Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH2:8]O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:1]1[C@H:2]2[C@H:7]([CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2)[CH2:8]1)(=[O:35])=[O:34])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](N)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
The product of Example 61D (39.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with triethylamine (16.7 mL, 0.120 mol) followed by 2-nitrobenzenesulfonyl chloride (19.5 g, 88.0 mmol). The ice-bath was removed and the solution stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue dissolved in a mixture of ethanol and 5% aqueous NaOH (2:1, 200 mL). The mixture was stirred for 30 minutes, concentrated under reduced pressure, diluted with ethyl acetate (200 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (11.0 g, 27.7 mmol, 70% yield for two steps). MS (DCI/NH3) m/z 415 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[C:9](#[N:13])[CH2:10][C:11]#[N:12]>C(O)C.N1CCCCC1>[NH2:13][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]2=[CH:7][C:10]=1[C:11]#[N:12]
Reactant: N#CCC#N
Reactant: Nc1sccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2ccsc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
2-Amino-thiophene-3-carbaldehyde described in Preparation Example T-4 (38 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol) were dissolved in ethanol (1 mL) to which piperidine (several drops) had been added, and the solution was stirred for 1 hour under reflux. The reaction solution was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (50 mg, 0.29 mmol, 96%) was obtained as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C1(C)C=CC=CC=1.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a distillation device and a dropping funnel and having an inner volume of 500 ml were charged 11.0 g (0.2 mol) of sodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere, and the temperature of the mixture was raised to 110 to 120° C. while stirring, then, 27.0 g (0.2 mol) of dimethyl malonate with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred for 2 hours while removing methanol under reduced pressure of 0.010 to 0.013 MPa. Subsequently, the mixture was cooled to 100° C. under the same pressure, 16.2 g (0.1 mol) of 2,4-difluoronitrobenzene with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the mixture was further reacted at the same pressure and the same temperature for one hour. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of toluene was added to the mixture and 40 ml (0.2 mol) of 5 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. This organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it can be found that 20.6 g (yield: 76%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]3O[CH:18]32)=[CH:13][CH:12]=1)#[N:10].O>CS(C)=O>[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]=[C:18]2[N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[CH:13][CH:12]=1)#[N:10]
Reactant: CC1(C)Cc2ccc(C#N)cc2C2OC21
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C=C(N2CCCC2=O)c2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.18 g of 80% dispersion in oil) in dry dimethylsulphoxide (5 ml) was added 2-pyrrolidinone (0.51 g) in dimethylsulphoxide (5 ml) and the mixture was then stirred at room temperature, under nitrogen, for 1 hour. A solution of 7-cyano-1,2-epoxy-3,3-dimethyl-1,2,3,4,-tetrahydronaphthalene (1.0 g) in dimethylsulphoxide was then added dropwise, and the solution stirred for 18 hours at room temperature. The mixture was then poured into water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, and dried over sodium sulphate. Removal of drying agent and solvent, followed by chromatography of the residue on a silica gel column eluted with ethyl acetate-pentane (1:1), gave the title compound as a solid, which recrystallised from 60°-80° petrol-ethyl acetate (5:1) as yellow prisms (0.25 g) having mp 131°-2° C.;
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.Cl.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH2:27].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:21][O:22][C:23]([CH2:24][CH2:25][CH2:26][N:27]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1)=[O:28]
Reactant: COC(=O)CCCN
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: Cl
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)CCCN=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 135 °C

