Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:17])C=1C#N)#N.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH:11]=[O:17])=[CH:5][CH:4]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1ccc(OC)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC=O)cc1
Yield: 68 %

Procedure:
A mixture of 4-methoxy phenylpropane (2 g), silica gel (0.5-0.8 g), DDQ (7.5 g) and dioxane (5-8 ml) was taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was placed inside a microwave oven operating at medium power (600 W) and irradiated for 2-8 minutes. After completion of the reaction (monitored by TLC), the contents of the flask were poured into chloroform and passed through a bed of Celite and further washed with chloroform. The filtrate and washing were combined and the chloroform layers were washed with an aqueous NaOH (15%, 3×15 ml). The combined aqueous layers were further extracted with chloroform (3×15 ml). The chloroform layers were then combined and washed with saturated sodium chloride (3×15 m), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude product which was loaded on silica column and the column was first eluted with hexane (70-80 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 4-methoxy cinnamaldehyde in 68% yield as a solid; mp 57-58° C.; (lit. mp 58° C.). The physical and spectral data was found to similar as reported.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH:6]=[CH:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CC=Cc1cc3c(cnn3-c3ccc(F)cc3)cc12
Yield: 16 %

Procedure:
(3R,4aR,12bS)-12b-Ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.030 g, 0.067 mmol), NBS (0.013 g, 0.074 mmol), and AIBN (0.0011 g, 0.0067 mmol) were dissolved in CCl4 (1 mL) and then mixed at reflux for about 2 h. The reaction was diluted with DCM (10 mL) and then washed with water (2×3 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 10-95% MeCN in aq. NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aR,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (47, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0050 g, 16% yield); LC/MS, method 2, Rt=3.00 min.; MS m/z: 445 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.85-7.79 (m, 2H), 7.72 (s, 1H), 7.44-7.37 (m, 2H), 6.58 (dd, J=12.4, 2.5 Hz, 1H), 5.84-5.76 (m, 1H), 5.59 (s, 1H), 2.84-2.73 (m, 1H), 2.64-2.56 (m, 1H), 2.23-2.08 (m, 2H), 2.06-1.96 (m, 1H), 1.78-1.38 (m, 6H), 0.65 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[C:31]([O:30][C:29]([NH:28][CH2:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Cl)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of methyl 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylate (600.6 mg, 1.924 mmol), tert-butyl piperidin-2-ylmethylcarbamate (500.9 mg, 2.337 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.4 mL, 2.296 mmol) in DMF (10 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the mixture, which was extracted with EtOAc (2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a clear oil (310.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.74 (m, 15H), 2.35-2.37 (m, 3H), 3.03-3.21 (m, 2H), 3.60-3.71 (m, 1H), 3.90 (s, 3H), 4.43-5.04 (m, 3H), 6.94-6.98 (m, 1H), 7.23-7.46 (m, 3H), 10.13-10.43 (m, 1H). [M+H] calc'd for C24H33ClN5O4, 490. found, 490.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[F:11])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NNc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred mixture of 80.0 g of 4-fluorophenylhydrazine hydrochloride in 500 ml of dry pyridine, under nitrogen and cooled in an ice bath, was added, dropwise, 85.8 g of 2-fluorobenzoyl chloride. Upon completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and a precipitate formed. The precipitate was recrystallized from ethanol-water to give 97.1 g (80%) of 2-fluorobenzoic acid, 2-(4-fluorophenyl)hydrazide.
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].N([O-])=[O:18].[Na+].Cl>Cl[Cu]>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([S:2]([Cl:4])(=[O:1])=[O:18])=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Reactant: O=S(Cl)Cl
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Yield: 99.2 %

