Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:33]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.CCOC(C)=O>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([F:33])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about −78° C. followed by the addition of n-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0° C. and stirred for about 30 min and then cooled to about −40° C. To the mixture was added a solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between −40 to −30° C. The mixture was stirred for about 1 h at about −10° C. before being cooled to about −78° C. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about −65 and −78° C. The mixture was then stirred for about 1 h at about −78° C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl 1-benzyl-4-fluoropiperidine-4-carboxylate (7.13 g, 66%): LC/MS (Table 2, Method h) Rt=2.21 min; MS m/z: 266 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58](O)=[O:59]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:58]([C@H:54]2[CH2:55][CH2:56][CH2:57][O:53]2)=[O:59])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@H]1CCCO1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol) in dry THF: DMF (4:1 mL) was added TBTU (0.182 g, 0.567 mmol) and TEA (3 mL) and stirred for 1 h under nitrogen atmosphere. To the reaction mixture (R)-(+)tetrahydro-2-furoic acid (0.032 g, 0.283 mmol) was added and stirred for 18 h at room temperature. The reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.025 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.23 (s, 2H), 1.74-1.92 (m, 3H), 2.09-2.24, (m, 1H), 3.75-3.80 (m, 1H), 3.89-3.94 (m, 1H), 4.26-4.37 (m, 3H), 7.43-7.45 (d, J=8.4 Hz, 1H), 7.61-7.63 (d, J=8.4 Hz, 2H), 7.85-7.87 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.8 Hz, 2H), 8.50-8.53 (m, 1H), 12.71 (br s, 1H); MS (m/z): 465.55 (M−H−).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:23])[C:15]([NH2:22])=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:14]1[CH:13]=[C:12]([Cl:11])[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][C:15]=1[NH:22][C:8](=[O:10])[CH2:7][CH2:6][CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1
Reactant: O=C(O)CCC1CC(=O)C1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
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
Product: Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CCC1CC(=O)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 30.9 %

Procedure:
A solution of 3-(3-oxocyclobutyl)propanoic acid (157 mg, 0.696 mmol) and 4-chloro-5-(trifluoromethyl)benzene-1,2-diamine (146 mg, 0.696 mmol) in N,N-dimethylformamide (2.5 mL) was cooled at 0° C. The solution was treated with N,N-diisopropylethylamine (0.364 mL, 2.09 mmol) dropwise followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (291 mg, 0.765 mmol) in one portion. The solution was allowed to stir and slowly warm to room temperature. After 40 h, the reaction mixture was concentrated partially under high vac. The remaining brown liquid was taken up in 25 mL EA and 15 mL 1/1 sat NaHCO3/H2O and extracted. The aqueous phase was washed with two 15 mL portions of ethyl acetate and the combined organic phase was washed with 30 mL portions of H2O and brine. The organic phase was dried over MgSO4, filtered and concentrated to yield a tannish brown viscous oil/glass. The crude material was purified by flash chromatography (40 g silica gel, 50-80% EA/hept) to yield the title compound (72 mg, 31%) as a slightly tan glass/stiff foam: MS (ESI+) for C14H14ClF3N2O2 m/z 335.2 (M+H)+; MS (ESI−) for C14H14ClF3N2O2 m/z 333.3 (M−H)−; HPLC purity 78.2% (ret. time, 3.56 min).
