Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Cl:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>C(O)(CC)C>[Cl:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: O=C(Nc1c[nH]c2ncc(Cl)c(F)c12)C1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Temperature: 130 °C
Yield: 57.5 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (192 mg, 0.96 mmol) was added to N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (90 mg, 0.32 mmol) in s-BuOH (2 mL), and the reaction mixture was heated to 130° C. for 30 hours in a sealed tube. After cooling down, the reaction was concentrated to dryness, dissolved in AcOEt (10 mL) and washed with 10% aqueous citric acid and brine. The aqueous phase was diluted with hexanes (10 mL) and passed through a short plug of silica gel. The silica gel was rinsed with AcOEt/hexanes (1/1, 100 mL), and the combined organic phases were concentrated in vacuo. The resulting solid was crystallized from AcOEt to yield (R)-tert-butyl 1-(5-chloro-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (85 mg, 58% yield) as a solid.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[OH-].[K+]>C(OC(=O)C)C>[N:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow liquid (50%). 1H-NMR (400 MHz, CDCl3) δ(ppm) 7.79 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 7.05 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7].C(O)(C)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 102.7 %

Procedure:
A flame-dried 1 L 3-necked flask, fitted with a 30 cm Vigreux column topped with a distillation head, an argon inlet tube and a magnetic stirring bar, was charged with 36.8 g (0.189 mol) of (3E,6R)-6,10-dimethyl-3,9-undecadiene-2-one (GC purity 93.6%), 500 mL of isopropanol and 40.0 g (0.196 mol) of aluminum isopropoxide. The reaction mixture was stirred and heated to gentle reflux under argon. Acetone was allowed to distill off at a rate of about 30 drops/min. while maintaining a head temperature of ca. 80° C. After 3.5 hours the reaction was shown by GC to be almost complete with 5% of starting material remaining. The reaction was cooled in an ice bath and the pressure was reduced to ca. 54 mmHg. Isopropanol was distilled off at a head temperature of 30° C.-31° C. until the reaction mixture was concentrated to a volume of about 200 mL. The residual oil was cooled in an ice bath, 200 mL of 2N HCl were carefully added with stirring and the mixture was poured into a separatory funnel containing 200 mL of ether. An additional 200 mL of 2N HCl were added to dissolve some remaining white solid material. The layers were separated and the aqueous phase was extracted with 2×200 mL of ether. The combined organic layers were washed successively with 200 mL of sat. NaHCO3 -solution and 200 mL of brine, dried over MgSO4, filtered and concentrated on the rotovapor. The residue was dried at 0.1 mm for 30 minutes to afford 38.1 g (102.6%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol as a light yellow liquid. GC analysis indicated a purity of 94.6%. This material was used as is in Example 2.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[N:34]([CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CN=[N+]=[N-]
Yield: 83 %

Procedure:
A slurry of Compound 3 (950 mg) and sodium azide (255 mg) in dry N,N-dimethylformamide (10 mL) was heated at 70° C. for 3 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and directly eluted on a silica gel using 2% ethanol in dichloromethane to afford the required product in 83% yield (800 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:31])[C@H:27]([CH2:29][SH:30])[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41].C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:31])[C@H:27]([CH2:29][S:30][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=1)[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CS)c1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CSC[C@H](N)C(=O)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-L-cysteinamide (0.72 g, 1.51 mmol), methyl 3-(bromomethyl)-benzoate (0.35 g, 1.51 mmol), and diisopropylethylamine (0.27 mL, 1.53 mmol) is stirred at room temperature overnight. Solvent is evaporated, and the residue is treated with 1 N HCl (50 mL), and filtered to collect a white solid, which is washed with water and Et2O (100 mL each). Drying in vacuo yields N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-S-[[3-(methoxycarbonyl)phenyl]methyl]-L-cysteinamide, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][N:13](C(=O)C)[C:7]=2[CH:6]=1.C([O-])(O)=O.[Na+]>Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1
Reactant: CC(=O)n1ncc2cnc(Oc3ccc(F)cc3F)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1ccc(Oc2cc3[nH]ncc3cn2)c(F)c1
Yield: 94.5 %