Procedure:
To a suspension of 0.2 g (0.79 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide and 0.1 g (0.67 mmol) of methyl-4-aminobutyrate hydrochloride in 5 mL of xylene was added 0.07 g (0.49 mmol) of boron trifluoride diethyl etherate. The resulting mixture was heated at 135° C. for seven hours and then allowed to cool to room temperature. The mixture was then filtered and the residue was extracted with toluene. The combined extracts were evaporated under reduced pressure and the residue chromatographed on silica gel using a 4:1 mixture of petroleum ether-ethyl acetate. Chromatographically homogenous fractions were pooled and the solvents were removed under reduced pressure to give the desired product as a yellow oil which crystallised on standing to give yellow crystals which decomposed on heating without melting.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].[ClH:13].[CH2:14](O)[CH3:15]>>[ClH:13].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:14][CH3:15])=[O:11]
Reactant: CCO
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: Cl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (S)-indoline-2-carboxylic acid (6.02 g., 36.9 mmol.) in ethanol (70 ml.) at 0° was saturated with hydrochloric acid and allowed to warm to room temperature. After 3 hours at room temperature, the resulting clear, red solution was purged with nitrogen and diluted with ethyl ether (200 ml.). The crystallized product was collected, washed with ethyl ether and dried in vacuo to give 6.43 g. of the title compound as white needles, m.p. 168°-169°; α!D =-70.7° (c=0.68, chloroform). TLC (ethyl acetate-hexane, 1:1) Rf =0.63 (as free base).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [186132-96-7] (500 mg, 2.162 mmol; Chem-Impex International, Inc.) in MeOH (9.0 mL), cooled to 0° C., was added with stirring a solution of Cs2CO3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0° C., followed by addition of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO3 (2×) and water (2×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as an oil. MS (LC/MS): 322 [M+H]+, 665 [2M+Na]+; tR (HPLC conditions b): 4.12 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2].[BrH:13].BrBr>O>[CH2:1]([C:3]1[CH:9]=[C:8]([Br:13])[C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2]
Reactant: Br
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Agent: BrBr
Solvent: O
Product: CCc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 7 °C
Reaction time: 1 h

Procedure:
5-Ethyl-7-bromo-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester ##STR24## Mix 4-ethyl-2-nitroaniline (16.6g, 0.1mol) in water (400mL) and add 48% hydrobromic acid (1kg). Add bromine (16g, 0.1mol) with stirring and stir for 1 hour. Dilute to 2L and cool to 7° C. Filter, wash with water and dry to give 4-ethyl-2-nitro-6-bromoaniline.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)SCCO2
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)SCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.2 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[3,2-c]pyridazine (200 mg, 1.11 mmol) in 1,4-dioxane/water (10 ml/2 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 1 ml) and sodium periodate (0.55 g), initially stirred in an ice-bath for 1.5 hours, then allowed to warm to room temperature. After 1.5 hours the mixture was treated with sodium bicarbonate solution, evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (20 g), and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a pale yellow solid (63 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][N:32]=[C:33]=[S:34]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:33]([NH:32][CH3:31])=[S:34])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 20 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 73 mg (1 mmol) of methyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. Purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) resulted in 90 mg (20%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:27][CH2:15][CH2:14][CH2:13][CH:12]([CH3:17])[CH:11]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCCBr)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (170 mg, 0.437 mmol) obtained in Example 40 and carbon tetrabromide (170 mg, 0.648 mmol) were dissolved in methylene chloride (8 ml). While stirring under ice cooling, triphenylphosphine (135 mg, 0.515 mmol) was added to the resulting solution, followed by stirring at room temperature for 14 hours. To the reaction mixture were added carbon tetrabromide (170 mg, 0.437 mmol) and triphenylphosphine (135 mg, 0.515 mmol) under ice cooling. The reaction mixture was stirred at room temperature for 6 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=10:1), whereby the title compound (192 mg, 97%) was obtained as a colorless oil.
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[CH3:6][O:7][N:8]=[C:9]([C:26](=NNC(OCC)=O)[CH3:27])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]>CC(C)=O>[CH3:6][O:7][N:8]=[C:9]([C:26](=[O:2])[CH3:27])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
70% Aqueous perchloric acid (0.05 ml.) was added to a solution of 7-(2-methoxyimino-3-ethoxycarbonylhydrazonobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 40 mg.) in acetone (5 ml.), and stirred at room temperature for 30 minutes. The reaction mixture was treated in a similar manner to that of Example 10-(4) to give 7-(2-methoxyimino-3-oxobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 26 mg.).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:32])[N:21]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:17]([C:33]([O:35]CC)=O)[N:16]=1)=O)(C)(C)C.[NH2:38]C1C(C(OCC)=O)=NC(NC[C@@H]2CCCN2C(OC(C)(C)C)=O)=NC=1NC1C=CC=CC=1OC>ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[C:20](=[O:32])[NH:19][C:18]2[C:22]1=[N:23][C:15]([NH:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:16][C:17]=2[C:33]([NH2:38])=[O:35]
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@@H]3CCCN3)nc21
Yield: 98 %

