Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12]O[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:47]2[CH:46]=[CH:45][N:44]=[CH:43][C:42]=2[CH:41]=1)CCC.[C:57]1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:57][CH2:12][CH2:13][C@H:14]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:47]3[CH:46]=[CH:45][N:44]=[CH:43][C:42]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cnccc2s1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3cnccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol), 2-(tributylstannyl)thieno[3,2-c]pyridine (339 mg, 0.798 mmol) and tetrakis(triphenylphosphine)palladium(0) (461 mg, 0.399 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. After the solvent was removed, the crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The fractions were collected to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was first dissolved in DCM (3 mL) and then TFA/DCM (1:1, 10 mL) at 60° C. for 1 hour. After removal of solvent, the resulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) and purified via preparative mass triggered LCMS, eluting with a gradient of 30-40% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The mixture was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×300 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (30 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.10 (m, 8H), 3.82 (br s, 1H), 4.33 (d, J=3.54 Hz, 1H), 4.47 (s, 2H), 7.30 (d, J=6.06 Hz, 1H), 7.89 (br s, 2H), 8.39 (d, J=5.05 Hz, 1H), 8.57 (s, 1H), 8.77 (s, 1H), 9.44 (s, 1H), 9.71 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20FN5OS, 398. found, 398.
Reaction SMILES: C1(C23COC([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)(OC2)OC3)CCCCC1.[CH:21]1([C:27]2([CH2:31][OH:32])[CH2:30][O:29][CH2:28]2)[CH2:26][CH2:25]CCC1.C1(C(CO)(CO)[CH2:40][OH:41])CCCCC1.OCC1(CCC)COC1>>[CH2:21]([C:27]12[CH2:30][O:29][C:28]([C:17]3[CH:16]=[CH:15][CH:20]=[CH:19][N:18]=3)([O:32][CH2:31]1)[O:41][CH2:40]2)[CH2:26][CH3:25]
Reactant: OCC1(C2CCCCC2)COC1
Reactant: c1cc(C23OCC(C4CCCCC4)(CO2)CO3)ccn1
Reactant: OCC(CO)(CO)C1CCCCC1
Agent: CCCC1(CO)COC1
Product: CCCC12COC(c3ccccn3)(OC1)OC2

Procedure:
4-Cyclohexyl-1-(4-pyridyl)-2,6,7-trioxabicyclo[2.2.2]octane (from 3-cyclohexyl-3-hydroxymethyloxetane which was prepared from 2-cyclohexyl-2-hydroxymethylpropan-1,3-diol in a manner described for the synthesis of 3-hydroxymethyl-3-n-propyloxetane).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])(=O)=O>C(O)(=O)C>[C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH2:21][Cl:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Yield: 93.1 %

Procedure:
A solution of ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.), sulfuryl chloride (13.5 g.) and acetic acid (30 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[CH2:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[SH:23].Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CCCCCC.CC(=O)OCC>CN(C=O)C>[CH:10]12[CH2:13][CH:7]([CH:8]([CH2:14][NH:15][C:16]([C:17]3[C:18]([S:23][CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:24])[CH2:9]1)[CH2:12][CH2:11]2
Reactant: Fc1ccc(CCCBr)cc1
Reactant: O=C(NCC1CC2CCC1C2)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(NCC1CC2CCC1C2)c1cccnc1SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
178 mg (1.29 mmol) of K2CO3 were added to a solution of 308 mg (1.18 mmol) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide in DMF (5 ml), and the mixture was stirred for 60 min at RT. 255 mg (1.18 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were then added and the mixture was stirred for a further 16 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water, dried over MgSO4, filtered and concentrated in vacuo. CC (hexane/EA 2:1) of the residue yielded 333 mg (0.83 mmol, 71%) of N-(5-bicyclo-[2.2.1]heptanyl-methyl)-2-[3-(4-fluorophenyl)-propyl-sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 399.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH:21][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(F)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(F)cc1-c1ccccc1

Procedure:
The resultant product from Example 13B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:48](=[O:50])[CH3:49])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.0551 g, 0.097 mmol) and pyridine (0.05 mL, 0.618 mmol) in DMF (2 mL) was treated dropwise with acetic anhydride (Aldrich) (10.0 μl, 0.107 mmol) at 0° C. The orange solution was stirred at rt overnight. The mixture was concentrated in vacuo to reduce the solvent volume to about 1 mL. Water (2 mL) and brine (20 mL) were added and the aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.060 g, 100% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 8.75 (d, J=2.19 Hz, 1H); 8.47 (s, 1H); 8.24 (d, J=2.34 Hz, 1H); 8.06-8.16 (m, 1H); 7.86-7.95 (m, 1H); 7.83 (br. s., 1H); 7.19 (t, J=8.48 Hz, 4H); 6.87 (d, J=6.58 Hz, 4H); 4.84 (d, J=10.96 Hz, 4H); 3.80 (d, J=4.09 Hz, 6H); 2.59 (s, 3H); 2.20 (s, 3H). m/z (ESI, +ve ion) 611.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:6]1[C:5]([CH3:15])([CH3:14])[C:4]2[C:8](=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:13])[CH:17]=[CH:18][CH3:19]
Reactant: C=CC(C)O
Reactant: COc1cc2c(cc1Cl)C(C)(C)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)c(Cl)cc2C1(C)C
Yield: 66 %