Procedure:
A mixture of 1-[6-(2,4-difluorophenoxy)pyrazolo[4,3-c]pyridine-1-yl]ethanone (0.26 g) in 15 mL of 20% aqueous hydrochloric acid was heated for 3 hours on a steam bath, cooled, neutralized with NaHCO3, and extracted with CH2Cl2 to give 0.21 g of 6-(2,4-difluorophenoxy)-1H-pyrazolo[4,3-c]pyridine (95% yield). Mass Spec. M+H=248.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7]
Reactant: OCCCCC(F)(F)F
Solvent: ClCCl
Product: O=CCCCC(F)(F)F
Reaction time: 4 h
Yield: 43.2 %

Procedure:
Combine 3,3,3-triacetoxy-3-iodophthalide (17.91 g, 1.2 eq) and dichloromethane (95 mL). Add 5,5,5-trifluoro-1-pentanol (5.00 g, 35.18 mmol) in dichloromethane (238 mL) dropwise under nitrogen. After 4 hours, filter the reaction mixture through Celite®. Concentrate the filtrate in vacuo; combine with 50 mL of dichloromethane and wash with 1:1 10% sodium thiosulphate:aqueous sodium hydroxide (1N). Dry the organics with anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a colorless oil (2.13 g, 43%). 1HNMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 2.50 (m, 2H), 2.21 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(C)=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{2-[(acetyl-ethyl-amino)-methyl]-4-amino-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and 4-chlorobenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:17])[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2[C:4]([N:3]=1)=[N:17][C:18](=[O:19])[N:16]=2
Reactant: Nc1nc(N)c(N)c(OCC2CCCCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(OCC2CCCCC2)c2c(n1)=NC(=O)N=2
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of 2,5,6-triamino-4-cyclohexylmethyloxypyrimidine (1.0 g, 4.24 mmol) and 1,1′-carbonyldiimidazole (0.69 g, 4.24 mmol) in anhydrous DMF (5 ml) was stirred under nitrogen at ambient temperature for 48 h. Addition of water (100 ml) afforded a white solid which was collected by filtration, redissolved in 2 M sodium hydroxide solution (200 ml), and filtered. The filtrate was neutralised with glacial acetic acid and allowed to stand at 4° C. for 2 h, when the precipitate which deposited was collected and washed thoroughly with water. Recrystallisation from aqueous ethanol yielded the required product (0.65 g, 58%), m.p. 297° C.; (Found: C. 54.66; H, 6.47;. N, 26.63% C12 H17 N5O2 requires C, 54.75; H, 6.46; N, 26.62%); δH (200 MHz, d6-DMSO) 1.04-1.39 (δH, m, C6H11), 1.76-1.90 (6H, m, C6H11), 4.17 (2H, OCH2, J=6.53 Hz), 6.15 (2H. br s, NH2), 10.49 (1H, br s, NH), 1 1.09 (1H, br s, NH); m/z (+EI) 263 (M+, 75%), 167 (MH+—C7H13, 100), 81 (6), 69 (7).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=12)([O-])=O>[Zn].C(O)C.O>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=12
Reactant: O=[N+]([O-])c1ccc2c([N+](=O)[O-])cnn2c1
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(N)cnn2c1

Procedure:
The reduction of 3,6-dinitropyrazolo[1,5-a]pyridine was carried out using zinc in an ethanol/water mixture.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>C(#N)C>[Cl:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(O)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 0.25 h

Procedure:
In 100 ml of acetonitrile was dissolved 4.0 g (0.026 mole) of methyl 6-hydroxynicotinate followed by addition of 0.9 ml of triethylamine. The mixture was refluxed and 3.7 ml of phosphorus oxychloride was added dropwise with stirring over a period of 15 minutes. The mixture was further refluxed for 3 hours. After cooling, the acetonitrile was distilled off and the residue was diluted with 20 ml of water and adjusted to pH about 8 with a saturated aqueous solution of sodium hydrogen carbonate. The resulting crystals are collected by filtration, rinsed with water and dried to give 3.6 g of methyl 6-chloronicotinate as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Fc1ccc(C(OCCN2CCCC2)c2ccc(F)cc2)cc1
Yield: 47.7 %