Procedure:
(S)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 5-amino-2-((1-(tert-butoxy-carbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.340 g, 0.740 mmol) and carbonyldiimidiazole (1.13 g, 7.40 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title product (0.352 g, 98%). MS (ESI) m/z 513.5 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:32](O)([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:19]=[C:13]1[O:12][C@H:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:15]([C:16]([O:18][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:17])[CH2:14]1
Reactant: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)OCc2ccccc2)O1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 7.93 g of (2S,3R)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid in 75 ml of chloroform, 5.5 g of 4-dimethylaminopyridine, 8.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 5.7 ml of tert-butyl alcohol were successively added, and the resulting reaction solution was stirred at room temperature for 60 hours. The reaction solution was poured into 1N hydrochloric acid cooled with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 6.48 g of the title compound as a white solid.
Reaction SMILES: C([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[N:8]([CH2:19][CH2:20][CH3:21])[CH:7]=[N:6][C:5]1=2)C=C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[CH2:19]([N:8]1[C:9](=[O:18])[C:10]2[NH:11][C:12]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:4][C:5]=2[N:6]=[CH:7]1)[CH2:20][CH3:21]
Reactant: C=CCn1c(-c2cccs2)nc2c(=O)n(CCC)cnc21
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCn1cnc2nc(-c3cccs3)[nH]c2c1=O
Temperature: 100 °C
Yield: 10.5 %

Procedure:
The above compound, 9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 0.33 mmol) and Wilkinson's catalyst were taken in acetonitrile:water (6:1, 7 ml) and refluxed for 5 h at 100° C. Solvent was removed and further purified by preparative TLC to get pure 1-propyl-8-thiophen-2-yl-1,7-dihydro-purin-6-one (9 mg, 10%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.C([O:23][C:24](=O)[CH:25]([Cl:27])[Cl:26])C>CO>[Cl:26][CH:25]([Cl:27])[C:24]([NH:1][C@H:2]([CH2:12][F:13])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:23]
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (5.0 g, 20.0 mmol) in methanol (100 mL) is added triethylamine (9.56 mL, 67.8 mmol) and ethyldichloroacetate (6.22 mL, 50.8 mmol) and the mixture heated to reflux for 16 hours. After allowing to cool to room temperature, the solvent is removed under reduced pressure the resultant oil purified by column chromatography eluting from neat heptanes to 80% ethylacetate/heptanes to give the title compound (5.94 g). m/z (Cl) M+H 405.
Reaction SMILES: Br[C:2]#[N:3].N1C=CN=C1.[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][NH2:22])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C(Cl)Cl.C1COCC1>[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[O:20][C:2]([NH2:3])=[N:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NNC(=O)c1ccc2cnccc2c1
Reactant: N#CBr
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1nnc(-c2ccc3cnccc3c2)o1
Yield: 95.1 %

Procedure:
A 3 M DCM solution of bromoformonitrile (0.2 mL, 0.6 mmol) (commercially available from Aldrich) was mixed with imidazole (0.157 g, 2.3 mmol) (commercially available from Aldrich) in 10 mL DCM. The mixture was heated and maintained to reflux for 30 minutes in a round bottom flask. After the DCM was removed under a reduced pressure, isoquinoline-6-carbohydrazide (0.1 g, 0.53 mmol) suspended in 50 mL THF was added into the flask. The mixture was heated and maintained at reflux for 3 hours. After removing the THF, the remaining residue was mixed with 10 mL water and filtered. After washing with water and air drying, a white solid was obtained as the desired product (0.107 g, 96%) LCMS (API-ES) m/z (%): 213.0 (100%, M++H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:30])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3ccc(N)nc3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
A mixture of N-((5-((6′-(bis(tert-butoxycarbonyl)amino)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (0.23 g, 0.379 mmol) and TFA (0.44 mL, 5.7 mmol) in DCM (4 mL) was stirred at RT for 16 h. The mixture was concentrated to dryness, treated with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-((5-((6′-amino-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (125 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.45 (br s, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.7 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.01 (dd, J=8.7, 2.5 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.74 (dd, J=5.7, 2.4 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 6.27 (d, J=4.7 Hz, 2H), 1.21 (s, 9H); MS (ESI) m/z: 407.2 (M+H+).