Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:16]1[CH2:17][CH:13]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]2)[CH2:14][C:15]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A 15.13 g (59.5 mmol) portion of 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone was dissolved in 30.0 ml of N,N-dimethylformamide, cooled in an ice bath, mixed with 2.62 g (65.44 mmol) of sodium hydride (60% oil suspension) and then stirred at room temperature for 30 minutes. This was mixed with 7.78 ml (65.44 mmol) of benzyl bromide and stirred overnight at room temperature. Since the starting material partially remained, 1.19 g (29.74 mmol) of sodium hydride and 3.54 ml (29.74 mmol) of benzyl bromide were further added and stirred for additional 5 hours at room temperature. After evaporation of the solvent, the resulting residue was mixed with water, extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated. Thereafter, the resulting residue was purified by a silica gel column chromatography (silica gel 800 ml, ethyl acetate:hexane=10:1→1:1→2:1) to yield 5.65 g (28%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:16]([CH3:27])[CH2:15]2)[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:27])[CH2:15]1)=[N:5]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate (230 mg, 0.56 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.88 (1H, d, J=12.9 Hz), 6.80 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.58 (1H, t, J=2.3 Hz), 4.38 (1H, br. s.), 3.98 (1H, d, J=13.1 Hz), 3.85 (4H, dd, J=5.7, 3.9 Hz), 3.70 (1H, d, J=10.2 Hz), 3.56 (1H, dt, J=12.9, 1.8 Hz), 3.32 (1H, td, J=12.7, 3.1 Hz), 3.14-3.21 (4H, m), 3.11 (1H, dd, J=12.8, 3.8 Hz), 2.92 (1H, td, J=12.5, 3.3 Hz), 2.10 (3H, s), 1.50 (9H, s), 1.29 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=555.7 (M+1).
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[CH2:27](/[C:29](=[CH:35]/O)/[C:30](OCC)=[O:31])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:35]=[C:29]([CH2:27][CH3:28])[C:30](=[O:31])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: CCOC(=O)/C(=C\O)CC
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c[nH]c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Temperature: 110 °C
Yield: 27.5 %

Procedure:
A mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (250 mg, 0.459 mmol), ethyl (2Z)-2-ethyl-3-hydroxy-2-propenoate (132 mg, 0.918 mmol) and K2CO3 (127 mg, 0.918 mmol) in DMF (3 mL) was heated with a microwave condition at 110° C. for 1.5 h. Purification via MDAP afforded the title compound (60 mg, 27.5% yield). LCMS: rt=3.83 min, [M+H+]=475
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[N:4]([C:31]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:32])[CH2:3]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)N2CC(C)(C)c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc32)CC1

Procedure:
N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Example 7, Step A)(300 mg, 0.96 mmol) was treated with 4-methyl-piperazine-1-carbonyl chloride (200 mg, 1 mmol) in the presence of DIEA (40 mL) in THF overnight at 65° C. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with H2O and brine, then dried over Na2SO4. The organic solution was concentrated in vacuo to yield the desired compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2N)c1
Reaction time: 2.5 h

Procedure:
2-(3-tert-Butyldimethylsilyloxyphenyl)nitrobenzene from Step C, (11.94 g, 36.24 mmol) was dissolved in EtOH (250 mL) and EtOAc (250 mL), degassed with argon and Pd/C (1.19 g, 10 wt %) was added. The vessel was subjected to H2 (1 atm) while vigorously stirring for 2.5 hour. The reaction was filtered through a celite pad and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C.C(O)=O.NC1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:22]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.2 g, 5.7 mmol) in THF:toluene (1:1, 5 mL) was reacted with PtO2 (1% w/w) on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The filtered solution was cooled to 0° C. and a solution of acetic anhydride (0.161 mL, 0.569 mmol) and formic acid (0.043 mL, 1.140 mmol) was added dropwise to a mixing solution of the aniline. The reaction was allowed to proceed at 0° C. for 30 min then warmed to rt and reacted for another 2 h. The reaction mixture was concentrated to near dryness then water was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4 (s), and concentrated to give a residue. Chromatography (1:1 Hexanes/EtOAc) gives the title compound (156 mg, 78% 2 steps). ES/MS calcd. C16H17BrNO3+350.0. found m/z=350 (M+H)+.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]3([C:18]4[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=4[C:11]=2[CH:10]=1)[CH2:17][O:16]3>ClCCl>[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]([F:7])([CH2:17][OH:16])[C:18]3[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Reactant: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2c(s1)C(F)(CO)COc1ccc(Br)cc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