Reaction SMILES: [F:1][C:2]1([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.NN.C(Cl)Cl>C(O)C>[F:1][C:2]1([CH2:8][NH2:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NCC1(F)CCOCC1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 409B (1.4 g) and hydrazine (1.548 mL) in ethanol (40 mL) was heated at 70° C. overnight, cooled to room temperature, slurried with CH2Cl2 (200 mL) and the solid removed by filtration. The filtrate was concentrated and chromatographed on silica gel with 100:5:1 ethyl acetate/methanol/NH4OH as eluent to give the product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10](F)=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[NH4+:31].[NH4+]>CN(C=O)C>[NH2:31][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[C:8]2[C:13](=[C:12]([O:14][CH3:15])[C:11]=1[F:16])[N:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:21]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(N)c([N+](=O)[O-])c2c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (5.00 g, 13.5 mmol) and ammonium carbonate (11.7 g, 122 mmol) in DMF (50 mL) was stirred at 90° C. for 18 h. After the reaction mixture was poured into ice-water, the crude product was extracted with CH2Cl2, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product washed with EtOH and dried to yield ethyl 6-amino-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.55 g, 52%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH3:6][C:7]1[C:8](N2C=NC=N2)=[N:9][C:10](=[O:13])[NH:11][CH:12]=1.C(O)(=O)C>CN(C)C=O>[CH2:3]([S:5][C:8]1[C:7]([CH3:6])=[CH:12][NH:11][C:10](=[O:13])[N:9]=1)[CH3:4]
Reactant: CCS
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCSc1nc(=O)[nH]cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
786 mg (18 mmol) of a 55% strength sodium hydride emulsion are added to 0.7 ml (9 mmol) of ethylmercaptan in 25 ml of dry dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at 0° C. 1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are then added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is neutralized by addition of acetic acid, concentrated and chromatographed on silica gel using dichloromethane/methanol 20/1. 0.64 g (62.7% of theory) of 4-ethylthio-5-methylpyrimidin-2(1H)-one is obtained with melting point 181°-184° C. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 11.45 (s, 1H), 7.55 (s, 1H), 3.10 (q, 2H), 1.90 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]3[N:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#N)=[CH:11][CH:10]=2)=[CH:5][N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:52])C>CCCCCC>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]3[N:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[O:52])=[CH:11][CH:10]=2)=[CH:5][N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1nn(-c2ccccn2)cc1COc1ccc(COc2ncccc2C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(COc2ncccc2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile (2.03 g) and anhydrous toluene (100 mL) was dropwise added a solution (0.95 M, 11.8 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (30 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and the mixture was stirred at room temperature for 30 min. Insoluble materials were filtered off, and the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.61 g, 30%) of 2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 106-1-07° C.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[CH:12][C:11]=1[F:20])[CH3:7]
Reactant: NCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Difluoro-ethylamine (2.4 g, 29.8 mmol) in THF is added at 0° C. to ethyl-2,4-difluoro-5-nitro-benzoate (4.6 g, 20 mmol) and it is stirred overnight at rt. Water is added to the mixture and the mixture is concentrated. The precipitate is filtered, washed with water and dried with P2O5 in vacuo. Yield: 3.8 g (66%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:16]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1CC(C(=O)C(F)(F)F)Cc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was then added over about 5 min. The reaction mixture was then stirred at room temperature for 14 h and then was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer washed with 3N HCl, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was then taken up in 70 mL of boiling ethanol/water and allowed to cool to room temperature whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give 32 g, 81% of pure product with mp 48°-49° C. 1H NMR CDCl3 δ2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ72.0. EI GC-MS M+=242.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2.Cl>CCO.CO.N>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)[C:2]([NH:35][C:36]3[C:37]4[CH:38]=[CH:39][NH:40][C:41]=4[CH:42]=[CH:43][CH:44]=3)=[N:3][CH:4]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Product: COc1ccc(COCc2cnc(Nc3cccc4[nH]ccc34)c(-c3nc(C)nc4[nH]cnc34)c2)cc1
Temperature: 100 °C
Reaction time: 1.75 h
Yield: 7.2 %

Procedure:
6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (171.2 mg, 0.3694 mmol) and 4-aminoindole (Aldrich, St. Louis, Mo., 69.2 mg, 0.524 mmol) were suspended in EtOH (2.0 mL) and hydrochloric acid (J.T. Baker, Phillipsburg, N.J., 5 N, 0.090 mL, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred for about 105 minutes. Then, the reaction was cooled to room temperature and diluted with MeOH and 2 N ammonia in MeOH. The reaction was concentrated and treated with DMF and DCM and filtered. The filtrate was filtered again, and the solid was again washed with DCM. This filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 ml/min). The fractions with product were collected, concentrated, and filtered through a silica gel filter (about 1 inch, 10:1 DCM/2 N ammonia in MeOH) to give N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (13.1 mg, 7% yield). MS (ESI pos. ion) m/z 492 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.49 (s, 1H), 11.17 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=6.85 Hz, 1H), 7.38-7.32 (m, 3H), 7.12-7.04 (m, 2H), 6.93 (d, J=8.80 Hz, 2H), 6.72 (s, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 3.75 (s, 3H), 2.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1)=O.Cl.[NH2:32][OH:33].C(O)C.[OH-].[K+]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4](=[N:32][OH:33])[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1