Procedure:
In a similar fashion using route 3a general procedure 10, SOCl2 (2.5 ml, 33.7 mmol), CuCl (30 mg, 0.30 mmol), 4-amino-3-nitrobenzonitrile (1 g, 6.13 mmol), NaNO2 (0.61 g, 8.83 mmol) and conc. HCl (6.2 ml) gave the title compound (1.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: C1COCC1.C(=S)(OC1C=CC=CC=1)[O:7][C@H:8]1[CH2:15][C@@:14]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@H:10]([C:11](=[O:25])[CH:12]=[C:13]2[O:23][CH3:24])[C@:9]1([CH3:40])[CH2:26][CH2:27][CH2:28][C:29]([CH3:39])([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:30].[Li]N1C(C)(C)CCCC1(C)C.CCCCCC>CCOC(C)=O>[OH:7][C@@H:8]1[C@@:9]([CH3:40])([CH2:26][CH2:27][CH2:28][C:29]([CH3:30])([O:31][Si:32]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:33][CH3:34])[CH3:39])[C@@H:10]2[C:16](=[O:17])[C@@:14]([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])([C:13]([O:23][CH3:24])=[CH:12][C:11]2=[O:25])[CH2:15]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1OC(=S)Oc1ccccc1)C2=O
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)C2=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A THF (2 mL) solution of 40 (144 mg, 0.269 mmol, 1 equiv.) was cooled to −78° C. in a 25-mL recovery flask, and a freshly prepared THF solution of lithium tetramethylpiperidide (0.50 M, 2.2 mL, 1.1 mmol, 4 equiv.) was added. The resulting orange solution was stirred at −78° C. for 15 min and then stirred at 0° C. for 40 min. The reaction was then quenched with saturated aqueous NaHCO3 at 0° C. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an orange oil. Flash column chromatography (75 mL SiO2, 7:3 hexane:EtOAc) afforded 104.3 mg (0.2117 mmol, 79% yield) of 41 as a faint yellow oil. TLC Rf 0.56 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.63 (s, 1H), 4.95 (t, J=7.0 Hz, 1H), 3.78 (d, J=7.8 Hz, 1H), 3.73 (s, 3H), 3.15 (s, 1H), 2.47 (dd, J=14.5, 6.4 Hz, 1H), 2.37 (dd, J=14.5, 7.6 Hz, 1H), 2.09 (dd, J=13.4, 5.4 Hz, 1H), 1.88 (s, 1H), 1.73 (dd, J=13.3, 11.6 Hz, 1H), 1.65 (m, 7H), 1.52 (td, J=12.6, 3.5 Hz, 1H), 1.39 (td, J=12.5, 4.1 Hz, 1H), 1.34-1.27 (m, 2H), 1.23 (m, 4H), 1.18 (s, 3H), 0.92 (t, J=7.9 Hz, 9H), 0.86 (s, 3H), 0.54 (q, J=7.8 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 205.4, 193.1, 177.4, 134.4, 119.0, 105.9, 73.6, 72.0, 69.2, 57.0, 56.0, 46.2, 45.6, 39.4, 38.4, 30.6, 29.50, 29.48, 26.1, 18.1, 17.9, 15.7, 7.3, 6.9. HRMS-ESI (m/z): [M+Na]+ calculated for C28H48O5Si, 515.3163. found, 515.3170.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH2:29])[CH:3]=1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN1C(=O)CCC1>[NH2:30][C:31]1[C:32]([C:38]([NH:29][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:5]=2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Cc1cc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 35 %

Procedure:
Method 27 was followed using 6-methyl-N2,N2-di-BOC-4,4′-bipyridine-2,3′-diamine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv.), EDC (1.0 equiv.), HOAt (1.0 equiv.) in NMP (0.48M) to yield 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (35%). LCMS (m/z): 599.1/601.1 (MH+); LC Rt=3.69 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:32][C:33](=[NH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH3:16])[CH:10]([C:11]1[O:13][N:40]=[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=1)[OH:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent:ethyl acetate) to yield 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (290 mg, 0.83 mmol). 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield 2(S)-amino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1([CH3:17])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([OH:16])[CH:7]=[CH:6][C:5]1=2.[CH2:18]([OH:20])[CH3:19]>>[CH3:3][C:4]1([CH3:17])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([O:16][CH2:19][CH2:18][O:20][C:11]3[CH:12]=[CH:13][C:4]([CH:3]=[O:1])=[CH:5][CH:10]=3)[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Product: CC1(C)CCC(C)(C)c2cc(OCCOc3ccc(C=O)cc3)ccc21
Temperature: -5 °C
Yield: 46.4 %

Procedure:
To a solution of potassium hydroxide (0.67 g, 9.80 mmol) in ethanol (30 ml) is added 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol (2.00 g, 9.80 mmol) and 4-(2-bromoethoxy)benzaldehy (2.25 g, 9.80 mmol). Then the mixture is heated to reflux for 8 hours. After cooled to −5° C., the precipitate is collected by filtration, washed with water, and dried under vacuum to give the title product (1.60 g, 46.4%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]2[CH2:32][N:31]([C:33]3[N:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH2:30]2)=[O:28])=[CH:22][CH:21]=1.Br[C:40]1C=CC(N)=CC=1>>[CH3:40][C:2]([CH3:3])([CH3:4])[CH2:1][N:5]1[CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]3[CH2:32][N:31]([C:33]4[N:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH2:30]3)=[O:28])=[CH:22][CH:21]=2)[CH:7]=[N:6]1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN(c2cccnn2)C1
Product: CC(C)(C)Cn1cc(-c2ccc(NC(=O)C3CN(c4cccnn4)C3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 148A, substituting 1-neopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and N-(4-bromophenyl)-1-(pyridazin-3-yl)azetidine-3-carboxamide for 4-bromoaniline. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.14 (s, 1H), 8.57 (dd, J=4.5, 1.2 Hz, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.66-7.58 (m, 2H), 7.55-7.51 (m, 2H), 7.48 (dd, J=9.1, 4.5 Hz, 1H), 6.98 (dd, J=9.1, 1.1 Hz, 1H), 4.30 (t, J=8.6 Hz, 2H), 4.22 (dd, J=8.4, 6.0 Hz, 2H), 3.90 (s, 2H), 3.77 (tt, J=8.6, 5.9 Hz, 1H), 0.92 (s, 9H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: C1O[C:9]2C=CC(N)=[CH:4][C:3]=2O1.C(OC)(=O)C(C)=O.[CH3:18][O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>C(O)C(C)C>[CH2:18]([O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[CH:3]([CH3:4])[CH3:9]
Reactant: COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2
Reactant: Nc1ccc2c(c1)OCO2
Agent: COC(=O)C(C)=O
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2

