Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]2([CH:41]([F:43])[F:42])[CH2:40][CH2:39]2)[CH:35]=[C:34]([Br:44])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Br:44][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]2([CH:41]([F:43])[F:42])[CH2:39][CH2:40]2)[CH:35]=1
Reactant: CCOC(=O)C[C@H](N)c1cc(Br)cc(C2(C(F)F)CC2)c1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Br)cc(C2(C(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (197.22 mg, 0.64 mmol), (S)-ethyl 3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoate hydrochloride salt (from step 1 above) (253 mg, 0.635 mmol) and 1-hydroxybenzotriazole hydrate (19.44 mg, 0.127 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimide (142 μL, 0.917 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature overnight (16 h) under nitrogen atmosphere. The solvent was evaporated in vacuo to give a yellow gummy residue of the intermediate product. LC-MS analysis shows the desired product: (3S)-ethyl 3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 652 (79BrM+H), m/z 654 (81BrM+H). The crude residue will be used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH3:25])[CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]2=[O:34])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH:38](N(C)C)OC(C)(C)C)[CH3:37].C(OCC)(=O)C.O>CN(C)C=O>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:35][N:36]([CH3:38])[CH3:37])[CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]2=[O:34])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (90.5 g) is dissolved in anhydrous N,N-dimethylformamide (400 cc). The solution obtained is heated at 80° C. under a nitrogen atmosphere. A solution of bis-dimethylamino-tert.-butoxymethane (36.1 g) in anhydrous N,N-dimethylformamide (60 cc), preheated to 80° C., is then added rapidly. The reaction mixture is kept at 80° C. for 5 minutes and then poured into ethyl acetate (3 liters). After addition of distilled water (1 liter), the organic phase is decanted, washed with distilled water (4×1 liter), dried over sodium sulphate and filtered in the presence of decolorising charcoal. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 30° C. and 2-benzhydryloxycarbonyl7-tert.-butoxycarbonylamino-3-(2-dimethylamino-vinyl)8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (101 g) is obtained in the form of an orange-coloured froth.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:10]=2)[CH2:6][CH2:7]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)C(=O)CC3)nc1
Yield: 38.1 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-1-indanone (J. Med. Chem. (1998), 41(7), 1068-1083) (2.07 g, 13.9 mmol), 6-chloronicotinamide (2.08 g, 13.3 mmol) and K2CO3 (2.75 g, 19.9 mmol) gives the title compound (1.36 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.26 (d, 1H), 8.02 (s, 1H), 7.63 (d, 1H), 7.46 (m, 2H), 7.33 (s, 1H), 7.14 (d, 1H), 3.10 (t, 2H), 2.68 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:6]=1[CH:7]=[O:8].CC(=CC)C.P([O-])(O)(O)=[O:28].[Na+].Cl([O-])=O.[Na+].Cl>CC(O)(C)C.O.CC#N>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:6]=1[C:7]([OH:28])=[O:8]
Reactant: O=Cc1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 122.9 %

Procedure:
To a solution of 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (31 g, 97.29 mmol) in tBuOH (155.0 mL), water (100.8 mL), CH3CN (155.0 mL) and 2-methyl-2-butene (51.45 mL, 486.4 mmol) was added sodium dihydrogen phosphate (35.02 g, 291.9 mmol) and the mixture was cooled to 0° C. Sodium chlorite (26.40 g, 291.9 mmol) was added in one portion and the mixture was stirred at 25° C. for 1 hour. The pH of the reaction was adjusted to 2-3 with 1N HCl and the layers were separated. The aqueous layer was extracted with EtOAc (3×). All the organic layers were combined, and solid sodium sulfite (˜5 g) was added followed by brine (50 ml) and 1N NaOH (10 ml) and the mixture was shaken until the yellow color disappeared. The layers were separated and the organic was washed with brine, dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (40 g, 98%) as an oil that was used in the next step without further purification. ESI-MS m/z calc. 334.00, found 335.1 (M+1)+; Retention time: 1.58 minutes (3 minutes run).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.C([Sn]([C:41]#[N:42])(CCCC)CCCC)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:41]#[N:42])[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C#N)nc2ccnn12
