Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:21]#[N:22]>CS(C)=O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:21]#[N:22])=[N:6]1
Reactant: Cc1ncc2c(I)nn(Cc3ccccc3F)c2n1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: Cc1ncc2c(C#N)nn(Cc3ccccc3F)c2n1
Temperature: 150 °C

Procedure:
1.485 g (4.03 mmol) of 1-(2-fluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 397 mg (4.44 mmol) of copper(I) cyanide were put in 11 ml of absolute DMSO and heated for 2 h at 150° C. After cooling, the reaction mixture was filtered on Celite and then washed with ethyl acetate and THF. The organic phase was washed with 25% aqueous ammonia solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. 994 mg (purity 81%, 75% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7](OC(=O)C)[C@@H:6]1[NH:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:11][C@H:10]1[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7]2[C@H:6]([N:24]=[C:25]([CH3:26])[O:27]2)[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: CC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 120.3 %

Procedure:
Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 ml, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step. MS (ISP): 330.0 [M+H]+.
Reaction SMILES: [C:1]([Si](C)(C)C)#[CH:2].Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1>C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)#[CH:2]
Reactant: Fc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
In a 1 Liter, round-bottom, three neck flask, a solution of 50 mL (0.51 Mol) ethynyltrimethylsilane, 1.5 g of palladium[II]acetate, 2.0 g of copper[I] iodide, 3.0 g of triphenylphosphine and 58 mL (0.52 Mol) of 4-bromofluorobenzene in 500 mL of de-aerated triethylamine were heated to 80° C. with stirring under an argon blanket for 2 hr. A white precipitate started to form after approximately 30 min. The reaction mixture was then cooled to 50° C. and stirred for an additional 2 h and then allowed to cool to room temperature with stirring overnight. The orange reaction mixture was filtered and a white precipitate of triethylamine hydrobromide was removed. The filtrate was concentrated by removal of the solvent. The residue was dissolved in 200 mL of dichloromethane and the resulting solution washed with water (3×150 mL), 5% HCl (3×150 mL), saturated sodium bicarbonate solution (3×150 mL), brine and then dried over sodium sulfate. After removal of the solvent, a clear oil was obtained 42.3 g (93%). The clear oil was further purified by dissolving the oil in 200 mL of methanol, to which 2 g of potassium carbonate was added with stirring. The stirring was continued overnight at ambient temperature. Upon distillation, 22.8 g, (0.19 Mol, 82%) of 1-ethynyl-4-fluorobenzene was obtained as a clear colorless liquid.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][C:8]1[C:9]([CH3:35])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]=3[CH3:29])=[O:23])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:33]1[C:26]2[O:25][C:24]([C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[C:12]([CH3:13])=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]([CH3:35])=[N:10]4)=[CH:16][CH:17]=3)=[O:23])=[C:28]([CH3:29])[C:27]=2[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.8 %

Procedure:
To a solution of 7-chloro-3-methylbenzofuran-2-carboxylic acid (185 mg, 0.88 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.123 mL, 1.14 mmol) and a drop of dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid tert-butyl ester (428 mg, 1 mmol) in form of the toluene sulfonate salt and diisopropylethylamine (0.39 mL, 2.27 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo to yield 426 mg of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.60 min (method H)). b) To a solution of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (426 mg, 0.84 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (400 mL, 5.2 mmol) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with diethyl ether and the precipitating product is filtered off to yield 174 mg of the title compound (ESI mass spectrum: [M+H]+=452; Retention time HPLC: 1.39 min (method J)).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:18]=[CH:17][C:16]=2[OH:27])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]#[CH:22])[CH:18]=[CH:17][C:16]=2[OH:27])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[Si](C)(C)C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]benzamide 233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2 N sodium hydroxide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethanol-water to give the title compound (67 mg, 35.9%) as a light gray crystal.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][N:18]4C(OCC3C=CC=CC=3)=O)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1>[Pd].CO>[CH:16]12[CH2:21][CH:19]([NH:18][CH2:17]1)[CH2:20][N:15]2[C:13](=[O:14])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CC1CN2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CC1CN2