HF-pyridine (70%) (2 mL) was added dropwise to a stirred solution of ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-oxirane]-2-carboxylate (600 mg, 1.57 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. After being stirred for 1 h at 0° C. the reaction was quenched with brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give 270 mg (43%) of the titled compound as a off-white solid; LC-MS (ES, m/z) 402, 404 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:42][C:43]1[CH:63]=[C:62]([S:64]([CH3:67])(=[O:66])=[O:65])[CH:61]=[CH:60][C:44]=1[O:45][C:46]1[C:51]([CH3:52])=[C:50]([O:53][CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:57]2[CH2:58][CH2:59][CH:54]([O:53][C:50]3[C:51]([CH3:52])=[C:46]([O:45][C:44]4[CH:60]=[CH:61][C:62]([S:64]([CH3:67])(=[O:65])=[O:66])=[CH:63][C:43]=4[F:42])[N:47]=[CH:48][N:49]=3)[CH2:55][CH2:56]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
6-Amino-nicotinic acid (21.5 mg, 0.155 mmol), HATU (59 mg, 0.155 mmol) and triethylamine (0.05 mL, 0.359 mmol) were mixed in DMF and stirred at rt for 20 min. 4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine was then added and the mixture stirred at rt for 2 h. The crude was purified by HPLC to afford Compound C5 as a yellow solid (67 mg, 90.7%). 1H NMR (CDCl3, 400 MHz) δ 1.88-1.87 (m, 2H), 1.99-2.01 (m, 2H), 2.15 (s, 3H), 3.03 (s, 3H), 3.58-3.60 (m, 2H), 3.77-3.78 (m, 2H), 5.37-5.41 (m, 1H), 6.78-6.82 (d, 1H), 7.33-7.38 (m, 1H), 7.69-7.74 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (s, 1H). Exact mass calculated for C23H24FN5O5S 501.15, found 502.4 (MH+).
Reaction SMILES: [C:1](/[C:4](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])([OH:3])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>ClCCl>[CH2:39]([NH:46][C:1](/[C:4](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:5]/[CH2:6][CH2:7]/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[O:3])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)C(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
660 mg of (E,Z,E) and (E,E,E)-7-carboxy-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol was dissolved in 10 ml of dichloromethane. The solution was cooled to 0° C., 440 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for 1 hour. Then, 0.5 ml of benzylamine was added and stirring was continued for 1 hour. The reaction mixture was left at room temperature overnight and water was added followed by extraction with ethyl ether. The oily substance derived from the extract was purified by a thin-layer chromatography to afford 315 mg of the end product.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:20][C:21]([N:23]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]1[C:29]#[N:30])=[O:22].C(N(CC)CC)C.C(#N)C>Cl.O1CCOCC1.CC(C)=O.CCOCC>[ClH:1].[F:28][C@@H:26]1[CH2:27][N:23]([C:21](=[O:22])[CH2:20][NH:16][CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[C@H:24]([C:29]#[N:30])[CH2:25]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: NC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
A round bottom flask was mixed with 1-[4-(trifluoromethyl)phenyl]piperidin-4-amine hydrochloride (337 mg, 1.34 mmol), (2S,4S)-1-(bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (316 mg, 1.34 mmol), trietylamine (408 mg, 04.03 mmol) and acetonitrile (20 mL). The reaction mixture was allowed to stir at RT for 17.0 hours. The reaction mixture was concentrated to dryness. The reaction mixture was partitioned between EtOAc and saturated NaHCO3 and the organics were dried over MgSO4. The organics were concentrated to dryness and dried in vacuo. The resulting crude solid was purified using silica gel chromatography (99% CH2Cl2/1% MeOH, with 1.7% NH3) to yield a pure solid. The solid was dissolved into a 1/1 acetone/ether solution and mixed with several drops of 4.0 N HCl in 1,4-dioxane. The resulting solid was filtered and dried in vacuo to give a total of 277 mg of pure solid.