Procedure:
Following reductive amination General Procedure A above and using 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-methylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure Q above and using iso-butanol to provide the title compound as an oil. The reaction was monitored by silica gel tlc (Rf=0.61 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC(=O)[NH:29][C:30](=NC(OC(C)(C)C)=O)[N:31]1C=CC=N1)(C)(C)C.C(OC(=O)NC(CCCN(CC1C(C)=CC=CN=1)C1C2N=CC=CC=2CCC1)=NC(OC(C)(C)C)=O)(C)(C)C>C1COCC1>[CH3:1][C:2]1[C:3]([N:8]([CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11][NH:12][C:30]([NH2:31])=[NH:29])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N(CCCN)C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: Cc1cccnc1CN(CCCC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1CCCc2cccnc21
Solvent: C1CCOC1
Product: Cc1cccnc1N(CCCNC(=N)N)C1CCCc2cccnc21

Procedure:
N1-(3-methyl-pyridin-2-yl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (63 mg, 0.20 mmol) and (tert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butyl ester (110 mg, 0.31 mmol) was stirred in THF (0.3 mL) for 16 hours. The solvent was removed under reduced pressure, CH2Cl2 (10 mL) was added and the organic phase washed with 15% aqueous NaOH solution (5×5 mL). The organic phase was then dried (Na2SO4) and concentrated under reduced pressure to afford, after column chromatography with silica gel (33:1:0.1 CH2Cl2/MeOH:NH4OH), ({3-[(3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-tert-butoxycarbonylimino-methyl)-carbamic acid tert butyl ester as a pale brown sticky solid (50 mg, 49%),
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[S:24]
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CCCCCCBr
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
(3S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g) is dissolved in dimethylsulfoxide (10 ml), and thereto are added triethylamine (1.67 ml) and CS2 (0.72 ml), and the mixture is stirred at room temperature for 20 minutes. To the reaction mixture is added dropwise n-hexyl bromide (1.98 g), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is poured onto ice-water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate, and then distilled to remove the solvent. The residue is recrystallized from ether-n-hexane to give the title compound (2.65 g, 73.2%) as colorless needles, m.p. 102°-106° C. NMR (CDCl3, δ): 0.90 (broad, t, 3H, --(CH2)5 --CH3); Mass m/e: 362 (M+), 244 (M+ --C6H13SH); [α]D20 +130.0° (c=1.0, methanol).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH3:46][C:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:53][S:50]([C:47]6([CH3:46])[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:45])[C:13]([O:43][CH3:44])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (58) and 1-methylcyclopropylsulfonamide following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl]-(cyclopropyl)sulfonamide 11: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15-1.45 (m, 4H), 1.45 (d, J=6.9 Hz, 6H), 1.4-1.5 (m, 3H), 1.55 (s, 3H), 1.6-1.8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2.25 (m, 2H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3.0 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.3 Hz, J=3.6 Hz, 1H), 4.6 (t, J=8.0 Hz, 1H), 5.0 (t, J=10.6 Hz, 1H), 5.5 (t, J=3.3 Hz, 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.2 Hz, 1H), 7.5 (s, 1H), 7.9 (d, J=9.2 Hz, 1H), 11 (br s, 1H).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([NH2:19])[N:4]=1.[Br:20]Br.[CH2:22]([OH:26])[CH2:23][CH2:24][CH3:25]>>[Br:20][C:8]1[N:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:10]2[C:6]([N:7]=1)=[C:5]([NH2:19])[N:4]=[C:3]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[N:11]=2
Reactant: BrBr
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1cccnc1
Reactant: CCCCO
Agent: [Na]
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3cccnc3)c2n1

Procedure:
Potassium carbonate (1.1 g, 8 mmol) and 3-chloromethylpyridine hydrochloride (660 mg, 5 mmol) were added to a DMF solution (30 ml) comprising 2-chloroadenine (520 mg, 3 mmol), and the resultant was stirred while heating at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration. Thus, 2-chloro-9-(3-pyridylmethyl)adenine was obtained (yield: 759 mg). Sodium (750 mg, 30 mmol) was added to butanol (50 ml), and the temperature of the mixture was raised to 90° C. to completely dissolve sodium therein. Subsequently, 2-chloro-9-(3-pyridylmethyl)adenine (430 mg, 1.5 mmol) was added thereto, and the resultant was heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, water was added to the residue, and concentrated hydrochloric acid was added dropwise under ice cooling to neutralize the solution. Liquid separation was carried out with the addition of methylene chloride, and the organic layer was concentrated under reduced pressure. Acetic acid (30 ml) was added to the residue to dissolve it, bromine (660 mg, 5.5 mmol) was added thereto, and the resultant was allowed to react at room temperature all day and night. The reaction solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1). Thus, 310 mg of 8-bromo-2-butoxy-9-(3-pyridylmethyl)adenine was obtained. Subsequently, the title compound was obtained in the same manner as in Reference Example 3 and Example 1.