Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12](I)[N:11]=[CH:10]1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[NH4+].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[N:11]=[CH:10]1
Reactant: Fc1ccc(F)c(-n2cnc(I)c2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)ccc2F)cn1
Reaction time: 1.5 h
Yield: 111.1 %

Procedure:
A solution of 1-(2,5-difluorophenyl)-4-iodo-1H-imidazole (0.115 g, 0.38 mmol) in 2 mL of tetrahydrofuran was chilled in an ice/water bath 5 min. Isopropylmagnesium chloride solution (2.0 M in tetrahydrofuran, 0.190 mL, 0.38 mmol) was added all at once. The bath was removed, and the pale yellow solution stirred 1.5 h. Tributyltin chloride (0.105 mL, 0.39 mmol) was added all at once, and the pale yellow solution was stirred 1.5 h. A sat. aq. NH4Cl solution (10 mL) was added, and the mixture was extracted with two 10 mL portions of ethyl acetate. The combined organic layers were washed with 20 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to provide 0.198 g of 1-(2,5-difluoro-phenyl)-4-tributylstannanyl-1H-imidazole as a yellow oil which was used without further purification. MS: (M+H)+=471.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([OH:21])[CH:15]=2)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH:30]([O:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:12]([CH2:11][NH2:10])[NH:13]2)=[CH:18][CH:17]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:35]
Reactant: O=C(NCc1cc2ccc(O)cc2[nH]1)OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1ccc2cc(CN)[nH]c2c1)C(=O)OCC
Reaction time: 8 h

Procedure:
(6-Hydroxy-1H-indol-2-ylmethyl)-carbamic acid benzyl ester was dissolved in 10 ml acetone, Cs2CO3 and diethyl chloromalonate were added. The reaction is stirred overnight. HPLC and TLC indicated the reaction is done. The mixture was diluted with ethyl acetate and filtered through silica gel plug. The filtrate is concentrated and redissolved in ethanol, hydrogenated for 3 hours at 40 psi of hydrogen. The mixture is filtered, washed with ethyl acetate. The filtrate is concentrated to give 2-(2-Aminomethyl-1H-indol-6-yloxy)-malonic acid diethyl ester.
Reaction SMILES: [C:1]([C:3]([C:24]#[N:25])=[C:4]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:5]1([C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:3]([C:1]#[N:2])[C:24]#[N:25])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=C(C#N)C#N)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Reaction time: 16 h
Yield: 71 %

Procedure:
tert-Butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate (2 g) was dissolved in a 33.3% solution of TFA in methylene chloride (20 ml). After 16 hour at room temperature, solvents were removed under vacuum to offer a residue which was purified using silica gel chromatography to give 2-(phenyl(piperazin-1-yl)methylene)malononitrile (1 g). 1H NMR (500 MHz, CD3OD) □7.62 (m, 5H), 3.70 (b, 4H), 3.47 (b, 4H); 13C NMR (125 MHz, CD3OD) □172.9, 132.7, 132.5, 129.6, 116.6, 116.0, 55.2, 43.4. MS m/z: (M+H)+ calcd for C14H15N4 239.13, found 239.13. Retention time 0.56 min (column A).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Br)cnc2N)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
(R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (4.97 g, 22.40 mmol) was dissolved in DMSO (80 ml), and then 3,5-dibromopyrazine-2-amine (8.5 g, 33.60 mmol) and Et3N (6.3 ml) were added, followed by stirring at 130° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (R)-tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, two steps: 26%).
