Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=[O:4].FC1C=CC(C2C(C[P+](CCCC)(CCCC)CCCC)=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=2)=CC=1.[Si:44]([O:51][C@H:52]1[CH2:57][C:56](=[O:58])[O:55][C@H:54]([CH:59]=[O:60])[CH2:53]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].O>C1(C)C=CC=CC=1>[Si:44]([O:51][C@@H:52]1[CH2:53][C@@H:54]([CH:59]([OH:4])[OH:60])[O:55][C:56](=[O:58])[CH2:57]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Agent: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)tributylphosphonium 2,2,2-trifluoro-acetate (50.4, 77 mmol) at room temperature in dry toluene (800 mL) sodium hexamethyldisilazane (NaHDMS) in toluene (130 mL of 0.6 M, 77 mmol) was added portionwise in 10 minutes. The reaction mixture was stirred for 60 min and treated at room temperature with a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (20 g, 77 mmol) in 2.5 L of dry toluene obtained by dissolution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (21.4 g, 77 mmol) in toluene and removal of released water. After 24 hours of stirring at room temperature the solution was treated with saturated ammonium chloride solution or water. The aqueous phase was extracted with methyl t-butyl ether (2×2 L), and the combined organic layers dried and concentrated to give oily residue with 25-40% HPLC area of RSVLTBS.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8](OCC)=[O:9])[C@@H:4]([C:13](OCC)=[O:14])[C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].[Li+].[BH4-]>C1COCC1>[OH:14][CH2:13][C@@H:4]1[C@@H:5]([CH2:8][OH:9])[CH2:6][CH2:7][C@H:2]([OH:1])[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O)CC[C@@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H]1[C@H](CO)[C@@H](CO)CC[C@@H]1O
Temperature: 75 °C
Yield: 90.9 %

Procedure:
To a solution of diethyl (1S,2S,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate (Step G, 64.1 g, 192 mmol) in 250 mL THF under nitrogen atmosphere was slowly added LiBH4 powder (16.7 g, 767 mmol, excess) at 0° C. The resulting mixture was heated at 75° C. for 12 hr then cooled to RT. The reaction mixture was carefully quenched by addition of 30 mL water at 0° C., then 30 mL 2 N hydrochloric acid. The organic layer was separated and the aqueous was extracted with EtOAc. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, filtered and the solvent evaporated under vacuum to give 43.7 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.30-7.13 (4H, m), 3.93-3.68 (3H, m), 3.53 (1H, dd, J1=11.2 Hz, J2=2.3 Hz), 3.27 (1H, dd, J1=11.2 Hz, J2=5.1 Hz), 2.85 (1H, t, J=10.5 Hz), 2.39 (3H, s), 2.19 (1H, m), 1.86 (3H, bs), 1.67 (2H, m), 1.55 (1H, m), 1.45 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=[CH:9]2)#[N:2].[ClH:25]>[Pd].CO>[ClH:25].[ClH:25].[NH2:2][CH2:1][C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=[CH:9]2
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 40 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate (10.00 g, 30.74 mmol) was placed in a 2500 mL Parr hydrogenation vessel. Methanol (0.1M, 310 mL) and concentrated HCl (25.62 ml, 307.4 mmol) were added. 10% Pd/C (2.0 g, Degussa type) was added and the vessel was purged with hydrogen gas (three times, no vacuum evacuation was done). The vessel was charged with hydrogen gas at 40 psi and was left on the shaker for 18 hours. To the mixture was added additional 1.0 g of 10% Pd/C and the mixture was placed back in the Parr hydrogenator for an additional 18 hours. The mixture was filtered through a Celite pad and concentrated under reduced pressure (bath temperature kept below 20° C.). The residue was azeotroped with MeOH (3×100 mL). The bath temperature was raised to 40° C. after the third azeotrope. The residue (oil) was dried under high vacuum for 2 hours to provide the desired product as a yellow solid (11.6 g, 93.8%). MS (APCI+) m/z 330 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 6.84-7.76 (m, 6H), 5.43 (s, 2H), 4.8 (br, 2H), 4.105 (q, 2H, J=5.6 Hz), 3.68 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25](=[O:57])[NH:26][CH:27]([B:44]3[O:52][CH:51]4[C:46]([CH3:56])([CH:47]5[CH2:53][CH:49]([CH2:50]4)[C:48]5([CH3:55])[CH3:54])[O:45]3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]C(C)(C)C)=[O:36])[C:30]=3[O:42][CH3:43])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:24][C:25]([NH:26][CH:27]([B:44]3[O:52][CH:51]4[C:46]([CH3:56])([CH:47]5[CH2:53][CH:49]([CH2:50]4)[C:48]5([CH3:55])[CH3:54])[O:45]3)[CH2:28][C:29]3[C:30]([O:42][CH3:43])=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]([OH:37])=[O:36])=[O:57])=[CH:19][CH:18]=2)[CH2:23][NH:15]1
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.60 mL, 8.08 mmol) was added to a solution of 5-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (0.285 g, 0.414 mmol) in CH2Cl2 (3.0 mL) under argon. The reaction was stirred at room temperature for 2 hr then concentrated in vacuo and carried to the next step without purification. ESI-MS m/z 533 (MH)+.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:9]([NH:10][C:11]([O:13]C(C)(C)C)=O)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3].Cl.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([NH:36][CH2:37]C(O)=O)=[O:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CO>[CH2:1]([O:4][C@H:5]1[C@H:9]([NH:10][C:11](=[O:13])[CH2:37][NH:36][C:34](=[O:35])[C:33]2[CH:41]=[CH:42][CH:43]=[C:31]([C:30]([F:29])([F:45])[F:44])[CH:32]=2)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Product: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the solution of benzyl rel-(3R,4R)-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (200 mg, 0.53 mmol) in MeOH (5 mL) was added HCl (4.0 M in 1, 2 dioxane, 15 mL) dropwise. The reaction mixture was stirred at room temperature for 6 h, and the reaction mixture was concentrated under reduced pressure and the crude product was used in the following stop without further purification. The crude product was dissolved in DCM (5 mL). To this solution was added TEA (33.7 mg, 1.61 mmol), {[3-(trifluoromethyl)benzoyl]amino}acetic acid (200 mg, 0.81 mmol), EDC (205 mg, 1.07 mmol) and HOBt (145 mg, 1.07 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water (5 mL). The mixture was extracted with EtOAc (5 mL×3). The organic layers were combined, dried over MgSO4, filtered, concentrated under reduced pressure and subjected to column chromatography (EtOAc:hexanes, 1:3 to 1:1) to afford benzyl rel-(3R,4R)-3-(allyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate (222.5 mg (82%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]#[N:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1>N.CO.[Ni]>[F:1][C:2]1[C:3]([CH2:17][NH2:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: N#Cc1cc2ncn(C3CCCCO3)c2cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc2ncn(C3CCCCO3)c2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 104 (245 mg, 1.0 mmol) in 7N NH3 in MeOH (20 mL) was added Ra—Ni (50 mg), and then it was stirred under hydrogen (1 atm) at RT overnight. The dark mixture was filtered and the filtrate was concentrated in vacuo to afford 230 mg (96%) of (6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (106) as yellow oil: MS (ESI): m/z=250 [M+1]+.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].B[O-].C(=O)C.[CH3:12][C:13]1[CH:18]2C(C)(C)C(C2)[CH2:15][CH:14]=1.B([O-])[O-].N(CCO)CCO>CCOCC.C1COCC1>[CH3:4][CH:3]([CH2:2][C@@H:1]([OH:6])[CH2:18][C:13]([CH:14]=[CH2:15])=[CH2:12])[CH3:5]
Reactant: CC(C)CC=O
Reactant: CC1=CCC2CC1C2(C)C
Agent: B[O-]
Agent: CC=O
Agent: [O-]B[O-]
Solvent: CCOCC