Temperature: 150 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (1.5 g, 3.5 mmol), tributyltin cyanide (1.7 g, 5.3 mmol), tetrakis(triphenylphosphine) palladium (0.8 g, 0.7 mmol), bis(tri-t-butylphosphine) palladium (0.4 g, 0.7 mmol) were charged in a pressure tube. The tube was evacuated and charged with argon for three cycles. Dioxane (20 ml) was added, and the tube was capped and heated at 150° C. with stirring for one hour. After cooling, the mixture was diluted with EtOAc (100 ml) and washed with brine (1×20 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-35%) gave desired product, 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino) pyrazolo[1,5-a]pyrimidine-5-carbonitrile (1.3 g, 90%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][C@H:22]1[CH2:34][CH2:35][CH2:36][OH:37])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28])[CH2:23][C@H:22]1[CH2:34][CH2:35][CH:36]=[O:37])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCCO)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCC=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (0.32 ml) was dissolved in 7.9 ml of dry dichloromethane, and 0.56 ml of dry dimethylsulfoxide was added thereto at -45° to -56° C. in a nitrogen stream, followed by stirring at the same temperature for 20 minutes. To the reaction mixture was added a solution of 1.30 g of (2R,4R)-1-benzyloxycarbonyl-2-(3-hydroxypropyl)-4-t-butyldimethylsilyloxypyrrolidine in 6.2 ml of dry dichloromethane at -50° to -60° C., followed by stirring at the same temparature for 15 minutes. Then, 2.2 ml of triethylamine was added thereto at -50° to -60° C. The temparature was elevated to room temperature, and the reaction mixture was washed successively with brine, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to obtain (2R,4R)-1-benzyloxycarbonyl-2-(2-formylethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.O.C1(C)C=CC=CC=1>CN(C)C=O.[Mn]>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Mn]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 129 mg (2.35 mmol) of manganese (powder) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for 6 hours. To the reaction mixture was added dropwise 601 mg (10 mmol) of acetic acid and then 10 cm3 of water and 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 675 mg (3.63 mmol) of diphenylphosphine in 77% yield.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>O.C(Cl)Cl>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: S=C(Cl)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCL4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2Cl2) to afford 480 mg (73%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15 (d, J=0.9 Hz, 1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.46 (dd, J=13.8 and 6.0 Hz).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH:12][CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]3=[O:35])[CH:21]=[CH:22][C:17]=2[S:16][N:15]=1.CN1C(C(F)(F)F)=CC(=[O:47])N(C2C=CC3SN=C(C=O)C=3C=2)C1=O>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH3:34][N:25]1[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:27][C:28](=[O:29])[N:23]([C:20]2[CH:21]=[CH:22][C:17]3[S:16][N:15]=[C:14]([C:13]([OH:47])=[O:12])[C:18]=3[CH:19]=2)[C:24]1=[O:35]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CO)c3c2)c1=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0° C., treated dropwise with a solution of a 2:3 mixture of 3-[3-(hydroxymethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152° C.).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)[CH:23]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (126 mg), (5-chloro-3-thienyl)methanol (139 mg) and tributylphosphine (0.347 ml) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (354 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (90 mg) as a white solid.
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[C:8](=[O:9])[NH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[N:5]1)([CH3:3])[CH3:2].C[Li].[CH3:20][C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1>O1CCCC1.C(OCC)C.C(Cl)Cl>[OH:27][CH:26]([C:15]1[C:10]([C:6]2[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:5]=2)=[N:11][CH:12]=[C:13]([CH3:16])[CH:14]=1)[C:24]1[S:25][C:21]([CH3:20])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Reactant: Cc1ccc(C=O)s1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(O)c2ccc(C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A stirred solution of 4-isopropyl-4-methyl-2-(5-methyl-2-pyridyl)-2-imidazolin-5-one (10.0 g, 0.043 mol) in anhydrous tetrahydrofuran (200 mL) is cooled to -78° C. and treated with a 1.5 molar solution of methyl lithium in diethyl ether (60.6 mL). The resultant suspension is stirred at -78° C. for 30 minutes and at 0° C. for 30 minutes. The reaction mixture is recooled to -78° C. and 5-methyl-2-thiophenecarboxaldehyde (15.35 g, 0.043 mol) is added dropwise. After 30 minutes, the cooling bath is removed and the reaction mixture is stirred at room temperature overnight then diluted with water. The aqueous mixture is acidified to pH 6 with acetic acid and extracted with diethyl ether. The combined organic extracts are washed with water, dried (Na2SO4) and concentrated in vacuo to obtain an orange oil. Chromatography of the oil using silica gel and a 20% diethyl ether in methylene chloride mixture gives a yellow oil which is triturated with diethyl ether to obtain the title product as a white solid (2.0 g, mp 147°-148° C.)