Reaction SMILES: C(C1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.Cl.[C:24]([OH:27])(=[O:26])[CH3:25]>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:25]([CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:9])=[O:10])[C:24]([OH:27])=[O:26]
Reactant: CC(=O)O
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Oc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.3 g) and concentrated hydrochloric acid (13 ml) in acetic acid (8 ml) was refluxed for 8 hours. The precipitates were filtered, washed with water, dried, and recrystallized from a mixture of ethyl acetate and hexane to give crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzoic acid (0.72 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: OC1CN2CCC1CC2
Product: O=[N+]([O-])c1ccc(OC2CN3CCC2CC3)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 g, 10 mmol) was treated with 1-iodo-4-nitro-benzene (5 g, 20 mmol) according to the procedure of Example 14A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) (1.02 g, yield, 21%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.65–1.90 (m, 2H), 1.90–2.08 (m, 1H), 2.15–2.25 (m, 1H), 2.75–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.69 (m, 1H), 7.07 (d, J=9.5 Hz, 2H), 8.21 (d, J=9.2, Hz, 2H) ppm. MS (DCl/NH3) m/z 249 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:5][CH:6]1[CH2:14][CH2:13][CH:12]2[CH:7]1[CH2:8][CH:9]=[C:10]([O:15]C)[CH2:11]2)(=[O:4])[CH3:3]>CO>[C:2]([O:5][CH:6]1[CH2:14][CH2:13][CH:12]2[CH:7]1[CH2:8][CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: COC1=CCC2C(CCC2OC(C)=O)C1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1CCC2CC(=O)CCC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Concentrated hydrochloric acid (3.5 ml) was added to a solution of 7-acetoxy-3-methoxybicyclo[4,3,0]non-3-ene (58.9 g; prepared as described in Reference Example 3) in methanol (500 ml), and the mixture was stirred at the ambient temperature for 5 minutes. It was then concentrated under reduced pressure, to give 7-acetoxybicyclo[4,3,0]nonan-3-one (54.7 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([C:11]([S:14]([CH3:17])(=[O:16])=[O:15])([CH3:13])[CH3:12])[N:3]=1>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:11]([S:14]([CH3:17])(=[O:16])=[O:15])([CH3:13])[CH3:12])[N:3]=1
Reactant: Cc1nc(C(C)(C)S(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(C(C)(C)S(C)(=O)=O)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 2-methyl-6-(2-(methylsulfonyl)propan-2-yl)-3-nitropyridine (1.27 g, 4.92 mmol) in 50 mL acetic acid, zinc dust (1.6 g, 24.5 mmol) was added in small portions under ice-cooling. After 1 h, more zinc dust (ca. 2 g, 31 mmol) was added in small portions and mixture was stirred at room temperature for another hour. Solids were filtered off, washed with CH3CN, and filtrate was concentrated. Residue was purified by CC(CH2Cl2/MeOH 20:1+1% NEt3). Fractions containing product were concentrated and re-purified by HPLC. Fractions containing product were partly concentrated and residue was extracted with 1M NaHCO3 and CH2Cl2. Organic phases were dried over MgSO4, filtered and concentrated to give 2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-amine (0.664 g, 59% yield) as a white solid. 1HNMR (CDCl3, 400 MHz) δ 1.84 (s, 6H), 2.39 (s, 3H), 2.76 (s, 3H), 3.68 (s, 2H), 6.92-6.94 (d, J=8.3 Hz, 1H), 7.29-7.31 (d, J=8.3 Hz, 1H). Exact mass calculated for C10H16N2O2S 228.09 found 229.2 (MH+).