Procedure:
Benzyl 5-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (517 mg, 1.24 mmol) and palladium on carbon (131 mg) in methanol (50 mL) were stirred under a hydrogen atmosphere (balloon) for overnight. The reaction mixture was filtered and concentrated to afford 1-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone. LC/MS: [(M+1)]+=285.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]3)([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]([N:14]5[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CC(C)(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 401. (400 MHz CDCl3): 1.48 (6H, s, CH3), 2.66-2.68 (4H, m, CH2), 2.75 (3H, s, CH3), 3.21 (4H, m, CH2), 3.86-3.88 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 7.29 (1H, s, ar), 7.42-7.46 (1H, m, ar), 7.53 (1 h, d (J=8.33), ar), 8.21 (1 h, d (J=7.09), ar), 8.95 (1H, s, ar), 10.04 (1H, b, NH). MH+=542.46
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)(O)[O-].[Na+].[Cl:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25]>O1CCOCC1>[Cl:18][C:19]1[C:20]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:21][CH:22]=[C:23]([C:24]#[N:25])[CH:26]=1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCNc1ncc(C#N)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4-aminobutanoate hydrochloride (Bachem F-3755, 8.54 g, 28.9 mmol), sodium bicarbonate (6.0 g, 72.2 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 5.0 g, 28.9 mmol) was prepared in dioxane under nitrogen, and then heated at 50° C. for 16 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (1H, d), 8.05 (1H, d), 7.58 (1H, t), 3.42 (2H, m), 2.21 (2H, t), 1.76 (2H, m), 1.37 (9H, s).
Reaction SMILES: ClC[C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5](CC2C=CC(F)=CC=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:15][O:14][C:12]([C:9]2[CH:10]=[C:11]3[CH:3]=[CH:4][NH:5][C:6]3=[CH:7][N:8]=2)=[O:13])[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](COCOC(=O)c2cc3cc[nH]c3cn2)O1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (0.37 ml, 2.955 mmol, 5.0 eq.) followed by i-Pr2NEt (0.4079, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 50:50 v/v, 1.0 L, 25 mL fractions) using the flash technique. Fractions 30-54 were combined to afford 0.224 g (85%) of Methyl 1-(2,4-difluorobenzyl)-3-({([(4R)-2,2-dimethyl -1,3-dioxolan-4-yl]methoxy}methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate as a colorless oil.
Reaction SMILES: C([O-])(=O)C.C[O:6][C:7]1[CH:8]=[C:9]([NH+:13]2[CH2:18][C@H:17]([CH3:19])[NH:16][CH2:15][C@H:14]2[CH3:20])[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+]>CO>[CH3:20][C@@H:14]1[CH2:15][NH:16][C@@H:17]([CH3:19])[CH2:18][N:13]1[C:9]1[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc([NH+]2C[C@H](C)NC[C@H]2C)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN[C@@H](C)CN1c1cccc(O)c1
Yield: 63 %

