Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.COCCOC.[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][C:17]([F:22])([F:21])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: FC(F)(F)CNc1ccc(Br)cc1Cl
Temperature: 110 °C

Procedure:
4-Bromo-2-chloroaniline (5000 mg, 24.22 mmol) was dissolved in trifluoroacetic acid (40 ml) and 1,2-dimethoxyethane (50 ml) then cooled under argon to 0° C. To the mixture was added 2-picoline borane complex (12951.34 mg, 121.08 mmol) and then the reaction mixture was heated 110° C. for 90 minutes. Solvents were removed under reduced pressure and crude material was taken up in 1N HCl and stirred at 110° C. 30 minutes. Crude mixture was then diluted with EtOAc and water and extracted EtOAc (3 times). Organics were washed with water then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crude material was purified by silica gel chromatography using EtOAc/Hexanes as the eluent to afford 4-bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][NH:7][C:8]([NH2:10])=[S:9].C(O)C.[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[NH:17][N:16]=1>O>[CH3:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH:24]=[N:6][NH:7][C:8]([NH2:10])=[S:9])[CH:22]=2)[NH:17][N:16]=1
Reactant: Cc1n[nH]c2ncc(C=O)cc12
Reactant: NNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2ncc(C=NNC(N)=S)cc12
Temperature: 80 °C

Procedure:
Sodium acetate (166 mg, 2.02 mmol), thiosemicarbazide (333 mg, 3.66 mmol), 100 ml ethanol and 2 ml distilled water were charged into a 250 ml round bottom flask. The resulting suspension was heated to 80° C. until it becomes a clear solution. The reaction was then cooled down to room temperature and the resulting mixture was added into a 250 ml round bottom flask containing 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (333 mg, 2.1 mmol). After the addition, the resulting mixture was heated to 80° C. for 16 hours. The mixture was cooled to room temperature and solid was precipitated out. The solid was filtered off and washed with ether (50 ml). The product (500 mg, y=95%) was used directly for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=O.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].O>C(O)(=O)C>[Cl:18][C:15]1[CH:14]=[C:4]2[C:3](=[CH:17][CH:16]=1)[N:2]=[C:21]([S:20][CH3:19])[C:22]([N+:23]([O-:25])=[O:24])=[C:5]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc2ccc(Cl)cc2c(-c2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 2-amino-2',5-dichlorobenzophenone hydrochloride (1.6 g, 5.3 mmol) and 1,1-bis(methylthio)-2-nitroethylene (875 mg, 5.3 mmol) in 12 ml acetic acid was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, 30 ml of water was added and the resulting mixture was extracted with 2×60 ml ethyl acetate. The ethyl acetate extracts were washed with 2×50 ml water, 2×50 ml saturated sodium bicarbonate solution and 50 ml brine, and then dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (440 g, 230-400 mesh), eluting with 85:15 hexane/ethyl acetate to yield the title compound as a yellow solid (1.65 g, 72% yield).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CCOCC>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCCC1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a chilled (0°-5° C.) and stirred ethereal solution (500 ml) containing cyclopentyl amine (75 g, 0.88 mol) and triethyl amine (101 g, 1.0 mol) was added t-butyl bromoacetate (136.5 g, 0.7 mol) in ether (300 ml). The reaction mixture was stirred overnight. The ethereal mixture was then concentrated and the residue redissolved in methylene chloride (750 ml). This solution was washed with saturated aqueous sodium bicarbonate (1000 ml), water (2×3000 ml), and brine (2000 ml). The organic portion was separated, dried over MgSO4, filtered and evaporated yielding N-cyclopentylglycine t-butyl ester (92 g, 66%) as a brown oil which slowly crystallized on standing.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=1.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[Cl:24][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:10]([F:23])([F:22])[F:9])[CH:21]=[CH:20][C:15]=2[N:16]=1
Reactant: Cl
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing dry copper (II) chloride (3.44 g, 25.62 mmol) and tri(ethylene glycol)dimethyl ether (10 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.5 mL, 32.02 mmol). The reaction mixture was stirred at rt under argon for 30 minutes. To this suspension was added dropwise, a solution containing 6-trifluoromethoxy-1,3-benzothiazol-2-ylamine (5 g, 21.35 mmol) and tri(ethylene glycol)dimethyl ether (10 g). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 3 h. The mixture was cooled to rt, poured cautiously into aqueous 6 N HCl, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous HCl and brine, and concentrated under reduced pressure to give the desired compound in near-quantitative yield, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3].P(Br)(Br)[Br:29].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:22]=[C:21]([CH2:23][Br:29])[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1cccc(Cl)c1
Reactant: BrP(Br)Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1cccc(Cl)c1

