Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.P(Br)(Br)[Br:16].N>O>[Br:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(-c2cncc(Cl)n2)cc1
Agent: N
Solvent: O
Product: Cc1ccc(-c2cncc(Br)n2)cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-chloro-6-(4-methylphenyl)pyrazine (2.5 g, 12.3 mmol), was added phosphorus tribromide (20 mL) and the mixture heated at reflux for 6 h under nitrogen. The reaction mixture was cooled to room temperature prior to pouring carefully into iced water (600 mL). The resulting solution was adjusted to pH 6–7 using aqueous ammonia and extracted with Et2O (2×250 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a white solid (2.32 g).
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25]O)[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:30])=O.[Na+].[Cl-]>ClCCl.CN(C=O)C>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25][Cl:30])[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CO)c2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CCl)c2cccnc21
Reaction time: 3 h
Yield: 73.9 %

Procedure:
To a solution of 15 (3.5 g, 10.4 mmol) in dichloromethane (20 mL) was charged DMF (0.04 mL, 0.5 mmol). This solution was cooled under an ice bath. Thionyl chloride (0.85 mL, 11.5 mmol) was then added under 5° C., and the resulting reaction was aged for 3 h at this temperature. Once the reaction was complete, 5% aqueous NaCl (16.5 mL) was added. The organic layer was separated and washed with 5% aqueous NaCl (16.5 mL). The solvent was removed via rotovap, and the crude was purified by silica gel column chromatography (0 to 10% AcOEt/hexane) to give the desired compound 16 as an oil (3.05 g, 74%). 1H NMR (CDCl3, 500 MHz): δ 8.20 (dd, J=5.1, 1.7 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1, 1.1 Hz, 1H), 7.18 (s, 1H), 7.12 (dd, J=6.3, 2.7 Hz, 1H), 6.88 (dd, J=7.3, 5.1 Hz, 1H), 4.77 (ABq, J=12.9 Hz, 2H), 3.72 (m, 1H), 3.46 (dd, J=14.2, 4.4, 1H), 3.18 (dd, J=14.2, 8.7 Hz, 1H), 1.67 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 177.6, 159.1, 146.5, 143.3, 136.6, 131.0, 129.7 (m, 2C), 124.0, 123.0, 123.9 (q, J=271 Hz), 117.4, 126.6, 62.4, 58.8, 46.1, 32.9, 28.6.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:21]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCOC(C)=O.CCCCCC.CCOC(C)=O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]#[CH:23])[CH:21]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#C[Si](C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reaction time: 1.75 h

