, 0.1 mmol, 7 eq) were added and the reaction was stirred at rt for 2 h. This solution was combined with the concentrated filtrate and purified on the MDPS yielding the title compound. 1H NMR (400 MHz, MeOH-d4): δ=1.51 (s, 9H), 2.64 (s, br, 2H), 3.70 (s, br, 2H), 4.17 (s, br, 2H), 6.46 (s, br, 1H), 6.74 (s, 1H), 7.61 (dd, J=8.4, 4.4 Hz, 1H), 8.13 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.74 (d, J=4.4 Hz, 1H). MS (ES+): m/z 435.00 (62) [MH+]. HPLC: tR=3.36 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([Cl:17])=[N:12][CH:13]=[N:14][C:15]=1Cl)=[O:9].[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:18]1([C:15]2[C:10]([C:8]([C:3]3[CH:4]=[N:5][N:6]([CH3:7])[C:2]=3[Br:1])=[O:9])=[C:11]([Cl:17])[N:12]=[CH:13][N:14]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2Cl)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(5-Bromo-1-methyl-1H-pyrazol-4-yl)(4,6-dichloropyrimidin-5-yl)methanone (C26) (1.14 g, 3.39 mmol) was combined with azetidine (98%, 0.212 mL, 3.08 mmol) and N,N-diisopropylethylamine (0.645 mL, 3.70 mmol) in acetonitrile (30 mL) at 0° C. The mixture was then allowed to warm to room temperature and stir for 18 hours. After removal of volatiles in vacuo, the residue was purificed via silica gel chromatography (Eluent: 100:1 ethyl acetate/methanol) to afford the product. Yield: 1.07 g, 3.00 mmol, 97%. LCMS m/z 356.2, 358.2, 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.25-2.36 (m, 2H), 3.94 (s, 3H), 3.96-4.09 (br m, 4H), 7.85 (br s, 1H), 8.37 (s, 1H).
Reaction SMILES: Cl.CN.N1C=CC=C[CH:5]=1.Cl[NH:11][C:12](=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH3:5][NH:11][C:12](=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccncc1
Reactant: O=C(NCl)Oc1ccccc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Oc1ccccc1
Temperature: 5 °C
Yield: 65.4 %

Procedure:
A mixture of commercially available methylamine hydrochloride (50 g, 0.74 mol), pyridine (124 mL, 1.53 mol), and N,N-dimethylformamide (500 mL) was stirred at 5° C., and commercially available phenyl chlorocarbamate (94 mL, 0.75 mol) was added dropwise over 2 hours. After the dripping was complete, the mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was added to ice water (2 L) and extracted with ethyl acetate (1.5 L) twice. The organic layer was washed with water (1 L) and a saturated saline solution (300 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. n-Heptane and ethyl acetate were added to the concentrated residue and the precipitate was collected by filteration and washed with n-heptane and tert-butyl methyl ether to obtain the title compound (74.2 g, 66%).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].CN1CCOCC1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[CH3:7][C:2]([NH:1][C:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:18])([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(C)(C)N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of Methyl 2-amino-2-methylpropanoate (5 g, 32 mmol) and N-Methyl morpholine (11 mL, 98 mmol) in DCM (30 mL) was added in one portion 4-nitrophenyl chloroformate (9.8 g, 49 mmol). Diluted reaction with DCM (50 mL) washed with 1N HCl (2×20 mL) and sat. NaHCO3 (2×20 mL), dried organic fraction over magnesium sulfate, filtered and evaporated volatiles in vacuo.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH3:17])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: CCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
53 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propanal (31 mg, 0.138 mmol), 1-(2-fluorophenyl)piperazine (28 mg, 0.154 mmol), DIPEA (0.036 mL, 0.206 mmol) and NaBH(OAc)3 (89 mg, 0.418 mmol).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:20]=[CH:19][C:8]2[O:9][CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=1)[C:3]#[N:4].Cl.[OH-:22].[NH4+]>>[NH2:1][CH:2]([C:5]1[CH:20]=[CH:19][C:8]2[O:9][CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=1)[C:3]([NH2:4])=[O:22]
Reactant: [OH-]
Reactant: N#CC(N)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Agent: [NH4+]
Product: NC(=O)C(N)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C

Procedure:
Stir at room temperature 5.0 gm. of the aminoacetonitrile of Step B in 30 ml. of concentrated hydrochloric acid for 30 minutes. Slowly pour the reaction mixture into cold ammonium hydroxide. Extract the mixture with ether and dry over sodium sulfate. Evaporate the extract to dryness to obtain the title product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39]C1C=C(C=CC=1F)C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[C:36]([F:39])[CH:37]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccc(F)c(F)c1