Procedure:
To a solution of 1.133 g (0.29 mmol) of the product of Step B dissolved in 10 mL of carbon tetrachloride was added 0.138 mL (1.45 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 30 min as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from carbon tetrachloride several times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 10% EtOAc-hexane. Combination and evaporation of the purified fractions in vacuo afforded 1.063 (81%) of the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.[C:11]([O-:14])([O-])=O.C([O-])([O-])=[O:16].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:7]1[CH:6]2[CH:10]3[O:16][CH:9]3[CH:8]1[CH:4]1[CH:5]2[CH:1]2[O:14][CH:11]2[CH2:3]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C1C2OC2C2C1C1CC2C2OC12
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Dicyclopentadiene (1.32 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium percarbonate (10.5 g, 66.7 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.62 g (99% yields) of dicyclopentadiene diepoxide with a GC purity of 100% was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[O:10])=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([O:22][CH3:21])=[CH:7][N:6]=1)=[O:10]
Reactant: C[O-]
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(Br)cn1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cnc(NC(=O)Nc2cc(C)ccc2OC)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 13 %

Procedure:
To a stirred solution of 1-(5-bromo-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (47 mg; 0.14 mmol) in N-methyl pyrrolidinone (300 μL) was added sodium methoxide (0.5 mmol). The reaction was heated to 100° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), brine (30 mL), then dried (MgSO4), and filtered. The crude product was purified using a 0.5 mm prep plate eluting with hexane and ethyl acetate (1:1) to yield a yellow solid (13% yield). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 6.80 (dd, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 2.38 (s, 3H). LRMS (ESI, Positive) m/e 289.10 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH2:2][CH3:3].[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH2:2][CH3:3]
Reactant: CCCc1cc(Br)c2ncccc2c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCCc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-propyl-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-propyl-8-(3-nitrophenyl)quinoline,
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:30][CH3:31])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([O:30][CH3:31])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: COC(=O)c1ccccc1S
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 92.7 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.27 g (1.6 mmol) of methyl thiosalicylate. The product was triturated with ether, filtered, washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 288-290° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([CH:8]([CH3:10])[CH3:9])[CH2:6][OH:7])[CH2:3][CH2:2]1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C1COCC1>[CH:1]1([N:4]([CH:5]([CH2:6][OH:7])[CH:8]([CH3:10])[CH3:9])[C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:11])([F:22])[F:23])=[O:21])[CH2:3][CH2:2]1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CC(C)C(CO)NC1CC1
Solvent: C1CCOC1
Product: CC(C)C(CO)N(C(=O)Nc1ccccc1C(F)(F)F)C1CC1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
To a solution of crude 2-cyclopropylamino-3-methyl-butan-1-ol (195 mg) in THF (10 mL) was slowly added a solution of 2-trifluoromethylphenylisocyanate (225 mg) in THF (3 mL) at 0° C. The mixture was then heated to 60° C. for 12 hours. After cooling, the solution was concentrated in vacuo and the residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as an eluent to give the desired material as a colorless solid (245 mg). MS (ESI): 331.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Product: CCN1Cc2cc(C)sc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=1[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:26][C:27]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:28]=3[O:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.39 g (0.0028 mole) of anhydrous potassium carbonate, and 0.92 g (0.0038 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate in 20 mL of N,N-dimethylformamide was heated at 90° C. for approximately 17 hours. At the end of this period the mixture was poured over ice, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an orange oil as a residue. This oil was placed on a silica gel column and eluted first with methylene chloride and then with methylene chloride/ethyl acetate (97.5/2.5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 0.82 g of 2-[2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate was recovered as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.30 (s, 3H); 2.44 (s, 3H); 3.76 (s, 3H); 4.84 (q, 1H, JHH=8.0 Hz); 5.16 (dd, 2H, JHH=10.0 Hz); 6.56 (s, 1H); 6.78-7.32 (m, 6H).
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[CH2:24]([O:23][C:21]([O:22][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:26])[C:17]1[CH:16]=[CH:15][C:14]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=1)[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(O[Si](C)(C)C)=C(C)c1ccc(CC(C)C)cc1
Temperature: -70 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -70° C. and 37.5 g (0.16 mol) of ethyl 4-isobutyl-α-methylphenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added. The reaction mixture was stirred overnight at 25° C., filtered and then distilled to give 34.3 g (70% yield) of β-ethoxy-4-isobutyl-α-methyl-β-(trimethylsiloxy)-styrene as a colorless liquid, bp 129°-130° C. (0.4 mm). Anal. Calcd. for C18H30O2Si: C, 70.53; H, 9.87; Found: C, 70.38; H, 9.78.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]2)=[O:15])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (300 mg, 1.47 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (396 mg, 1.62 mmol, Bioorg. Med. Chem., 2002, 10, 1399-1415) in N,N-dimethylformamide (15 mL) were added diethyl cyanophosphonate (0.27 mL, 1.76 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.76 mmol) at room temperature. The resulting mixture was stirred for 14 h at the same temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), and the solution was washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (3:1) to give 618 mg (98%) of the title compound as a white amorphous solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](O)(=[O:37])[C@H:34]([CH3:36])[OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[C@@H:34]([OH:35])[CH3:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)[C@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.4 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.23 mmol), L-lactic acid (23 mg, 0.25 mmol) and DIPEA (45 μL, 0.25 mmol) in DCM (2 mL) was added HATU (96 mg, 0.25 mmol). The resulting yellow mixture was stirred for 2.5 h at r.t. then partitioned between DCM and H2O. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 20-35%) affording 718 as a white solid (19 mg, 16%). LCMS (method I): RT 2.92 min, [M+H]+ 505.2. 1H NMR (CDCl3, 400 MHz): δ 7.98-7.97 (1 H, m), 7.90-7.80 (1 H, m), 7.40-7.30 (2 H, m), 4.33-4.32 (7 H, m), 4.01-4.00 (1 H, m), 3.86-3.85 (5 H, m), 3.77 (3 H, d, J=1.96 Hz), 3.50-3.35 (4 H, m), 3.19-3.17 (2 H, m), 1.48 (3 H, t, J=7.42 Hz), 1.34 (3 H, dd, J=6.69, 4.73 Hz),
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:40]([Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[O:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:41])[CH3:42]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of Intermediate A (223 mg, 1.37 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 168 mg, 4.20 mmol) and the mixture stirred at RT for 15 min. A solution of Intermediate 54b (555 mg, 1.37 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a brown gum (344 mg, 46%). LCMS (Method 3): Rt 3.29 min, m/z 550 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=1)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([Cl:16])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cccnc1Cl
Yield: 50 %

