Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])[C:8](=[O:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O1CCOCC1.O>[CH3:3][S:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])[C:8](=[O:20])[C:7]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)N1COC(CSC)=C(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Temperature: 60 °C
Yield: 38.7 %

Procedure:
A solution of sodium hydroxide (16.43 g) in 10 water was added to a stirred solution of ethyl 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (68 g) in a mixture of ethanol and 1,4-dioxan. The solution was heated at 60° C. for 6 hours, allowed to cool and the solvent was removed under reduced pressure to give an orange oil which was dissolved in water. The aqueous solution was washed with dichloromethane, acidified to pH 1 with concentrated hydrochloric acid, extracted with dichloromethane, the extract dried (magnesium sulphate) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (24.2 g) as a yellow solid, m.p. 136-137° C.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC=CC=1.[S:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:6]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)=[C:3]([C:8]([O:10][CH3:11])=[O:9])[S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (compound 7a, 9.0 g, 38.0 mmol) in ethanol: toluene (100:30 ml) in sealed tube, (4-sulfamoylphenyl)boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) were added under a nitrogen atmosphere at room temperature (about 25° C.). Nitrogen gas was purged to this suspension for further 15 minute at room temperature (about 25° C.) and tetrakis(triphenyl phosphine)palladium(0) (2.21 g, 1.9 mmol) was added at 25° C. and sealed tube was closed. The reaction mixture was stirred at 105° C. for 15 hr and the progress of the reaction was monitored by TLC. Reaction mixture was filtered and washed with ethyl acetate (2×100 ml). Organic layer was concentrated under reduced pressure to obtain crude product as semi-solid (11.2 g); which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (8.8 g, 70.70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:32][C@H:33]([C:40](O)=O)[CH2:34]C1SC=CC=1)=O)C1C=CC=CC=1.[CH3:43]N1CCOCC1.C(OC(Cl)=O)C(C)C>C1COCC1>[C:33]([NH:32][C:19](=[O:21])[C@H:12]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:40])([CH3:43])[CH3:34]
Reactant: O=C(N[C@@H](Cc1cccs1)C(=O)O)OCc1ccccc1
Reactant: CN1CCOCC1
Reactant: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H](Cc1cccs1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 97 %

Procedure:
Into a 500 ml flask was placed 8.06 g of the subtitled compound of Example A, N-(Benzyloxycarbonyl)-3-(2-thienyl)-L-alanine, in 130 ml of THF. The compound was cooled to 0° C. N-Methylmorpholine (4.23 ml) was added, followed by isobutylchloroformate (4-04 ml) over two minutes. The mixture was stirred for 15-20 minutes, and 3.74 ml of t-butylamire was added. The bath was removed, and the mixture was stirred at room temperature for two hours. The mixture was concentrated on rotovap, and the residue was taken up in ethyl acetate. The residue was washed successively with H2O, HCl, and saturated NaHCO3 solution. The organics were separated and dried with Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in 100 ml hot hexane and cooled in a refrigerator overnight to give a solid. The hexane was decanted, followed by drying to yield a solid of 9.25 g N-(carbobenzyloxy)-3-(2-thienyl)-L-alanine-tert-butylamide (97% yield).
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[CH2:11][C:12](OCC)=[O:13])=[N:6][CH:5]=1.C(O)C>CCOCC>[Br:3][C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][OH:13])=[N:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)Nc1ncc(Br)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CCO)Nc1ncc(Br)s1
Yield: 58.4 %

Procedure:
A mixture of LiBH4 (44 mg, 2.02 mmol), ethyl 3-[(5-bromo-1,3-thiazol-2-yl)amino]-3-oxopropanoate (340 mg, 1.16 mmol), ethanol (0.082 ml, 2.02 mmol), and Et2O (50 ml) was refluxed for 20 min. The reaction was quenched with 1 N hydrochloric acid with ice-cooling. The mixture was then diluted with water and extracted with dichloromethane. The extract was dried and the solvent was evaporated under reduced pressure. Purification by silica gel chromatography (dichloromethane/methanol=98:2 and then 95:5) yielded the title compound as a white solid (0.17 g; 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]12.ClC1C=C(C=CC=1)C(OO)=O.[NH2:36][C:37]1[CH:38]=[N:39][C:40]2[CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][C:45]=2[CH:46]=1>C(Cl)Cl.C(OCC)(=O)C>[C:50]([O:49][C:47]([N:43]1[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][C:37]([NH:36][C:14]3[N:13]=[C:12]4[C:17]([C:18](=[O:19])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:10]5[N:11]4[CH:22]=[CH:23][N:24]=5)=[CH:16][N:15]=3)=[CH:46][C:45]=2[CH2:44]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(N)cc2C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Reaction time: 5 h