Procedure:
1-[Bis(4-fluorophenyl)methoxy]-2-chloroethane (3) (0.92 g, 3.3 mmol) was added to acetonitrile (50 ml) containing potassium carbonate (1.1 g, 8.0 mmol). This was followed by the addition of pyrrolidine (0.51 g, 7.2 mmol). The resulting mixture was then heated to reflux for 72 hours under an atmosphere of nitrogen. At the end of this time, the solution was added to ether (75 ml), washed with water (50 ml) and brine (50 ml). This was then dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give a clear light yellow oil. The oil was chromatographed on silica gel and eluted with 3:1 ethyl acetate/methanol to afford the desired product (4) (500 mg, 48%) as a clear light yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[N:16]=1>CN(C)C=O.[Cu]I>[S:25]1[CH:26]=[CH:27][C:23]([CH2:22][O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[CH:24]1
Reactant: Clc1cccc(OCc2ccsc2)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cccc(OCc3ccsc3)n2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (3.62 g, 0.0045×5.0 mol), sodium hydride (0.89 g, (Ca.60% in mineral oil), 0.0045×5.0 mol) and CuI (0.42 g, 0.0045×0.5 mol) in dimethylformamide, 2-chloro-6-(3-thienylmethyloxy)pyridine (1.0 g, 0.0045 mol) was added and the resultant solution was refluxed for about 3 hours.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)/[C:6](O)=[O:7])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH2:87]>CN(C=O)C>[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH:87][C:6](=[O:7])/[C:5](/[NH:4][C:1](=[O:3])[CH3:2])=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: CC(=O)N/C(=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Reactant: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OCCCCNC(=O)/C(=C\c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)NC(C)=O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (260 mg, 0.58 mmol) in DMF (10 mL) is added diisopropylethylamine (0.11 mL, 0.64 mmol) and HATU (243 mg, 0.64 mmol). The mixture is stirred at RT for 10 min then a solution of 2-(4-aminobutoxy)-6-benzyloxybenzoic acid methyl ester (Example 110, step C) (286 mg, 0.87 mmol) in DMF (1 mL) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19]Br>CCO>[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: Cc1cc(C)c(CBr)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c(C)c1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 2,4,6-Trimethylbenzylbromide (0.253 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Si:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.[W].N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
N-Bromosuccinimide (7.6 g) was added to a solution of methyl 2-(tert-butyldimethylsilyloxy)-6-methylbenzoate (Intermediate 13, 11.9 g) in carbon tetrachloride (150 mL) and the mixture was stirred and heated to reflux. Azo-bis-isobutyronitrile (0.1 g) was added and the mixture was illuminated with a 500 W tungsten filament lamp for 2 hours. The mixture was cooled and left to stand overnight then filtered through a 25 g silica cartridge eluting with a mixture of ethyl acetate and pentane (20%). The eluent was evaporated to dryness and the residue was redissolved in carbon tetrachloride (150 mL) and N-bromosuccinimide (6.96 g) was added. The mixture was heated to reflux and azo-bis-isobutyronitrile (0.1 g) was added. The resultant mixture was illuminated with a 500 W tungsten filament lamp overnight. After cooling, the mixture was filtered and the solid was washed with pentane. The combined organic solutions were evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of TBME and pentane with a gradient of 0-10% to give methyl 2-bromomethyl-6-(tert-butyldimethylsilyloxy)benzoate (4.99 g) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:32]4[C@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]4)[C@@H:27]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26]3)=[C:18]([NH:40][CH2:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:17]=2)[CH2:12]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@@H:32]4[O:31][C:30]([CH3:34])([CH3:33])[O:29][C@@H:28]4[C@@H:27]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26]3)=[C:18]([NH:40][CH2:41][CH:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:17]=2)[CH2:12]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reaction time: 8 h

Procedure:
To a solution of {(R)-1-[9-((3aS,4R,6S,6aR)-2,2-dimethyl-6-propionylamino-tetrahydro-cyclopenta[1,3]dioxol-4-yl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.598 g, 0.79 mmol) in ethanol (7.5 ml) under an inert atmosphere of Argon is added palladium hydroxide on carbon (10 mg). The reaction mixture is purged with Argon and placed under an atmosphere of hydrogen overnight. The mixture is filtered and purified by chromatography on silica eluting with 5% MeOH in DCM to yield the title compound. [MH+ 611].