Procedure:
A solution of 14.5 g of 5-chloro-6-methoxy-3,3-dimethyl-1-indanone, 13.3 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 150 ml of 2,2-dimethoxy-propane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm 2 mm, pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). In addition to 2.25 g of educt, there were obtained 11.9 g (66%) of (RS)-2-(2-buten-1-yl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone as a pale yellow solid with m.p. 86°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(Cl)c1Cl
Yield: 60.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.7 mmol), 2,3-dichlorobenzenesulfonyl chloride (190 mg, 0.8 mmol) and DMAP (cat.) gave the title compound (150 mg, 63%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.CO.[C:12](O)(=O)[CH3:13].[C:16]([BH3-])#N.[Na+]>>[CH:13]1([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]2)[CH2:12][CH2:16]1
Reactant: NC(=O)C1CCNCC1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 121.9 %

Procedure:
To a solution of piperidine-4-carboxamide (1 g, 7.8 mmol) in MeOH (80 mL) 1-ethoxy-1-trimethylsilyloxycyclopropane (2.35 mL, 11.7 mmol, 1.5 eq) was added, followed by acetic acid (1.34 mL, 23.4 mmol, 3 eq) and sodium cyanoborohydride (923 mg, 12.48 mmol, 1.6 eq) and the mixture was stirred at 60° C. overnight. The solvent was then concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM/MeOH/NH3 7 N in MeOH 90:9:1) affording 1.6 g of 1-cyclopropylpiperidine-4-carboxamide.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][P:12]([O:15][CH2:16][CH:17]1[O:21][CH:20]([N:22]2[C:27](=[O:28])[N:26]=[C:25]([NH2:29])[CH:24]=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])([O-:14])=[O:13])([O-:10])=[O:9])([CH3:4])[CH3:3].[Na+:32].CN(N=O)C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=O>O>[CH3:4][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][P:12]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[C:27](=[O:28])[N:26]=[C:25]([NH2:29])[CH:24]=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])([O-:14])=[O:13])([O-:10])=[O:9])([CH3:1])[CH3:3].[Na+:32]
Reactant: C[N+](C)(C)CCOP(=O)([O-])OP(=O)([O-])OCC1OC(n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Agent: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: C[N+](C)(C)CCOP(=O)([O-])OP(=O)([O-])OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O

Procedure:
CDP-choline Na was dissolved in distilled water and orally administered at a dose of 100 mg/kg once a day starting from the time point when 5 weeks passed from the administration of streptozotocin.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCOCC>[OH-].[Na+]>[CH2:13]([O:12][C:10]([NH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(N)CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
3-Amino-3-methylbutyric acid (2.40 g, 20.49 mmol) was dissolved in NaOH (2 M aq, 35 mL), the resulting mixture cooled to 0° C., and benzyl chloroformate (5.77 mL, 40.97 mmol) added. The reaction mixture was stirred vigorously at 0° C. for 1 h and at RT for 3 h. Et2O (50 mL) was then added, and the layers separated. The organic layer was discarded. The aqueous layer was acidified to pH 2, brine added, and the resulting mixture extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 3-benzyloxycarbonylamino-3-methyl-butyric acid (2.33 g, 46% yield) without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Product: O=C(Cl)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
4-Bromo-3-nitrobenzoic acid (500 mg) in thionyl chloride (3 ml) was heated at 110° C. for 2 hrs. The excess thionyl chloride was evaporated in vacuo to give 4-bromo-3-nitrobenzoyl chloride as a yellow solid (502 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:20])[CH3:19])[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:19])[CH3:20])[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CC(C)(O)c1ccc(C(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)O)cc1F
Yield: 93.5 %