Procedure:
In a round-bottom flask, 715 mg (2.74 mmol) of 12 was dissolved in 10 mL CH3COOH and 5 mL of H2O. To this mixture was added 50 mg of 10% Pd on carbon, and the suspension was heated and stirred at reflux for 12 h. The mixture was cooled, filtered, and the solvents evaporated under reduced pressure. To the residue was added 20 mL of conc. NaHCO3, and this mixture was extracted thoroughly with EtOAc. The pooled organic extracts were washed once with brine, dried over MgSO4, and the solvents removed under reduced pressure to yield 605 mg of an orange oil that was pure (2R,5S)-1-(3-methoxyphenyl)-2,5-dimethylpiperazinium acetate by NMR. 1H NMR (CDCl3) δ 7.21 (t, 1H), 6.73 (dd, 1H), 6.62 (m, 1H), 6.67 (m, 1H), 6.63 (m, 1H), 3.79 (s, 3H), 3.12-2.90 (m, 4H), 2.70 (dd, 1H), 2.46 (dd, 1H), 1.07 (d, 3H), 0.93 (d, 3H). ESIMS: m/z 221 (M+H+, 100). General procedure c. was employed using 363 mg (1.65 mmol) of this oil affording a residue that was dissolved in 5 mL of MeOH and stirred over excess NaHCO3. The mixture was filtered, and the solvents subjected to rotary evaporation to afford a residue that was purified by chromatography affording 215 mg of 13 as a white solid (63% yield). Spectral information for this compound was found to be identical to 17.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1>C(O)C.N1CCCCC1>[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:8]2[O:7][C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2=[O:16])=[CH:18]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NCCOC)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(NCCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.2 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.32 g, 2.2 mmol) in ethanol (3.0 mL), piperidine (5 drops) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65]C(C)(C)C)=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[Si:15]([O:14][C@H:13]1[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11][CH:10]([C@H:39]([OH:70])[C@@H:40]([C:63]([OH:65])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:9]1[OH:8])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)O)[C@@H](O)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
A solution of trifluoroacetic acid (0.3 drops) in methylene chloride (1 ml) was cooled to 0° C. tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (20 mg, 0.02 mmol, obtained from Example 10) was added and the resulting mixture was stirred at 0° C. for 20 minutes. Additional trifluoroacetic acid (0.9 ml) was gradually added over 1 hour after which the mixture was warmed to room temperature and stirred for 2 hours. The volatiles were removed in vacuo. The residue was azeotroped with toluene, and was then dissolved in methylene chloride (0.5 ml). Cold trifluoroacetic acid (0.5 ml) and the mixture was stirred for 3 hours. The volatiles were removed in vacuo and the residue was azeotroped with toluene to provide (5S,12S)-12-[(R)-[(3R,4R,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oic acid (16 mg, 95%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[CH:24][C:23]([B:26]([OH:28])[OH:27])=[CH:22][N:21]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][N:12]([C:20]2[N:25]=[CH:24][C:23]([B:26]([OH:28])[OH:27])=[CH:22][N:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
The title compound was synthesised from methyl 4-(tert-butoxycarbonylamino)-piperidine-4-carboxylate and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH2:36]([O:35][C:34](=[O:43])[NH:33][CH2:32][CH2:31][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
In around-bottomed flask equipped with a mechanical stirrer, 4-hydroxyacetophenone (5.00 g, 36.7 mmol) was dissolved in toluene (122 ml), and triphenylphosphine (14.4 g, 55.1 mmol), and benzyl N-(2-hydroxyethyl)carbamate (10.8 g, 55.1 mmol) were added. The reaction mixture was cooled to about 0° C., and 1,1′-(azodicarbonyl)dipiperidine (13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed to warm to room temperature, and after stirring for about ten minutes, an additional 122 ml of toluene and 122 ml of tetrahydrofuran were added to the thick orange solution. The mixture was stirred for an additional twenty-four hours, and the solids were filtered off. The filtrate was concentrated in vacuo and the resulting solid was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford 9.68 g (84% yield) of the desired product as a white solid. LRMS ([M−1]−)=312.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH3:24]>>[Cl:22][C:21]1[C:16]([Cl:15])=[C:17]([O:23][CH3:24])[CH:18]=[CH:19][C:20]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccccc2Cl)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 48.13 g of o-chlorobenzoyl chloride being combined with 36.7 g AlCl3 and 44.26 g of 2,3-dichloroanisole to yield a white crystalline product of 2,3-dichloro-4-methoxy-2'-chlorobenzophenone, mp 117°-120° C.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Cl)=[CH:6][CH:5]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCNC(=O)CCCCl)c2c1
Agent: [Na]
Solvent: CCO
Product: COc1ccc2cccc(CCN3CCCC3=O)c2c1

Procedure:
0.01 mol of sodium is dissolved in 50 ml of ethanol and the N-[2-(7-methoxynaphth-1-yl)ethyl]chloro-4-butyramide obtained in Example 7 is added under magnetic agitation. The agitation is maintained for 20 minutes, and then the mixture is dried and the residue is solubilized in 40 ml of anhydrous dimethylformamide. The solution is heated at boiling point for 7 hours, then evaporated under vacuum and the residue is taken up in ether, then filtered and dried. The residue is recrystallized in petroleum ether.