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: C=CC(=C)C[C@H](O)CC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Isovaleraldehyde (2.15 g, 2.68 mL, 25 mmol) in ether (6 mL) was added dropwise to a rapidly stirred solution of B- isoprenyldiisopinocampheylborane, lIpc2BIpn, maintained at -78° C. Stirring was continued for 1 h, when the 11B NMR spectrum of an aliquot showed a peak at δ 52 ppm corresponding to a borinate indicating completion of the reaction. The reaction mixture was warmed to 0° C. and acetaldehyde (2.1 mL, 37.5 mmol) was added when one equiv of α-pinene was eliminated. 11B NMR showed a peak at δ 32 ppm corresponding to a boronate. THF was substituted with EE and 1.1 equiv. of diethanolamine (2.6 mL), 27.5 mmol) was added and stirred for 2 h. The precipitated boron components were filtered and the filtrate was concentrated and distilled (92°-94° C./19 mm Hg) to yield 2.5 g (65%) of (-)-ipsenol. [α]D =-17.67° (c 1, MeOH) which corresponds to 96% ee. The spectral properties were identical to the racemic mixture of Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:27]([N:29]([CH2:40][CH3:41])[CH2:30][CH2:31][O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:28].FC(F)(F)C(O)=O.C(N(CC)CC)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>C(#N)C.CCCCCC>[CH2:40]([N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37][C:16]2[N:15]=[C:14]3[N:13]([CH2:24][CH3:25])[C:12](=[O:26])[N:11]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=4)[CH2:20][C:19]3=[CH:18][N:17]=2)=[CH:38][CH:39]=1)[CH3:41]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(CC)C(=O)N(c2cc(OC)cc(OC)c2)C3)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (0.5 g, 1.33 mmol), 4-(2-diethylaminoethoxy)aniline (0.55 g, 2.66 mmol, Helv. Chim. Acta, 1960; 43:1971-1979) and trifluoroacetic acid (0.46 g, 3.98 mmol) in acetonitrile (6 mL) was heated in a sealed tube at 100° C. for 18 hours. The solvent was removed under reduced pressure and the residue dissolved in water. The solution was made basic with 1N NaOH and extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ether (20 mL), triethylamine (0.27 g, 2.66 mmol), and BOC2O (0.32 g, 1.46 mmol) added, and the mixture stirred at ambient temperature for 4 hours. The reaction mixture was diluted with hexane and cooled to 0° C. The insoluble product was collected by filtration and washed with hexane to afford 0.56 g (81%) of the titled compound: mp 139-141° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 521.3
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCS(=O)(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NS(=O)(=O)CC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and ethanesulfonyl chloride according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 (t, J=7.45 Hz, 3H) 1.33 (t, J=7.33 Hz, 3H) 1.56 (dq, J=15.00, 7.46 Hz, 2H) 2.77-2.83 (m, 2H) 3.49-3.51 (m, 2H) 6.72 (d, J=8.59 Hz, 2H) 7.29 (d, J=8.34 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H) 12.92 (s, 1H); ESI-MS: m/z calc'd for C23H24N4O3S2 468.59. found 469.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.O[C:14]1C=C2C(C=CC(=O)O2)=C[CH:15]=1.S([O-])([O-])(=O)=O>CO.O>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH3:15]
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Product: CCOc1ccc2ccc(=O)oc2c1
Reaction time: 0.07 h

Procedure:
Four standards were used: 7-ethoxycoumarin, which was prepared as 1 mg/ml solution in methanol, and 10 μg/ml solutions prepared from the 1 mg/ml solutions in distilled water; the Phase I metabolite of ECOD, 7-hydroxycoumarin (7-HC), which was prepared as a 1 mg/ml solution in 50:50 methanol:water, and 10 μg/ml solutions diluted in distilled water; the Phase II metabolite, 7-HC-glucuronide, which was prepared as a 1 mg/ml solution in 50:50 methanol:water, and subsequently diluted in distilled water to yield a 10 μg/ml solution; and 7-HC-sulphate, prepared as a 1 mg/ml solution in 50:50 methanol:water, and subsequently diluted in distilled water to yield a 10 μg/ml solution. ECOD elutes between 12.919 to 14.647 minutes from the column, while 7-HC elutes at 3.709 to 4.668 minutes. The subsequent breakdown product, 7HC-glucuronide, is retained at 2.265 to 3.947 minutes, and 7HC-sulphate is retained from 10.230 to 12.878 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: CN(C)[C@]12C[C@H]1CN(CCCCl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1C[C@@H]2C[C@]2(N(C)C)C1