Reaction SMILES: C([O:5][C@@H:6]1[C@@H:10]([O:11]C(=O)CC)[C@@H:9]([C@@H:16]([CH2:22][O:23]C(=O)CC)[O:17]C(=O)CC)[O:8][C@H:7]1[N:28]1[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]1=[O:30])(=O)CC>CO.N>[C@@H:7]1([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:8][C@H:9]([C@@H:16]([CH2:22][OH:23])[OH:17])[C@H:10]([OH:11])[C@H:6]1[OH:5]
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Agent: N
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H]([C@H](O)CO)[C@H](O)[C@H]2O)c(=O)[nH]1
Reaction time: 8 h
Yield: 75 %

Procedure:
1-(2,3,5,6-Tetra-O-propanoyl-β-D-glucofuranosyl)uracil was dissolved in methanol saturated with ammonia (15 mL) and left at room temperature overnight. After concentrating in vacuo, the resulting residue was purified by flash silica chromatography, eluting with CHCl3/CH3OH/NH3 aq. (84:15:1), to give 1-βD-glucofuranosyluracil as a colourless solid (680 mg, 75%). A sample was recrystallised from EtOH to give the product as colourless needles, mp 175-176.5° C. (from EtOH), [α]D21=+9.91 (c 1.1 in H2O), (Found: C, 44.0; H, 5.0; N, 10.35. C10H14N2O7 requires C, 43.8; H, 5.15; N, 10.2%); δH (D2O) 7.82 (1H, d, J 8.1, 6-H), 5.79 (1H, d, J 8.1, 5-H), 5.75 (1H, s, 1′-H), 4.27-4.25 (2H, m, 2′- and 3′-H), 4.23 (1H, dd, J 8.6 and 2.7, 4′-H), 4.12 (1H, ddd, J 8.6, 5.4 and 2.7, 5′-H), 3.86 (1H, dd, J 12.1 and 2.7, 6′a-H), 3.37 (1H, dd, J 12.1 and 5.4, 6′b-H); δC (D2O) 166.8 (3-C), 151.9 (2-C), 142.6 (6-C), 101.5 (5-C), 92.4 (1′-C), 82.8 (4′-C), 80.7, 74.7 (2′- and 3′-C), 68.9 (5′-C), 63.8 (6′-C); m/z (FAB) 275.088448 (MH+, C10H15N2O7 requires 275.087926).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[S:30])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 18 h

Procedure:
t-Butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solution of pyridine (30 ml) and triethylamine (7 ml), and hydrogen sulfide gas was blown in for 10 minutes at room temperature, which was followed by stirring for 18 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with a 2N aqueous potassium hydrogensulfate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give t-butyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. The solid was dissolved in acetone (50 ml) and methyl iodide (2 ml) was added. The mixture was refluxed under heating for 40 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Thereto were added methanol (30 ml) and ammonium acetate (280 mg, 3.64 mmol), and the mixture was refluxed under heating for 3 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 596 mg of hydriodide of compound (8) as a yellow solid (quantitatively in 3 steps).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:36])[CH:9]=2)=[CH:4][CH:3]=1.[ClH:39]>ClCCl>[ClH:39].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:36])[CH:9]=2)=[CH:37][CH:38]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)cc31)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of tert-butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (120 mg, 0.23 mmol) in dichloromethane (1.0 mL) was added HCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred at room temperature overnight and concentrated under reduced pressure to afford the title compound (85 mg, 82%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.59 (d, J=8.5 Hz, 2H), 7.50 (dd, J=8.0, 5.5 Hz, 2H), 7.40 (s, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.30 (t, J=6.5 Hz, 1H), 6.14 (br s, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 3.54 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.34 (t, J=5.5 Hz, 2H), 3.24 (t, J=5.5 Hz, 2H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:5])[CH2:3][CH2:2]1.O[C:12]([CH3:27])([CH2:25][CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]>>[CH3:27][C@@:12]([O:9][C:8](=[O:10])[CH2:7][O:6][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])([CH2:25][CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]
Reactant: CCC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(OCC(=O)O)C1CC1
Product: CC[C@@](C)(OC(=O)COC(C)C1CC1)C(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound was prepared as described in Example 134 Step 2 using (1-cyclopropylethoxy)acetic acid and 2(R) 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one from Example 117, Step 3.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][NH2:29])[CH3:27])=[CH:22][CH:21]=1>CO>[CH3:7][O:6][CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[CH:1]=[N:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:21][CH:22]=1)[CH3:27]
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=O