Reaction SMILES: CI.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[NH:12][C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[C:33](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[N:12]([CH3:33])[C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(CCCCc2ccccc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(CCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 1.25 h

Procedure:
Methyl iodide (22 μl, 0.351 mmol) was added to a stirring mixture of 5-(4-fluorophenyl)-2-(4-phenylbutyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (140 mg, 0.351 mmol) and potassium carbonate (49 mg, 0.351 mmol) in N,N-dimethylformamide (5 ml). After 75 min, it was evaporated and the resultant product purified on a silica gel column (hexane-acetone=3:1; 2:1) to provide the title compound. MS (m/z): 414.3 (M+H)+; C26H24FN3O requir. 413.5.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH:24]([CH3:26])[CH3:25].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1.ClCCl>C(#N)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: C/C(=C(\F)CO)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C/C(=C(\F)C=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-139, 220 mg, 0.52 mmol), tetrapropylammonium peruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (151 mg, 1.25 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([N:19]2[CH2:20][CH2:21][CH2:22][C@H:17]([CH3:16])[C@@H:18]2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1ccc(-n2ccnc2)c(C(=O)O)c1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-n2ccnc2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 2-(1H-imidazol-1-yl)-5-methylbenzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 458, [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[CH2:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][C:18]1=2>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:33]=2)[C:18]2[C:23](=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)CCCC2(OCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 mmol of triethylamine and 2.0 mmol of methanesulphonyl chloride are added to a solution of 1.0 mmol of 5-(2-hydroxyethoxy)-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is identified on the basis of the Rf and used without further purification in the next stage.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:52][CH:53]1[C@H:57]2[C@H:58](OC3CCCCO3)[N:59](C(OC(C)(C)C)=O)[C:60]3[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[C@H:25]2[C@H:26](OC3CCCCO3)[N:27](C(OC(C)(C)C)=O)[C:28]3[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:19]([O:20][CH:21]1[C@@H:25]2[CH:26]=[N:27][C:28]3[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:52][CH:53]1[C@@H:57]2[CH:58]=[N:59][C:60]3[CH:67]=[C:66]([O:68][CH3:69])[CH:65]=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 84.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8j (208 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9j (107 mg, 0.16 mmol, 85%) as a solid: [α]20D=+506° (c=0.15, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.52 (m, 16H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H, 17′-H), 1.83-1.92 (m, 4H, 13-H, 13′-H), 2.01-2.12 (m, 4H, 2-H, 2′-H), 2.28-2.37 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.77 (m, 2H, 11a-H, 11a′-H), 3.78-3.87 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.03-4.19 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.54, 29.57, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6,; IR (neat): 3338, 2926, 1600, 1507, 1448, 1261, 1217, 1024 cm−1; MS (FAB) m/z (relative intensity) 723 ([M+2×MeOH]+., 14), 691 ([M+MeOH]+., 20), 659 (M+., 100).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:13][CH2:14][CH2:15][OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=CCC(O[Si](C)(C)C(C)(C)C)[C@H](C)NC(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(CCCO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (10 mL) of benzyl((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpent-4-en-1-yl)carbamate (600 mg) in tetrahydrofuran was added 0.5 mol/L solution (13.2 mL) of 9-BBN in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture were added 1 mol/L aqueous sodium hydroxide solution (12 mL) and 30% aqueous hydrogen peroxide (5 mL), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give the title compound as a colorless oil (yield: 436 mg).