Procedure:
A mixture of 1.56 g (8.6 mol) of 3-pyridineacetic acid ethyl ester 1-oxide (for preparation, see A. R. Katritzky, J. Chem. Soc., 1956, 2404) and 15 ml of phosphorous oxychloride was heated to 80° C. for 3 hours. After cooling, the solvent was evaporated and the residue was poured onto ice water and solid sodium bicarbonate was added until the pH was basic. The organic layer was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and evaporated to an oil which was purified by flash chromatography with an ethyl acetate-hexane (1:4-1:1) eluant. The fractions containing the less polar isomer (Rf 0.3, ethyl acetate-hexane (3:7)) were combined and evaporated to yield 584 mg (50%) of the title compound of this preparation as an oil. 1H NMR (CDCl3): δ 1.22 (3H, t, J=7), 3.76 (2H, s), 4.15 (2H, q, J=7), 7.11-7.21 (2H, m), 8.25-8.31 (1H, m).
Reaction SMILES: FC(F)O[C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1.[Li+].[OH-:20].Cl>C1COCC1.CO>[O:20]=[C:4]([CH3:9])[CH2:5][CH2:6][C:9]1[CH:4]=[CH:5][C:6]2[N:7]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc2cc(OC(F)F)ccn12
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-carboxylate (79) (150 mg, 0.585 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 5 mL) was heated at 60° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 1N HCl. The solvent was partially reduced and the crude product was purified by reverse phase preparative HPLC to yield 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (80). MS m/z 229.03 (M+1)+.