Procedure:
In the same manner as in Example 7, 213.3 mg of the title compound was obtained as colorless amorphous compound from 490.8 mg of Referential Compound 3 and 215 μL of 3,4-difluorobenzaldehyde.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:34]=[CH:33][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C@@H:17]([NH:24]C(=O)OC(C)(C)C)[CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.Cl>O1CCOCC1>[NH2:24][C@@H:17]([CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:34]=[CH:33][C:6]=3[N:7]=2)[CH2:15][CH2:14]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The (S)-tert-butyl 1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (83 mg) was dissolved in dry 1,4-dioxane (3 mL) and HCl (4N in 1,4-dioxane, 1 mL) was added. The resulting solution was stirred overnight at room temperature, then concentrated to a white solid. The solid was chromatographed (94.5:5:0.5 dichloromethane:methanol:ammonium hydroxide) to yield the title compound as a colorless oil, which was added to HCl/ether to yield (S)-2-amino-1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-3-(thiophen-2-yl)propan-1-one as a white precipitate, which was collected by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1COCCN1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCOCC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and morpholine. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (d, J=1.95 Hz, 3H) 3.34 (br. s., 2H) 3.64 (br. s., 6H) 7.64 (br. s., 1H) 7.74 (t, J=7.32 Hz, 1H) 7.90-8.63 (m, 4H). ESI-MS m/z [M+H]+ 408.3.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[NH:22]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:23]([C:25](O)=[O:26])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OC(=O)C)C.O>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[C@@H:5]([N:7]([CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:25](=[O:26])[C@@H:23]([NH:22][C:28](=[O:29])[O:30][CH2:31][CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:24])[CH3:6])[CH3:21]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-2) 12.9 g (45 mmol) and Fmoc-Ala-OH 18.3 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (25.6 g, 67.5 mmol) and DIEA (diisopropylethylamine) (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (ethylacetate) (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE (petroleum ether): EA=30:1 to 5:1 to give the title compound 18.6 g, (yield 71%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:20]>>[CH:3]12[O:20][CH:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)N1CC=CCC1
Product: O=C(c1ccccc1)N1CCC2OC2C1

Procedure:
The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(B2OC(C)(C)C(C)(C)O2)C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 2 (0.30 g) in dichloromethane (7 mL) was added triethylamine (0.11 mL) and acetyl chloride (55 uL). The reaction mixture was stirred overnight at room temperature. Evaporation gave a green-grey foam which was purified by chromatography, with chloroform:methanol (gradient, 50:1, 30:1) as the eluent, to yield the title compound (0.19 g) as a white powder; TLC: Rf =0.35, methanol:chloroform (5:95); NMR: 0.84 (d,3, J=6.7), 0.85 (d,3, J=6.8), 1.17 (s,12), 1.7-1.8 (m,1), 2.15 (s,3), 2.66 (t,1), 4.48 (s,2), 7.46-7.55 (m,5), 8.29 (d,1, J=5), 8.82 (s,1), 9.54 (s,1); MS: m/z=469(M+1). Analysis for C24H33BN4O5 : Calculated: C, 61.55; H, 7.10; N, 11.96; Found: C, 61.55; H, 7.23; N, 11.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)[nH]ncc2c1C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 75.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 6-methoxy-1-oxo-1,2-dihydro-phthalazin-5-yl ester (4.52 g, 13.94 mmoles), prepared as described in example 59, trimethylsilylethyne (3.94 ml, 27.88 mmoles), bis(triphenylphosphine)PdCl2 (245 mg, 0.384 mmole) and triethylamine (6.56 ml) in DMF (30 ml) was heated at 60° C. for 4 hours. Further trimethylsilylethyne (2 ml) was added and the mixture was heated at 90° C. for 3 hours. After evaporation of the solvent, the residue was taken up in ethyl acetate and the solid was filtered off. After evaporation, the residue was taken up in diethylcarbonate, washed with water, dried, evaporated again, taken up in ethyl ether and filtered giving 2.87 g of the title compound (yield: 75.6%).
Reaction SMILES: COC([O:5][C@@H:6]1[C@@:28]2([CH3:29])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([C:20](OC)=[O:21])[CH3:19])[CH2:9][C@@H:8]([O:31]C(OC)=O)[CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)C>[CH3:19][CH:18]([C@@H:17]1[C@:24]2([CH3:30])[C@H:14]([C:13]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:29])[C:10]([CH2:9][C@@H:8]([OH:31])[CH2:7][C@@H:6]2[OH:5])=[CH:11][CH:12]=3)[CH2:15][CH2:16]1)[CH2:20][OH:21]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
Methyl 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylate (70 mg) was added to a suspension of 10 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran with ice cooling and the mixture was stirred with ice cooling for 30 minutes. The resulting reaction mixture was diluted with diethyl ether and the excess reducing agent was decomposed with a saturated aqueous solution of sodium sulfate. The insoluble matter was filtered off and washed well with ethyl acetate. The filtrate and washings were combined and concentrated. The residue was washed with cold diethyl ether to give 58 mg of 20-methylpregna-5,7-diene-1α,3β,21-triol.