Reactant: NO
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3F)CC1)CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
To a solution of 7.0 g (0.0143 mole) of 3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 70 ml of pyridine, 5.4 g (0.0777 mole) of hydroxylamine hydrochloride and 100 ml of ethanol 1.6 g (0.0286 mole) of potassium hydroxide are added. The reaction mixture is heated to boiling for 10 hours, cooled to room temperature and the solvent is removed in vacuo. To the residue 100 ml of water are added and the mixture is extracted with 100 ml of dichloromethane. The organic phase is washed twice with 50 ml of water each, dried over anhydrous magnesium sulfate and evaporated. The residual crude product is recrystallized from ethyl acetate. Thus 4.2 g of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one are obtained. Yield 65.1%. According to HPLC analysis the purity of the product is 97.2%.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.Cl[Si](C)(C)[CH3:32].C(N(CC)CC)C.C(Cl)(=O)C>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:23])[CH3:32])[CH2:19][CH2:20]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(Br)ccc32)CC1
Reaction time: 17 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-((5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (STEP A, 740 mg, 1.59 mmol) in methanol (8 mL) was added chlorotrimethylsilane (4 mL). After stirring for 17 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane (8 mL) and added triethylamine (2.24 mL, 15.9 mmol) and acetyl chloride (227 microL, 3.19 mmol). After 20 min, the mixture was diluted with ethyl acetate and washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-methanol, gradient) to give the title compound (630 mg, 97%) as an amorphous.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[SiH](C)C.[CH3:14][Si:15]([CH3:22])([CH3:21])[NH:16][Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][Si:15]([CH3:22])([CH3:21])[N:16]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C1CCCCNCCC1
Agent: C[SiH](C)C
Agent: O=S(=O)([O-])[O-]
Product: C[Si](C)(C)N1CCCCCCCC1
Yield: 165.5 %

Procedure:
The silylamine of octahydroazonin is prepared by combining octahydroazonin (12.7 g, 0.1 moles) and trimethylsilane (0.12 moles) and 0.5 moles hexamethyldisilazane +150 mg of ammonium sulfate. The mixture is refluxed for 90 hr and distilled under vacuum to yield 16.5 g of 1-trimethylsilyl octahydroazonin (82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=O)=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=[N:34][OH:35])=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=NO)c1ccccc1C
Yield: 47.3 %

Procedure:
A mixture of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (0.49 g), hydroxylamine hydrochloride (0.1 g) and pyridine (0.1 g) in ethanol (10 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×50 mL) and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and filtered and the solvent is removed in vacuo, to give a yellow oil. Flash chromatography on silica gel, eluting with a mixture of petroleum ether (b.p.40-60° C.) and ethyl acetate (7:1 v/v), gives ethyl (RS)-4-(5-benzyloxy-2-hydroxyiminomethylphenoxy)-4-(2-methylphenyl)butanoate (E:Z ratio 4:1), (0.24 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1.[B:16](OC)([O:19]C)[O:17]C.[OH-].[Na+]>CCCCCC.C(OCC)C.O>[CH3:15][O:14][CH2:13][C:11]1[CH:12]=[C:7]([B:16]([OH:19])[OH:17])[CH:8]=[N:9][CH:10]=1
Reactant: COCc1cncc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: COCc1cncc(B(O)O)c1
Temperature: -100 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
To a solution of n-butyl lithium in hexane (6 ml of a 1.6M solution) in diethyl ether (40 ml) at -100° C. under nitrogen was added dropwise 3-bromo-5-methoxymethylpyridine (1.2 g, 6 mmol) (WO 95/28400) in diethyl ether (20 ml). After stirring for 45 minutes at -100° C., trimethyl borate (1.1 ml, 9.8 mmol) was added and the reaction mixture stirred at -100° C. for an extra 75 minutes. Water was added followed by 4N aqueous sodium hydroxide when the temperature reached 10° C. The aqueous layer was decanted, acidified to pH 5 with 2N aqueous hydrochloric acid and extracted 5 times with dichloromethane. The combined organics were dried (sodium sulphate) and evaporated to give the title compound as an oil (100 mg, 10%). MS, m/z 168 for (M+H)+. Rf 0.05 in ammonia/methanol/dichloromethane (1/10/90) on silica plate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH2:40]([O:39][CH:38]([O:42][CH2:43][CH3:44])[C@@H:37]([N:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH3:45])[CH3:41]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound IV-17) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@H:17]([OH:27])[CH2:18][CH2:19]2)/[C:14](=[CH:28]\[CH3:29])/[C:13]3=[O:30])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>>[OH:27][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15](/[C:14](=[CH:28]\[CH3:29])/[C:13](=[O:30])[C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:16]1
Reactant: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
reacting E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4) with NaOH to form E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5),