Temperature: 80 °C
Yield: 67.6 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (103 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at room temperature. The reaction mixture was heated at 80° C. for 11 h and cooled to room temperature. Then the reaction mixture was quenched with water (5 mL) and diluted with EtOAc (10 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (5 mL×3). The combined organic phases were, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH) to give the crude product, which was then recrystallized from CH2Cl2/PE to afford title compound as a yellow solid (138 mg, 67.7%), HPLC: 96.5%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.81 (1H, m), 1.11 (1H, m), 1.26 (1H, br s), 1.52 (1H, m), 2.38 (6H, s), 2.65-2.81 (3H, m), 3.11 (2H, m), 3.42 (1H, br s), 3.98 (3H, s), 4.18 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=14.4 Hz), 7.41 (1H, s), 7.66 (1H, m), 7.98 (1H, dd, J=5.2, 6.8 Hz), 8.64 (1H, s) ppm.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br-].[Mg+2].[Br-].O=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]1[C:30]([O:32]CC)=[O:31]>C1COCC1.CCOCC.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]2[C:30]([OH:32])=[O:31])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: [Br-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl (1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). The resulting p-methoxyphenyt magnesium bromide solution was added to a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et2O (300 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et2O/ hexanes. The solid which formed was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified by flash chromatography. The material which was isolated was treated with Et2O/ hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.
Reaction SMILES: C(O[CH:6]([N:38]=C=O)[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[O:20][CH2:19]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(C)(C)C.C(OCC)(=O)C.[ClH:47]>>[ClH:47].[ClH:47].[NH2:38][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[O:20][CH2:19]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)[C@H](CCCCC(N=C=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3.5 h

Procedure:
A solution of tert-butyl 3(S)-[6-tert-butoxy-carbonylamino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) in 5N hydrogen chloride-ethyl acetate solution (10 ml) is allowed to stand for 3.5 hours at room temperature. Petroleum ether (80 ml) is added to the solution, and the resulting precipitate is collected and dried in vacuo to give 3(S)-[6-amino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.4 g) as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][C:7]2=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CCO.O=[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C=C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-(7-bromo-1′-(2-adamantylcarbamoyl)spiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate (4 g, 8 mmol) in EtOH (50 mL) was added PtO2 (400 mg) at rt under N2. Then the reaction mixture was stirred at rt for 6 h under H2. The reaction mixture was filtered and the filtrate was concentrated to leave crude (±)-ethyl 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccco1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccco1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(2-furyl)acryloyl chloride (New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, R. F.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem., 1989, 32, 1147) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 287.32; mp: 164.0-165.0° C.; 1H-NMR (CDCl3) δ: 8.80-8.75 (1H, m), 8.00 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.83-7.78 (1H, m), 7.78 (1H, d, J=15.4 Hz), 7.54-7.39 (4H, m), 7.37-7.16 (2H, m), 7.01 (1H, d, J=15.4 Hz), 6.51 (1H, d, J=3.3 Hz), 6.44 (1H, dd, J=3.3, 1.8 Hz).