Procedure:
To a solution of 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (9.1 g, 45.7 mmol) in DMF (40 mL) was added cesium carbonate (22.3 g, 68.5 mmol) followed by benzyl bromide (11.7 g, 8.1 mL, 68.5 mmol) and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed sequentially with H2O (3×10 mL), brine solution. The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 10-20% EtOAc-hexanes to provide benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 21%) ESI-MS m/z calc. 288.2. found 289.3 (M+1)+; Retention time: 1.79 min (3 min run). To a solution of benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 9.71 mmol) in MeOH (50 mL) was added palladium on carbon (100 mg, 0.09 mmol) and the reaction mixture was subjected to an atmosphere of hydrogen for 16 hours. The catalyst was removed via filtration over Celite® and the solvent removed in vacuo to provide 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (1.8 g, 96%) as a white solid. ESI-MS m/z calc. 198.2. found 199.9 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[O:30]1[C:34]2([CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=[O:41])[CH2:35]2)[O:33][CH2:32][CH2:31]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:40]([OH:41])[CH2:39][CH:36]2[CH2:37][CH2:38][C:34]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:35]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: O=CCC1CCC2(C1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCC3(C2)OCCO3)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (4.2 g, 16 mmol) in dry tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6 M, 15 mL, 24 mmol) dropwise. The mixture was stirred at −78° C. for 15 min and then treated with (1,4-dioxa-spiro[4.4]non-7-yl)-acetaldehyde (5 g, 29 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 30% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol as a colorless oil (5.5 g, 74%): LC/MS m/e calcd for C22H24N2O5S [M+H]+ 429.51, observed 429.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CCN1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (6 mL), suspended in methanol and thereby washed, and the solid was collected by filtration to obtain (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.122 g, 62%).
Reaction SMILES: [Li].[CH2:2]1[O:9][C@@H:8]2[O:10][C@H:3]1[CH:4]=[CH:5][C:6]2=[O:7].O.CO>CCOCC.[H-]>[C@@H:8]12[O:9][CH2:2][C@@H:3]([O:10]1)[CH:4]=[CH:5][C@@H:6]2[OH:7]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Yield: 70.3 %

Procedure:
2.42 g (63.8 mmol) of lithium almunium hydride was added to 200 ml of dry ether to prepare a hydride solution, followed by adding dropwise a solution prepared by dissolving 7.98 g (63.3 mmol) of levoglucosenone in 130 ml of dry ether into the hydride solution while cooling the hydride solution in an ice water bath. After completion of the addition, the resultant solution was kept stirred at room temperature for an hour, followed by further adding dropwise 4.60 g (256 mmol) of water to the solution. Then, methanol was added to the reaction mixture, followed by removing the insoluble components by means of filtration. Further, the solvent was removed from the filtrate by means of distillation under reduced pressure, followed by refining the residue by means of a silica gel column chromatograph. A mixed solvent consisting of hexane and diethyl ether was used as an eluent for the column chromatograph. The mixing ratio of hexane to diethyl ether fell within a range of between 1:1 and 1:2. Finally, the formed product was recrystallized from a mixed solvent consisting of 4 parts of hexane and 1 part of diethyl ether so as to obtain 5.70 g of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose (compound 2). The product yield was 70.3%. The physical data of the formed product were found to be as follows:
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH2:31][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)CCN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCN(C)C)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
Sodium hydride (0.7 g) is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (8.0 g) in anhydrous dimethylformamide (125 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. and then treated with a solution of 4-dimethylamino-2-butanone (3.5 g) in anhydrous dimethylformamide (5 cc). The mixture is stirred for 3 hours at a temperature in the region of 20° C., and is then poured into distilled water (500 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is dissolved in ethyl acetate (400 cc) and the solution obtained is extracted with 1 N aqueous hydrochloric acid solution (2×100 cc). The aqueous phases are combined, washed with ethyl acetate (50 cc), alkalinized with 10 N aqueous sodium hydroxide solution to a pH in the region of 11 and extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with distilled water (3×30 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in acetonitrile, 3-(4-dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.6 g), m.p. 140° C., is obtained.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[N:9]=1)=[C:2]=[S:3].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2([C:29]#N)[CH2:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C[OH:32].Cl>CC(N(C)C)=O>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:2](=[S:3])[N:1]([C:4]3[CH:5]=[CH:6][C:7]4[N:8]([C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=4)[N:9]=3)[C:29](=[O:32])[C:25]32[CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=1
Reactant: N#CC1(Nc2ccc(O)cc2)CCC1
Reactant: CO
Reactant: FC(F)(F)c1nnc2ccc(N=C=S)nn12
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C1N(c2ccc3nnc(C(F)(F)F)n3n2)C(=S)N(c2ccc(O)cc2)C12CCC2
Temperature: 60 °C

Procedure:
A mixture of 6-isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (Intermediate 8, 545 mg, 2.22 mmol) and 1-((4-hydroxyphenyl)amino)cyclobutanecarbonitrile (Intermediate 25, 418 mg, 2.22 mmol) in DMA (15 mL) was heated to 60° C. for 2 h. MeOH (10 mL) and HCl (2M, 10 mL) were added and the mixture was refluxed for 1 h. The mixture was cooled to room temperature and slowly poured into an ice/water bath. The dark brown solid was filtered, washed with water, dried, and purified by reverse phase HPLC (Acetonitrile/water:TFA) to afford 5-(4-hydroxyphenyl)-6-thioxo-7-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,7-diazaspiro[3.4]octan-8-one as a light brown solid. LCMS [M+1]+ 435.4.