Procedure:
In a 50 mL round-bottom flask with stir bar, a solution of KOH (174 mg) in methanol (4 mL) was added to a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(trimethylsilyl)ethynyl]pyridine (560 mg, 1.55 mmol) in methanol (1 mL). The flask was loosely closed with a rubber stopper, and the mixture was stirred at room temperature for 3 h. A TLC taken after 105 min (silica gel, EtOAc/hexane 55:45) showed traces of starting material (Rf 0.6) and a new spot (Rf 0.5). The mixture was evaporated and the residue directly chromatographed on silica gel (24×2.5 cm, EtOAc/hexane 1:1). The product-containing fractions were evaporated, and the residue was dried (35° C./14 torr) to obtain 473 mg (nominally 106%) of the product, an orange-brown oil which darkened upon standing and appeared to be too unstable for more stringent drying. The excess mass balance was represented by EtOAc as shown by 1H NMR. The material was suitable in this form for the subsequent reaction. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.36-8.29 (m, 2H), 7.33 (dd, 1H, J=1.6, 2.7 Hz), 4.51 (m, 1H), 4.34 (m, 1H), 4.13 (dd, 1H, J=2.9, 10.1 Hz), 3.89 (t, 2H, J=7.6 Hz), 3.20 (s, 1H), 2.43-2.20 (m, 2H), 1.43 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.0, 154.3 (br), 145.1, 138.4, 123.5, 119.3 (br), 80.4, 80.0, 79.7, 68.7, 59.9, 47.0 (br), 28.3, 18.9.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][C:15]#[CH:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[N:24]=1>CS(C)=O>[Br:22][C:23]1[N:24]=[C:25]([CH2:29][N:8]2[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]3[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]2=3)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: BrCc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1cccc(Br)n1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (20 mL) followed by sodium tert-butoxide (153 mg, 1.588 mmol) and 2-bromo-6-(bromomethyl)pyridine (332 mg, 1.324 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.04 (m, 1H), 3.12-3.24 (m, 2H), 3.40-3.53 (m, 2H), 3.62-3.72 (m, 1H), 3.86-4.00 (m, 2H), 4.19-4.28 (m, 1H), 4.42-4.64 (m, 2H), 7.31 (s, 4H), 7.36-7.43 (m, 4H), 7.56 (s, 3H), 7.72 (d, J=7.83 Hz, 4H). ESI-MS m/z [M+H]+ calc'd for C15H15BrClN5O, 396.01. found 396.1.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=1>CN(C)C=O.O1CCOCC1>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:35]3[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrogen chloride salt (52 mg), ethyldiisopropylamine (59 mg), and 2-chloro-5-ethylpyrimidine (21 mg) in N,N-dimethylformamide (1.0 mL) and 1,4-dioxane (1.5 mL) is stirred over night at 120° C. After cooling to room temperature, the solvents are evaporated and the residue is purified by HPLC (H2O/MeOH/TFA) to give the title compound. LC (method 9): tR=1.74 min; Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][CH:14]=1)=[O:12].[C:21](=O)([O-])O.[Na+].O>C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:21]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=3)[N:1]=2)[CH:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O=C([O-])O
Reactant: Nc1ccc(F)cn1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(-c2cn3cc(F)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
2-Amino-5-fluoropyridine (2.5 g) and 2-bromo-4′-cyanoacetophenone (5.0 g) were dissolved in ethanol (100 mL), and sodium hydrogencarbonate (1.9 g) was added to the solution, followed by refluxing for 16 hours. Water (10 mL) was added to the reaction mixture. After the reaction mixture had been left to cool, the precipitated matter was recovered through filtration and dried, to thereby yield 4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)benzonitrile (2.1 g). Subsequently, the thus-obtained 4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)benzonitrile was dissolved in anhydrous tetrahydrofuran solution (30 mL), and diisobutylaluminum hydride (9.0 mL, 0.93M hexane solution) was added dropwise to the solution at −78° C., followed by stirring under a stream of argon at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Anhydrous magnesium sulfate and diethyl ether were added to the resultant mixture, followed by further stirring for 1 hour. The solvent was evaporated, and the residue was purified, to thereby yield 4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)benzaldehyde (0.6 g). Subsequently, this product was dissolved in anhydrous tetrahydrofuran solution (30 mL), and methyl magnesium bromide (0.78 mL, 3M hexane solution) was added dropwise to the mixture under a stream of argon at −78° C., followed by stirring under ice cooling for 15 minutes and then at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. The mixture was extracted with dichloromethane-methanol, and purified through silica gel chromatography (dichloromethane:methanol=95:5), to thereby yield 1-[4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl]-1-ethanol (530 mg). The thus-obtained 1-[4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl]-1-ethanol (530 mg) was dissolved in chloroform solution (50 mL), and manganese dioxide (721 mg) was added to the solution, followed by refluxing for 4 hours. After the reaction mixture had been filtered through Celite, the filtrate was concentrated, and the residue was purified through silica gel chromatography (dichloromethane:methanol=98:2), to thereby yield the title compound (410 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH2:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:19][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH:18]=[CH:17]3)[CH:23]=1
Reactant: Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccc3cccc(NCc4cccnc4)c3n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a mixture of 2-(3-(trifluoromethyl)phenyl)quinolin-8-amine (200 mg, 0.7 mmol), 3-pyridinecarbaldehyde (150 mg, 1.4 mmol) and acetic acid (84 mg, 1.4 mmol) in methanol (10 mL) was added NaCNBH3 (88 mg, 1.4 mmol) in portions at room temperature, then the reaction was stirred at room temperature for 5 h. The reaction was concentrated in vacuo, the residue was taken up in DCM, The solution was washed with water (1×50 mL), treated with active carbon and Na2SO4, filtered through a silica gel pad, and the pad was washed with CH2Cl2. The organic solutions were combined and concentrated in vacuo, triturated with a mixture of ethyl acetate/pentane and filtered to give N-(pyridin-3-ylmethyl)-2-(3-(trifluoromethyl)phenyl)quinolin-8-amine as a yellow solid (220 mg, yield 83%) MS (ESI) calcd for C22H16F3N3 (m/z): 379.13. found: 380 [M+1].
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]=[CH:13][C:14](=C)[CH3:15].[C:17]1(C)CCC(C(C)=C)CC=1>C1(C)C=CC=CC=1>[C:2]([CH:4]1[CH2:15][CH2:14][C:13]([CH3:12])=[CH:6][C:5]1([CH3:17])[CH3:7])(=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: C=CC(=C)C
Reactant: C=C(C)C1CC=C(C)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)C1CCC(C)=CC1(C)C
Reaction time: 48 h