Procedure:
A mixture of Example 95C (70.0 mg, 0.193 mmol) and m-chloroperoxybenzoic acid (52.0 mg, 0.232 mmol) in CH2Cl2 (2 ml) was stirred for 20 minutes. tert-Butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (57.9 mg, 0.232 mmol) was added to the reaction mixture. After 5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with ethyl acetate to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Product: FC(F)(F)c1ccc(Br)c(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [2-bromo-5-(trifluoromethyl)phenyl]methanol (4.4 g, 17 mmol) was added thionyl chloride (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Evaporation in vacuo gave the crude product as an oil. 1H NMR (CDCl3) δ 7.77 (d, J=8.3 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.53 (dd, J=8.5, 2.2 Hz, 1H), 5.66 (d, J=12.7 Hz, 1H), 5.46 (d, J=12.2 Hz).
Reaction SMILES: C(O[CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])C.[Na].[CH2:13]([SH:15])[CH3:14].O>C(O)C>[CH2:13]([S:15][CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH3:14]
Reactant: CCOC=C1SC(=O)NC1=O
Reactant: CCS
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCSC=C1SC(=O)NC1=O
Reaction time: 3 h

Procedure:
To a suspension of 5.20 g of 5-(ethoxymethylene)thiazolidine-2,4-dione (1:1.71 mixture with thiazolidine-2,4-dione, about 13.9 mmol) in 50 ml of ethanol, 5.0 g (59 mmol) of ethanethiol sodium salt was added at room temperature, followed by stirring under heating conditions for 3 hours. After cooling, the reaction mixture was poured into water and adjusted to a pH level of about 2. The resulting precipitate was collected by filtration, washed with water and then with n-hexane/diethyl ether and dried to yield 1.38 g (52.0%, light yellow powder) of the desired product.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15][C:14]=3[CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:22]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:11][P+:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][CH2:20]2)#[N:23]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cc(C#N)ccc3C2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N#Cc1ccc2c(c1)CCC(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 55.1 %

Procedure:
24.00 g of 5,6,7,8-tetrahydro-6-[(p-toluenesulfonyl)oxymethyl]-2-naphthalenecarbonitrile and 18.38 g of triphenylphosphine were mixed, and then heated at a temperature of 130° to 140° C. for 15 hours in a sealed container. The resulting reaction product was crystallized from an acetone/n-hexane mixture to obtain 23.3 g of the title compound in the form of light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[O:12])[CH:7]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc(C(=O)Cn2cc(Cl)cnc2=O)c1
Yield: 20.5 %

Procedure:
A solution of 5-chloropyrimidin-2-one (504 mg) and 2-bromo-3'-methoxyacetophenone (880 mg) in triethylamine (1 ml) and ethanol (50 ml) was stirred at ambient temperature for 20 hours. After evaporation of solvents, the residue was triturated with water (50 ml). The resulting solid was crystallised from ethyl acetate to give the title pyrimidinone (220 mg,); m.p. 134°-137°; λmaxEtOH 249.5 nm (ε 12660), 317 nm (ε 4070), λinf 334.5 nm (ε2950), 344.5 nm (ε 1990).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC/C=C(\CCC)c1c2cccc(Br)c2nn1C
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC/C=C(\CCC)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 7-bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (1.47 g, 4.79 mmol), 2,4-dichlorophenyl boronic acid (1.32 g, 6.94 mmol), 18 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol), and 20 mL of a 2 M aqueous Na2CO3 solution was stirred at 85° C. overnight, then allowed to cool. Ethyl acetate (50 mL) was added, and the mixture was washed with two 40 mL portions of a saturated aqueous NaCl solution. The combined aqueous layers were extracted with 20 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown oil. Column chromatography (0→5% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (15a; 1.57 g; 88%) as a white solid.
Reaction SMILES: C[C:2]1([OH:30])[CH:7]([OH:8])C2C=C3C(=O)C4C(=C(O)C=C(OC)C=4)C(=O)C3=[C:12]([OH:13])[C:5]=2[CH:4]([OH:27])[CH:3]1[O:28]C.CN(C)C=[O:34]>>[O:13]=[CH:12][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:7][OH:8])[OH:30])[OH:28])[OH:27])[OH:34]
Reactant: CN(C)C=O
Reactant: COc1cc(O)c2c(c1)C(=O)c1cc3c(c(O)c1C2=O)C(O)C(OC)C(C)(O)C3O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Steffimycinol (50 mg/l), as a milled aqueous suspension or dimethylformamide solution, is added aseptically at the time of inoculation.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8]2=[O:13])=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O.O>[O:13]=[C:8]1[CH2:7][CH:6]2[CH2:12][CH2:11][CH:9]1[CH2:10][CH:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1CC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC2CCC1CC2C(=O)O
Yield: 87.4 %