Reactant: CC(=NN)c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COC(C1=CN(C)CS1)c1ccccc1C=NN=C(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To 0.23 g (1 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylthiazole in 2 ml of methanol was added 0.22 g (1.1 mmol) of 4'-(trifluoromethyl)acetophenone hydrazone and stirred at room temperature for 3 hours. After completion of the reaction, methanol was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-{4-(4-trifluoromethylphenyl)-2,3-diaza-1,3-pentadienyl}benzyl]-3-methylthiazole (0.23 g, 55.4%) as oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C@H:2]([O:1][CH2:3][CH2:2][CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1 g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) and stirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for additional 16 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a crude product. Upon further purification, compound 9 was obtained as an oil (80 mg, 4%). MS [M+H]+ 273. Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203. Step 3: Preparation of (7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one, 12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg, 0.22 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10 min then the amine 11 (52 mg, 0.22 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1 N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid compound 12 (80 mg, 86%). MS [M+H]+ 423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]([CH3:30])=[C:12]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]3)[N:13]=2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]([CH3:30])=[C:12]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]3)[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=CC[C@H]1CCC[C@@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC[C@H]1CCC[C@@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
190 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-yl-methoxy]cyclohexyl}but-2-enoate are dissolved in 25 ml of methanol, and 20 mg of Pd (10% on activated carbon) are added. The mixture is stirred at room temperature and under an atmosphere of hydrogen for 7 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. This gives 110 mg of ethyl 4-{cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl}butyrate as an oil. C24H33NO5 (415.53), MS(ESI): 416 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:46])[NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]4[S:35][CH:34]=[C:33]([C:36]5[NH:37][C:38]([C@@H:41]6[CH2:45][CH2:44][CH2:43][NH:42]6)=[N:39][CH:40]=5)[C:30]=4[S:31][CH:32]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8].[C:47]([O:51][C:52]([NH:54][C@H:55]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:56](N1CCC[C@H]1C(O)=O)=[O:57])=[O:53])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C)C=O>[CH3:2][O:3][C:4](=[O:46])[NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]4[S:35][CH:34]=[C:33]([C:36]5[NH:37][C:38]([C@@H:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:56](=[O:57])[C@H:55]([NH:54][C:52]([O:51][CH3:47])=[O:53])[C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)=[N:39][CH:40]=5)[C:30]=4[S:31][CH:32]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6)[nH]5)csc34)cc2)c[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)csc34)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
To a mixture of compound 71 (0.078 mmol), compound 33 (0.085 mmol), and HATU (0.085 mmol) in dimethylformamide (1 mL) was added Et3N (0.465 mmol) dropwise. The reaction mixture was stirred at room temperature during 12 hrs. The solvent was removed under reduced pressure and the residue was dissolved in methanol. This mixture was eluted through a SCX-2 column. The filtrate was concentrated and the residue was purified by semi-preparative HPLC to give compound A200 as a white solid in 25% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.85 (d, J=6.46 Hz, 3H), 0.91 (d, J=6.64 Hz, 3H), 1.84-2.20 (m, 8H), 3.11-3.22 (m, 1H), 3.35-3.38 (m, 1H), 3.51-3.54 (m, 6H), 3.77-3.92 (m, 2H), 4.04-4.09 (m, 1H), 5.06-5.11 (m, 2H), 5.48-5.52 (m, 1H), 6.88-8.40 (m, 13H), 11.80-11.87 (m, 1H); MS (ESI, EI+) m/z=835.4 (MH+).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].Cl.[S:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[CH:7]1.C=O>ClCCl>[CH3:1][N:11]1[CH2:12][CH2:13][C:14]2[S:6][CH:7]=[CH:8][C:9]=2[CH2:10]1
Reactant: [BH3-]C#N
Reactant: c1cc2c(s1)CCNC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
Sodium cyanoborohydride (10 g, 160 mmol) was slowly added to a mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (7.0 g, 40.0 mmol) and formaldehyde (35% in water, 10 mL) in dichloromethane (100 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. Work-up: the reaction mixture was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1:5˜1:1) to afford the title compound as a white solids (2.0 g, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 7.26 (d, 1H), 6.77 (d, 1H), 3.37 (s, 2H), 2.80-2.77 (m, 2H), 2.64-2.60 (m, 2H), 2.34 (s, 3H).