Procedure:
Mesityl oxide (441 g) is added at 12°-16° C. to a stirred suspension of aluminum chloride (63 g) in toluene (2100 ml). A solution of isoprene (1224 g) in toluene (1800 ml) is then added over a period of 1.5 hr. at 15°-20° C. After approximately 48 hr. at 15°-25° C., the reaction mixture is washed successively with 10% hydrochloric acid sollution, water, 10% sodium bicarbonate solution, and water. The washed material is distilled rapidly at 3 mm Hg using a short column to give 626 g of crude product. Fractionation of 548 g of this material through a 12"×1", Goodloe packed column gives 478 g of 4-acetyl-1,3,3-trimethyl-1-cyclohexene containing a small amount of 1,8-p-menthadiene. The structure is confirmed by NMR (1H and 13C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred 0° C. solution of (2-bromo-pyridin-4-yl)-methanol (3.00 g, 16.0 mmol) and N,N-diisopropylethylamine (8.3 mL, 48 mmol) in dichloromethane (30 mL) is added methanesulfonyl chloride (1.30 mL, 16.8 mmol). The resulting mixture is warmed to room temperature. After 1 hour, the mixture is diluted with dichloromethane (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to afford crude methanesulfonic acid 2-bromo-pyridin-4-ylmethyl ester, which is used without purification.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH3:27][N:29]1[C:3]2[C@@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1
Reactant: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1ccc3ccccc3c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 460 mg, 2.14 mmol) in 1,2-dichloroethane (12 mL) was added to a cooled (0° C.) solution of triethylamine (410 μL, 2.94 mmol) and N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 36; 430 mg, 1.58 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred at room temperature for 30 min. A solution of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the reaction mixture was heated in an oil-bath at 100° C. for 30 min, and allowed to cool. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with 1:1 water/brine (30 mL) and the aqueous wash was back-extracted with dichloromethane (30 mL). The combined organic layers were dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was co-evaporated with methanol and then with diethyl ether, and dried under high vacuum at 40° C. to give (4S,7R)-1,7,8,8-tetramethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (337 mg, 64%) as an off-white foam. ES(+)-MS (M+H) 333.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6](NCCCNC)[CH:7]=1.[C:15]([N:22]1[CH:26]=NC=N1)([N:17]1[CH:21]=NC=N1)=[S:16].O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:14])=[C:4]([N:22]2[CH2:26][CH2:29][CH2:28][N:17]([CH3:21])[C:15]2=[S:16])[CH:3]=1
Reactant: CNCCCNc1cc(Cl)ccc1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: S=C(n1cncn1)n1cncn1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cl)cc1N1CCCN(C)C1=S
Yield: 63.7 %

Procedure:
To a solution of the diamine of Step A (3.8 g) in dioxane (100 mL) under nitrogen was added 1,1′-thiocarbonyl-di-1,2,4-triazole (3.38 g). After 45 minutes additional thiocarbonyl reagent (0.5 g) was added, followed after 30 minutes by para-toluenesulfonic acid monohydrate (6.88 g). The reaction mixture was heated at reflux for 4 hours at which point additional para-toluenesulfonic acid monohydrate (2.0 g) was added. After refluxing for 18 hours, another portion of para-toluenesulfonic acid monohydrate (1.5 g) was added. The reaction mixture was refluxed for an additional 24 hours, cooled and concentrated in vacuo to give a brown oil which crystallized on standing. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided a light pink solid which was triturated with diethyl ether to give the title compound (2.9 g, 63.9%) as a white solid, m.p. 143-145° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)[CH:2]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>CO.C(OCC)(=O)C>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: O=C(O)c1cccc(NCc2cccnc2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccnc4)c3C2=O)C(=O)N1
Yield: 46 %

Procedure:
3-[(Pyridin-3-ylmethyl)-amino]-phthalic acid (3.03 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was slurried in 50% methanol/ethyl acetate (20 ml) for 18 h to give 0.50 g (46%) of product as a yellow solid: mp 231-233° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.03 (t, J=6.6 Hz, 2H), 5.09 (dd, J=5.2 and 12.4 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.64-2.48 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.78, 170.05, 168.65, 167.22, 148.66, 148.27, 145.75, 136.14, 134.79, 134.54, 132.25, 123.58, 117.50, 110.92, 109.82, 48.57, 42.99, 30.96, 22.12; Anal. Calcd. For C19H16N4O4: C, 62.63; H, 4.43; N, 15.38. Found: C, 62.30; H, 4.27; N, 15.30.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([OH:37])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:26]=[C:27]([O:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:30]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(Oc2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 40 %

Procedure:
A mixture of N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamide (E2) (52 mg, 0.1 mmol), benzeneboronic acid (25 mg, 0.2 mmol), cupric acetate (18 mg, 0.1 mmol) and powdered 4 A molecular sieves in dichloromethane (1 ml) were treated with triethylamine (0.070 ml, 0.5 mmol). After stirring for 40 hrs at room temperature, the mixture was partitioned between ethyl acetate and 2N HCl and the product was extracted into ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and concentrated. Chromatography on silica gel (elution with ethyl acetate) gave E11 as a white solid (24 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].O1CCCC1>CO.[Pd]>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:30]
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methylurea (503 mg) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10% palladium on carbon (200 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was removed by filtration and washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=10:1) to provide the titled compound as a yellow oil (467 mg, 85.6%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(-c2cccnc2F)c(Sc2ccccc2)s1
Yield: 99 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (2.86 g) as a starting material, and using thiophenol (1.33 mL) and potassium carbonate (2.21 g), an operation similar to that of Reference Example 1 was performed to give the title compound as a pale-yellow oil (yield 3.11 g, yield 99%).