Reaction SMILES: FC(F)(F)C(O)=O.O.[C:9]([C:13]1[CH:63]=[CH:62][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH:22]3[CH2:25][CH:24]([N:26]([CH2:30][C@@H:31]4[C@H:35]5[O:36]C(C)(C)[O:38][C@H:34]5[C@H:33]([N:41]5[CH:49]=[N:48][C:47]6[C:42]5=[N:43][CH:44]=[N:45][C:46]=6[NH:50]CC5C=CC(OC)=CC=5OC)[CH2:32]4)[CH:27]([CH3:29])[CH3:28])[CH2:23]3)=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:50][C:46]1[N:45]=[CH:44][N:43]=[C:42]2[C:47]=1[N:48]=[CH:49][N:41]2[C@@H:33]1[CH2:32][C@H:31]([CH2:30][N:26]([CH:24]2[CH2:25][CH:22]([CH2:21][CH2:20][C:18]3[NH:17][C:16]4[CH:62]=[CH:63][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][C:15]=4[N:19]=3)[CH2:23]2)[CH:27]([CH3:28])[CH3:29])[C@@H:35]([OH:36])[C@H:34]1[OH:38]
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
Trifluoroacetic Acid (10 ml, 100 mmol) added to a mixture of Water (1 ml, 60 mmol) and 9-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-9H-purin-6-amine (0.91 g, 1.2 mmol) at RT. The reaction was stirred overnight at RT. The reaction was then heated to 35° C. and triethylsilane (0.39 ml, 2.4 mmol) was added. The reaction was stirred at 35° C. for a further 2 days. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls). 500 mgs of K2CO3 and 8 drops H2O were added and reaction stirred at RT for 1 hour. The mixture was filtered and filter cake washed with 10 mls MeOH. The filtrate was concentrated and the resulting residue was purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.142 g) as a colorless solid after several days of lyophilization.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH:7]=[CH:8][Sn](CCCC)(CCCC)CCCC)[C@@H:3]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[C:41]([C:40]1[CH:39]=[C:38]([CH:8]=[CH:7][C@@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[C@H:3]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:45]=[CH:44][CH:43]=1)#[N:42]
Reactant: N#Cc1cccc(Br)c1
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1cccc(C=C[C@@H]2CCC(=O)[C@H]2CCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Wang resin bound trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid (the compound of Preparation 1, Step F, 70 mg, 0.05 mmol, 1 eq), tris(dibenzylideneacetone)dipalladium(0) (18.2 mg, 0.02 mmol, 0.4 eq), diisopylethylamine (12.8 mg, 0.099 mmol, 2 eq), potassium carbonate (10 mg) and 3-bromo-benzonitrile (36.2 mg, 0.199 mmol, 4 eq) were placed in a well of a deep-well plate, and tetrahydrofuran was added until resin was just wet. The slurry was shaken at room temperature overnight. The resin was filtered and washed with N,N-dimethylformamide and methanol. It was repeatedly swollen with dichloromethane and shrunk with methanol. The resin was finally washed with diethyl ether to remove methanol. Cleavage of the product with trifluoroacetic acid as described in Step B of Example 3 with 90% trifluoroacetic acid in water gave the title compound of Example 66.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([CH2:36][CH2:37][O:38][CH2:39][O:40][CH3:41])=[C:26]([O:42][CH2:43][O:44][CH3:45])[C:25]=1[O:46][CH3:47].CN(C)CCN(C)C.[CH2:56]([Li])[CH2:57][CH2:58][CH3:59].C(I)CCC>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[C:7]([CH2:56][CH2:57][CH2:58][CH3:59])[C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([CH2:36][CH2:37][O:38][CH2:39][O:40][CH3:41])=[C:26]([O:42][CH2:43][O:44][CH3:45])[C:25]=1[O:46][CH3:47]
Reactant: COCOCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(CCOCOC)c(OC)c2OCOC)c(OC)c1OCOC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
550 Milligrams of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane was dissolved in a mixed solvent of 8 ml of toluene with 2 ml of hexamethylphosphoric triamide, to this solution was added 0.12 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath, then 0.64 ml of n-butyllithium was added to the reaction mixture. 15 Minutes later, 0.16 ml of n-butyl iodide was added to the reaction mixture, and temperature of the reaction mixture was gradually elevated to room temperature, and further stirred for 4 hours. 50 Milliliters of diethyl ether was added to the reaction mixture, and the organic layer was washed with water, a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue obtained was purified by means of a silica gel column chromatography (diameter 2 cm×length 10 cm, adsorbent: "Silica gel 60" manufactured by E. Merck A. G., developing solvent: 30% ethyl acetate-hexane) to obtain 520 mg of 1-[2,5-dimethoxy-4-butyl-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)4-(2-methoxymethyloxyethyl)phenyl]pentane. Amorphous powdery substance.