Procedure:
5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(Cc1ccc2c(ccn2C(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a stirred solution of tert-butyl 5-[(tert-butoxycarbonylamino)methyl]-pyrrolo-[3,2-b]pyridine-1-carboxylate (360.0 mg, 1.036 mmol) and iodomethane (0.065 mL, 1.036 mmol) in anhydrous THF (6.3 mL) cooled to −40° C. was added dropwise lithium bis(trimethylsilyl)amide in THF (1.24 mL, 1.24 mmol, 1M). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and then diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with a mixture of EtOAc containing 1% TEA and heptane to afford 130.0 mg (37.3%) of tert-butyl 5-((tert-butoxycarbonyl(methyl)amino)methyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate as a foam: 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.6 Hz, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.27-7.10 (m, 1H), 6.73 (d, J=3.7 Hz, 1H), 4.64 (s, 2H), 3.02-2.82 (m, 3H), 1.68 (s, 9H), 1.56-1.41 (m, 9H); MS (ESI) m/z: 362.3 [M+1]+
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][N:28]=[C:29]([O:30][C@@H:31]4[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:65])[C:61]([CH3:64])([CH3:63])[CH3:62])[C@@H:48]([O:49][C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:32]4[O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:22]=23)=[CH:15][CH:14]=1)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][N:28]=[C:29]([O:30][C@@H:31]4[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:65])[C:61]([CH3:64])([CH3:63])[CH3:62])[C@@H:48]([O:49][C:50](=[O:55])[C:51]([CH3:52])([CH3:53])[CH3:54])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:32]4[O:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])[C:22]=23)=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCCCOCc5ccccc5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCCCO)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-{2-[4-(3-Benzyloxypropoxy)phenyl]ethyl}-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo-[3,4-b]pyridine (0.4 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and methanol (6 mL). To the solution was added 10% palladium-carbon powder (160 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.36 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=O)[CH3:2].Cl.NC(C(OCC)=O)C(OCC)=[O:26].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C.O>[CH2:19]([O:18][C:17]([C:16]1[NH:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CCOC(=O)CCC(=O)C1=C(N2CCOCC2)CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c1CCCC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 109.6 %

Procedure:
Crude 4-(2-morpholin-4-ylcyclohex-1-enyl)-4-oxo-butyric acid ethyl ester (454 g), 398 g of diethyl aminomalonate hydrochloride, 162 g of sodium acetate and 350 mL of glacial acetic acid were heated to 108° C. over 30 minutes. The mixture was held at 100-108° C. for 2 hours and then cooled to about 50° C. in a water bath. Water (2500 mL) and 700 mL of ethyl acetate were added. The ethyl acetate layer was separated and washed three times with brine, twice with saturated sodium bicarbonate solutiona and once with brine. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was removed using a rotary evaporator to give 494 g (105% yield) of crude 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as an oil. The crude mixture was chromatographed on a silica gel column using a 1:10 mixture of ethyl acetate:hexane as the eluent to give 122.1 g of pure 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as a low melting solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[N:31](CO)[CH:32]=[CH:33][C:26]=34)=[O:23])=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].O>CO.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:31][CH:32]=[CH:33][C:26]=34)=[O:23])=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3ccn4CO)ccc21)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(N[C@H]1CCSc2cc(C(=O)Nc3ccnc4[nH]ccc34)ccc21)OCc1ccccc1
Yield: 70.1 %

Procedure:
The obtained (S)-4-(benzyloxycarbonylamino)-N-(1-hydroxymethylpyrrolo[2,3-b]pyridin-4-yl)thiochromane-7-carboxamide (766 mg) was dissolved in methanol (10 ml) and tetrahydrofuran (20 ml), and an aqueous solution (30 ml) of sodium acetate (5.00 g) was added. The reaction mixture was stirred under reflux for 5 hr and allowed to return to room temperature. Water (100 ml) was added and the precipitated crystals were collected by filtration to give the objective (S)-4-(benzyloxycarbonylamino)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiochromane-7-carboxamide (504 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]#[C:24]Br.C1COCC1.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:22]=[C:24]2[NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (3.96 g), cyanogen bromide (2.88 g), THF (60 mL) and water (15 mL) was stirred at room temperature for 48 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran), treated with activated carbon, and recrystallized from methanol/water to give the title compound (1.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20]>>[CH:19]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of 3,5-dimethoxyphenol (50 g, 320 mmol) in phosphorous oxychloride (60 mL, 650 mmol) at 0° C. was added dimethylformamide (37 mL, 490 mmol) over a period of 30 min and the mixture was warmed to room temperature and stirred overnight. The mixture was added to icewater (600 mL) and the mixture was washed with ether (3×200 mL). Then an 32% aqueous solution of sodium hydroxide was added until pH was 5.5 and the compound precipitated. The precipitate was separated and washed with water (100 mL) and ether (100 mL) and dried in vacuo. The precipitate was recrystallized from ethanol (600 mL) to give 22.6 g of 4-formyl-3,5-dimethoxyphenol. bp. 224-226° C.